NEw developments IN gynecological Oncology - PowerPoint Presentation

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NEw developments IN gynecological Oncology - PPT Presentation

highlights from the EUROPEAN society of medical oncology ESMO congress 2019 in B arcelona Legal Disclaimer This slidekit is intended for healthcare professionals only The authors of this report were supported by TESARO Bio Germany GmbH their participation at the ESMO 201 ID: 775157

patients cancer 2019 abstract patients cancer 2019 abstract ovarian esmo presentation study olaparib platinum pfs phase oral survival months

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Slide1

NEw developments IN gynecological Oncology

highlights from the

EUROPEAN

society

of medical oncology

(

ESMO

)

congress

2019

arcelona

Slide2

Legal Disclaimer

This slide-kit is intended for healthcare professionals onlyThe authors of this report were supported by TESARO Bio Germany GmbH, their participation at the ESMO 2019 was in agreement with legal and ethical guidelinesThe content presented here corresponds to opinions and impressions of the authors and does not necessarily reflect the views of TESARO Bio Germany GmbHTESARO BIO Germany GmbH is not responsible for the content of this report

Herausgeberin: TESARO Bio Germany GmbH Leopoldstraße 37 A 80802 München

Imprint

Slide3

Ovarian cancerEndometrial, cervical & rare tumors

News & Highlights for

Slide4

Author overview (listed alphabetically)

Ovarian Cancer Highlights Ovar 1PD Dr. med. Beyhan Ataseven | EssenDr. med. Jacek Grabowski | BerlinPD Dr. med. Stephan Seitz | RegensburgOvarian Cancer Highlights Ovar 2Dr. med. Johannes Ettl | MünchenPD Dr. med. Dominique Finas | MagdeburgEndometrial, Cervical & Rare Gynaecological Cancer HighlightsDr. med. Athina Kostara | EssenDr. med. Beate Rautenberg | FreiburgDr. med. Ralf Witteler | Münster

ESMO 2019 Highlights

from

BARCELONA

Slide5

OVERVIEW OF ESMO 2019 ORAL & POSTER PRESENTATIONS (I)

ovarian CArcinoma (OC)

BAROCCO: A randomized phase II study of weekly paclitaxel vs.

cediranib-olaparib

combination given with continuous or intermittent schedule in patients with recurrent platinum resistant ovarian cancer

(Colombo N et al. ESMO 2019, oral abstract LBA58)

Randomized Phase 2 Study of ATR inhibitor M6620 in Combination with Gemcitabine versus Gemcitabine alone in Platinum-Resistant High Grade Serous Ovarian Cancer (HGSOC)

(

Konstantinopoulos

PA et al. ESMO 2019, oral abstract LBA60)

OCTOPUS - A Randomised, Multi-centre Phase II Umbrella Trial of Weekly Paclitaxel+/- Novel Agents in Platinum-Resistant Ovarian Cancer:

vistusertib

(Banerjee S et al. ESMO 2019, oral abstract 993O)

Niraparib Treatment in Patients With Newly Diagnosed Advanced Ovarian Cancer (PRIMA/ENGOT-OV26/GOG-3012 study)

(González Martin A et al. ESMO 2019, oral abstract LBA1)

Phase III PAOLA-1/ENGOT-ov25: maintenance

olaparib

with bevacizumab in patients with newly diagnosed, advanced ovarian cancer treated with platinum-based chemotherapy and bevacizumab as standard of care

(Ray-

Coquard

IL et al. ESMO 2019, oral abstract LBA2)

VELIA/GOG-3005: Integration of veliparib with front-line chemotherapy and maintenance in women with high-grade serous carcinoma of ovarian, fallopian tube, or primary peritoneal origin (HGSC)

(Coleman RL et al. ESMO 2019, poster discussion abstract LBA3)

Slide6

OVERVIEW OF ESMO 2019 ORAL & POSTER PRESENTATIONS (II)

ovarian CArcinoma (OC)

FORWARD I (GOG 3011): A Phase III study of

mirvetuximab

soravtansine

, a folate receptor alpha (

FRa

)-targeting antibody-drug conjugate (ADC), versus chemotherapy in patients with platinum-resistant ovarian cancer (PROC)

(Moore KN et al. ESMO 2019, abstract 992O)

Time to second progression (PFS2) and second subsequent therapy (TSST) for patients with newly diagnosed, advanced ovarian cancer (OC) and a

BRCA

mutation (

BRCA

) treated with maintenance

olaparib

– Phase III SOLO1 trial

(

Oaknin

A et al. ESMO 2019, abstract 995PD)

Validation of the Geriatric Vulnerability Score (GVS) in older ovarian cancer (

oOC

) patients: an analysis from the GCIG-ENGOT-GINECO EWOC-1 study

(

Tinquaut

F et al. ESMO 2019, abstract 997PD)

Phase II study of

olaparib

durvalumab

(MEDIOLA): Updated results in germline

BRCA

-mutated platinum-sensitive relapsed (PSR) ovarian cancer (OC)

(Drew Y et al. ESMO 2019, abstract 1190PD)

Niraparib initial dose and its’ management in patients with recurrent high-grade serous ovarian cancer

(Grabowski J et al. ESMO 2019,

abstract 1006P)

Results of the 3rd interim analysis of C-Patrol: A non-interventional study on

olaparib

in German routine clinical practice

(

Sehouli

J et al. ESMO 2019, abstract 1007P)

Slide7

N. Colombo, M. Nicoletto, P. Benedetti Panici, G. Tognon, A. Bologna, A.A. Lissoni, A. Decensi, F. Tomao, R. Fossati, F. Tettamanzi, E. Rulli, F. Galli, M. De Luca, M.F. Alvisi, R. Mancari, M. Ratti, A. Baldoni, V. Torri, E. Biagioli

BAROCCO: A randomized phase II study of

weekly paclitaxel vs

cediranib-olaparib

combination given with continuous or intermittent

schedule in patients with recurrent platinum

resistant ovarian cancer (PROC)

(abstract LBA58)

Slide8

Study background and methods

Hypoxia induced by antiangiogenic agents could cause a functional impairment of homologous recombination, thus sensitizing wild-type (wt) BRCA tumor cells to PARP inhibitionIn a phase II study the combination of cediranib-olaparib increased progression free survival (PFS) in women with recurrent platinum sensitive OC with respect to olaparib1

123 patients with platinum resistant ovarian cancer were allocated in a 1:1:1 ratio to receive: 80 mg/m2 weekly paclitaxel up to 24 weeks (control), olaparib 600 mg tablet (300 mg twice daily) together with 20 mg cediranib daily (continuous schedule) or 20 mg cediranib given 5 days/week (intermittent schedule) until progressionPFS comparison between experimental schedules and the control arm* was the primary objective

1. Liu JF et al. Ann Oncol. 2019 Apr 1;30(4):551-557BAROCCO: A randomized phase II study of weekly paclitaxel vs. cediranib-olaparib combination given with continuous or intermittent schedule in patients with recurrent platinum resistant ovarian cancer (PROC)Colombo N et al., ESMO 2019, abstract LBA58 (oral presentation)

* alpha one-sided 5%; power 80% to detect a HR of 0.5

Slide9

Study Design and

objectives

PROC, platinum resistant ovarian cancer; PFS, progression free survival; PD, progressive disease;

RECIST, Response Evaluation

Criteria

in Solid Tumours.BAROCCO: A randomized phase II study of weekly paclitaxel vs. cediranib-olaparib combination given with continuous or intermittent schedule in patients with recurrent platinum resistant ovarian cancer (PROC)Colombo N et al., ESMO 2019, abstract LBA58 (oral presentation)

Stratification of treatmentLines: 1-2 vs ≥3 previous linesgBRCA status: wt vs mutated vs still unknownPrior antiangiogenetic: yes vs no

If both schedules superior in terms of PFS then safety comparison

Two

independent primary comparisons

terms of

PFS

1:1:1

Paclitaxel

mg/m

weekly

Continuous scheduleCediranib 20 mg/day 7 days per week Olaparib tablets 300 mg x 2/day 7 days/week

Intermittent scheduleCediranib 20 mg/day 5 days per week Olaparib tablets 300 mg x 2/day 7 days/week

RECIST tumor evaluation

every 8 weeks

to 24 weeks or

investigate the activity and toxicity of cediranib and olaparib in the PROC populationTo explore:If the combination of cediranib and olaparib was superior to weekly paclitaxel in terms of progression free survivalIf an intermittent schedule of the combination could improve the gastrointestinal tolerability in terms of diarrhoea severity

Platinum-

Resistant

Ovarian Cancer

Any

BRCA

status

Any

line

of treatment &

any

last

line

Slide10

Paclitaxeln=41Continuousn=41Intermittentn=41Mean age62.661.061.4Performance status 085%90%77% 115%10%23%Mean years from diagnosis2.63.83.1FIGO Stage I-II4%5%13% III-IV96%95%87%Unknown10%0%3%Histological Type Serous88%83%83% Clear cell9%5%10% Endometrioid3%7%7% Mixed Epithelial02%0 Unknown02%0Median Platinum Free interval (mos)1.82.41.5Months from last line to first dose (median)2.63.01.9

Patient Baseline Characteristics

BAROCCO: A randomized phase II study of weekly paclitaxel vs. cediranib-olaparib combination given with continuous or intermittent schedule in patients with recurrent platinum resistant ovarian cancer (PROC)Colombo N et al., ESMO 2019, abstract LBA58 (oral presentation)

Slide11

By BRCA status (n=123)

By previous anti-angiogenetic treatment(n=123)

By previous chemotherapy(n=123)

Stratification Factors

BAROCCO: A randomized phase II study of weekly paclitaxel vs.

cediranib-olaparib combination given with continuous or intermittent schedule in patients with recurrent platinum resistant ovarian cancer (PROC)Colombo N et al., ESMO 2019, abstract LBA58 (oral presentation)

89%

Wild type/Unknown

Slide12

Patients randomizedPaclitaxel*(n=41)Continuous(n=41)Intermittent(n=41)Patients treated29* 4141Treatment discontinued - n (%)28 (96.6)39 (95.1)41 (100) Death related to toxicity1 (3.6)0 (0.0)0 (0.0) Disease progression23 (82.1)31 (79.5)37 (90.2) Lost to follow-up0 (0.0)0 (0.0)1 (2.4) Subject refusal1 (3.6)1(2.6)0 (0.0) Adverse Event3 (10.7)7 (17.9)3 (7.3) Related to treatment131 Not related to treatment020 Missing222Treatment completed - n (%)1 (3.4)Not applicableNot applicableTreatment ongoing - n (%)0 (0.0)2 (4.9)0 (0.0)Dose reduction - n (%)7 (24.1)16 (39)10 (24.4)

* Excluded from the population 12 patients who never started treatment for patient decision after randomizationBAROCCO: A randomized phase II study of weekly paclitaxel vs. cediranib-olaparib combination given with continuous or intermittent schedule in patients with recurrent platinum resistant ovarian cancer (PROC)Colombo N et al., ESMO 2019, abstract LBA58 (oral presentation)

Treatment Compliance

Paclitaxel

Neurotoxicity

Continous

Myelodisplastic

Syndrome G5

Pneumonitis G3

Fatigue G3

Intermittent

Fatigue G2

Slide13

Primary Endpoint - PFS

PFS, progression free survival

Progression free survival

A: Paclitaxel

Cediranib

Olaparib Continuous

Cediranib + Olaparib Intermittent

Number of

eventsA: 26 (63.4%)B: 36 (87.8%)C: 40 (97.6%)

Median PFS (Q1 - Q3):Paclitaxel 3.1 (1.9 – 6.7) monthsContinuous 5.7 (3.5 – 8.3) monthsIntermittent 3.8 (2.0 – 5.8) monthsHR PFS [90% CI]; p-value log-rank:Paclitaxel vs Continuous 0.76 [0.49-1.17]; 0.29Paclitaxel vs Intermittent 1.08 [0.71-1.64]; 0.76Test for proportional hazard:Paclitaxel vs Continuous p=0.004 – Not proportionalDifference of area under the PFS curves:1.25 months (95% CI: -0.33 to 2.83; p=0.12) in favor of Continuous

TimeABC

0414141

Patients at risk

2183735

4132418

67179

8496

10343

12311

1.00.90.80.70.60.50.40.30.20.10.0

* by investigator

assessment

Slide14

SubgroupHR [95% CI]p valueHR [95% CI]BRCA statusContinuous vs PaclitaxelWild type/Unknown0.63 [0.36 – 1.10]0.13Mutated2.45 [0.50 – 11.97]Intermittent vs PaclitaxelWild type/Unknown0.96 [0.57 – 1.62]0.26Mutated2.37 [0.38 – 14.71]Previous chemotherapy linesContinuous vs PaclitaxelUp to two0.47 [0.21 – 1.07]Three or more0.97 [0.46 – 2.05]0.28Intermittent vs PaclitaxelUp to two1.08 [0.52 – 2.25]0.97Three or more1.12 [0.55 – 2.30]Previous antiangiogenetic treatmentContinuous vs PaclitaxelNo0.58 [0.27 – 1.23]0.46Yes0.93 [0.45 – 1.91]Intermittent vs PaclitaxelNo0.70 [0.34 – 1.42]0.18Yes1.39 [0.68 – 2.86]

0.01

0.1

100

PFS, progression free survival; HR, hazard ratio

BAROCCO: A randomized phase II study of weekly paclitaxel vs.

cediranib-olaparib

combination given with continuous or intermittent schedule in patients with recurrent platinum resistant ovarian cancer (PROC)

Colombo N et al.,

ESMO 2019, abstract LBA58 (oral presentation)

Favors

Experimental

Favors

Paclitaxel

PFS

subgroup

analysis

Slide15

In BRCAwt or still unknown patients

PFS, progression free survival; HR, hazard ratioBAROCCO: A randomized phase II study of weekly paclitaxel vs. cediranib-olaparib combination given with continuous or intermittent schedule in patients with recurrent platinum resistant ovarian cancer (PROC)Colombo N et al., ESMO 2019, abstract LBA58 (oral presentation)

Progression-free survival

Progression free survival

A: Paclitaxel

Cediranib

Olaparib

Continuous

Cediranib

Olaparib

Intermittent

Number of

events

A: 23 (62.2%)

B: 29 (85.3%)

C: 37 (97.4%)

Time

ABC

0373438

Patients at risk

2153033

4102017

66158

8386

10243

12211

Median PFS (Q1 - Q3):

Paclitaxel 2.1 (1.9, 6.7) months

Continuous

5.8 (3.8, 8.7) months

Intermittent

3.8 (2.0, 5.8) months

HR PFS [95% CI]; p-

value

log-rank:

Paclitaxel

Continuous

0.63 [0.36 – 1.10]; 0.10

Paclitaxel

Intermittent

0.96 [0.57 – 1.62]; 0.87

Test for proportional

hazard

Paclitaxel

Continuous

p= 0.006 - Not proportional

Difference

area

under

the PFS

curves

1.82 months (95% CI: 0.14 to 3.50; p= 0.03)

favour

Continuous

Slide16

RECIST 1.1

evaluations

Excluded from the population:12 patients who never started treatment (Paclitaxel); 1 death before 1st assessment (Paclitaxel); 2 consent withdrawals before 1st assessment (1 Paclitaxel, 1 Continuous); 10 patients without RECIST assessment (3 Paclitaxel, 1 Continuous; 6 intermittent)RECIST, Response Evaluation Criteria in Solid Tumors; CR, complete response; PD, progressive disease; PR, partial response; SD, stable diseaseBAROCCO: A randomized phase II study of weekly paclitaxel vs. cediranib-olaparib combination given with continuous or intermittent schedule in patients with recurrent platinum resistant ovarian cancer (PROC)Colombo N et al., ESMO 2019, abstract LBA58 (oral presentation)

BEST Response RATE

Evaluable PtsPaclitaxel(n=24)Continuous(n=39)Intermittent (n=35)CR - n (%)2 (8.3)0 (0.0)0 (0.0)PR - n (%)6 (25.0)7 (17.9)4 (11.4)SD - n (%)5 (20.8)26 (66.7)18 (51.4)PD - n (%)11 (45.8)6 (15.4)13 (37.1)

Evaluable PtsPaclitaxel(n=24)Continuous(n=39)Intermittent (n=35)54.184.662.8PD - n (%)11 (45.8)6 (15.4)13 (37.1)

Paclitaxel

(n=8)Continuous (n=7)Intermittent (n=4)Median(Q1-Q3) months4.4 (3.3-8.3)6.2 (5.4 - not re.)2.7 (1.3-3.6)

Clinical benefit

Duration of

response

Slide17

Paclitaxel

Best Response

140

130

120

110

100

-10

-20

-30

-40

-50

-60

-70

-80

-90

-100

Best Response

140

130

120

110

100

-10

-20

-30

-40

-50

-60

-70

-80

-90

-100

Continuous

Best Change Of Target Lesions Dimensions From Baseline

PD, progressive disease; SD, stable disease; PR, partial response; CR, complete response

BAROCCO: A randomized phase II study of weekly paclitaxel vs.

cediranib-olaparib

combination given with continuous or intermittent schedule in patients with recurrent platinum resistant ovarian cancer (PROC)

Colombo N et al.,

ESMO 2019, abstract LBA58 (oral presentation)

BEST Response RATE

Slide18

Paclitaxel

(n=28)Continuous(n=41)Intermittent(n=40)Subjects with at least one drug related adverse event70%78%78%Drug related adverse events (≥ 10% of patients)Any grade≥G3Any grade≥G3Any grade≥G3Neutrophil count decreased11%7%7%2%5%3%Anemia18%-17%10%18%13%Myelodysplastic syndrome--2%2%* G5--Diarrhoea4%-51%5%58%3%Mucositis oral7%-12%2%--Nausea18%-51%2%50%8%Vomiting--37%-38%5%Peripheral sensory neuropathy14%-----Fatigue25%-46%10%40%10%Sepsis4%4% G5----Alopecia18%-----Rash maculo-popular11%-5%-5%-Hypertension--29%12%18%13%

Drug related Adverse Events

Slide19

IQR, inter quartile range; PROC, platinum resistant ovarian cancer; * NRG GY005, NCT02502266 , CONCERTO, NCT02889900 BAROCCO: A randomized phase II study of weekly paclitaxel vs. cediranib-olaparib combination given with continuous or intermittent schedule in patients with recurrent platinum resistant ovarian cancer (PROC)Colombo N et al., ESMO 2019, abstract LBA58 (oral presentation)

BAROCCO included a difficult-to-treat population with a high unmet need:59% patients received three or more treatment linesMedian platinum-free interval: <3 months (IQR 0.7-4.0)BAROCCO is the first trial with the combination cediranib-olaparib in PROC with a control armAlthough not statistically significant, continuous administration shows a promising trend for improved PFS, particularly in gBRCAwt population with HR for PFS continuous vs paclitaxel 0.63 [95% CI 0.36-1.10] p=0.10Continuous administration of cediranib and olaparib is active in PROC with clinical benefit observed in 85% of patientsThe combination of cediranib and olaparib was well tolerated with few severe side effects: severe diarrhoea occurred only in 5% of patients with the continuous administrationInterruption of cediranib administration for two days may have a detrimental effect on PFS with no benefit on toxicityThe combination of cediranib plus olaparib represents an active, feasible, oral regimen, which deserves further investigation. These results support ongoing trials investigating the same combination in PROC patients*

SUMMARY & CONCLUSIONS

Slide20

P. Konstantinopoulos, A. Wahner Hendrickson, R. Penson, A. Doyle, E. Kohn, L. Duska, M. Crispens, A. Olawaiye, I. Winer, L. Barroilhet, S. Fu, M. Mchale, R. Schilder, A. Farkkila, J. Curtis, R. Quinn, C. Whalen, G. Shapiro, U. Matulonis

Randomized Phase 2 Study of ATR inhibitor M6620

in Combination with Gemcitabine versus

Gemcitabine alone in Platinum-Resistant

High Grade Serous Ovarian Cancer

(abstract LBA60)

Slide21

Study background and methods

High grade serous ovarian cancers (HGSOCs) exhibit genomic instability and high replication stress due to universal loss of the G1/S checkpoint (via TP53 mutations), presence of homologous recombination alterations and induction via amplification of MYC and CCNE1 oncogenes. It was hypothesized based on in vitro / in vivo data that addition of the selective ATR inhibitor M6620 to gemcitabine (gem) would demonstrate acceptable toxicity and superior efficacy in HGSOC

Multicenter, open-label, RP2 study of gem/M6620 versus gem alone (1:1 randomization) in platinum resistant HGSOC, stratification based on platinum free interval (PFI), (PFI≤3 months vs > 3 months)Primary endpoint was PFS while secondary endpoints included safety, objective response and clinical benefit ratePatients (pts) received gem 1000 mg/m2 IV on days 1 and 8 with or without M6620 210 mg/m2 IV on Days 2 and 9 of a 21-day cycle until disease progression (PD) or intolerable toxicity*

Randomized Phase 2 (RP2) Study of ATR inhibitor M6620 in Combination with Gemcitabine versus Gemcitabine alone in Platinum-Resistant High Grade Serous Ovarian Cancer (HGSOC) Konstantinopoulos PA et al., ESMO 2019, abstract LBA60 (oral presentation)

RP2, randomized phase 2

PFS, progression-free survival

* Patients on gem alone were allowed to crossover to gem/M6620 only if they developed progressive disease by RECIST

Slide22

Stalled Replication Fork

RESPONSE TO REPLICATION STRESS DEPENDS ON ATR

Activation of intra-S checkpointReplication fork stabilityDNA repairInhibition of origin firingReplication restart

Loss of the G1/S

checkpointPremature entry into S phaseDNA repair deficiencyOncogenic drive

Activation

of ATR

*Data from Ovarian TCGA Dataset,

Nature

2011

HGSOC, high grade serous

ovarian

cancer

Randomized Phase 2 (RP2) Study of ATR inhibitor M6620 in Combination with Gemcitabine versus Gemcitabine alone in Platinum-Resistant High Grade Serous Ovarian Cancer (HGSOC)

Konstantinopoulos

A et al.,

ESMO 2019, abstract LBA60 (oral presentation)

All these aforementioned mechanisms of increased replication stress are prevalent in HGSOCs:

Almost universal loss of the G1/S checkpoint (via deleterious TP53 mutations).

Premature entry into S phase of the cell cycle due to CCNE1 amplification (~20% of

tumors

or RB1 loss (~11% of

tumors

)* or CDKN2A mRNA downregulation (~32% of

tumors

)*.

Presence of homologous recombination repair (HRR) alterations (~50% of

tumors

)*.

Induction via amplification of various oncogenes such as MYC (~40% of

tumors

)*.

Slide23

Rationale

Inhibition of DNA repair by incorporation of gemcitabine nucleotides into the DNA

Inhibition of ribonucleotide reductase leading to depletion of the nucleotide pool required for replication and repair

Gemcitabine

Increased

dependence

on ATR

Randomized Phase 2 (RP2) Study of ATR inhibitor M6620 in Combination with Gemcitabine versus Gemcitabine alone in Platinum-Resistant High Grade Serous Ovarian Cancer (HGSOC)

Konstantinopoulos

A et al.,

ESMO 2019, abstract LBA60 (oral presentation)

Gemcitabine

with ATR

inhibitor

M6620

ATR inhibitor M6620 synergizes with gemcitabine

in vitro

and

in vivo

with maximal synergism when M6620 is administered 24 hours after starting gemcitabine

24 hours after gemcitabine is the highest accumulation of cells in S-phase with concomitant increase in ATR activity (measured by phosphorylated-CHK1)

Slide24

Study characteristics and design

RECIST, Response Evaluation Criteria in Solid Tumours.Randomized Phase 2 (RP2) Study of ATR inhibitor M6620 in Combination with Gemcitabine versus Gemcitabine alone in Platinum-Resistant High Grade Serous Ovarian Cancer (HGSOC) Konstantinopoulos PA et al., ESMO 2019, abstract LBA60 (oral presentation)

Weekly Gemcitabine

1000mg/m

IV - D1, D8 of 21-day cycle

Weekly Gemcitabine + M6620

Gem: 1000mg/m

IV D1 and D8M6620: 210mg/m2 IV D2 and D9 of 21-day cycle

Stratification factors:

Platinum Free interval (PFI): ≤3 months vs 3-6 months

Disease progression by RECIST

Allow Crossover

Platinum Resistant Ovarian Cancer

1:1

Hypothesis: M6620 may enhance activity of gemcitabine and show acceptable toxicity and superior efficacy to gemcitabine alone in platinum resistant ovarian cancer.Multicenter, randomized phase 2 trial (NCT02595892) sponsored by the National Cancer Institute (NCI).Patients enrolled in 11 different centers through the Experimental Therapeutics Clinical Trials Network (ETCTN)

Primary Endpoint:

Progression free survival

Key Secondary Endpoints:

Toxicity/Safety, overall survival, objective response rate by RECIST 1.1

Slide25

Histologically confirmed high-grade serous ovarian, primary peritoneal or fallopian tube cancerPlatinum Resistant disease defined as progression within 6 months after last platinum regimenNo primary platinum refractory diseaseMeasurable disease by RECIST v1.1 with at least one measurable target lesionNo line limit but no more than 1 prior regimens in the platinum resistant settingNo prior ATR/CHK1 inhibitors and no prior gemcitabine as single agentHormonal therapies and antiangiogenic therapies (as single agents) and PARP-inhibitors used as maintenance therapy do not count as separate lines

Key Eligibility criteria

Slide26

Primary endpoints

PFS, progression free survival Randomized Phase 2 (RP2) Study of ATR inhibitor M6620 in Combination with Gemcitabine versus Gemcitabine alone in Platinum-Resistant High Grade Serous Ovarian Cancer (HGSOC) Konstantinopoulos PA et al., ESMO 2019, abstract LBA60 (oral presentation)

PFS (Stratum: PFI ≤3 months)

0.00

1.00

0.75

0.50

0.25

Number at

risk

Am = ARM 1

Am = ARM 2

Median PFS:

9.0 weeks for

Gem

27.7 weeks for

Gem

/M6620

Gem

/M6620

Gem

: HR 0.31

(90% CI: 0.13-0.77)

One-sided

log-rank

P=0.0173

0.00

1.00

0.75

0.50

0.25

Number at

risk

Am = ARM 1

Am = ARM 2

Weeks

Gem

/M6620

Gem

: HR 0.95

(90% CI: 0.46-1.97)

One-sided

log-rank

P=0.45

PFS (Stratum: PFI >3 and <6 months)

Weeks

PFS probability

Slide27

Similar percentage of patients had treatment related grade 3 or above toxicities:(69% in the Gemcitabine alone versus 65% in the Gemcitabine/M6620 arm)One treatment-related death (G5 event) in the Gemcitabine alone arm due to sepsisOne treatment-related death (G5 event) in the Gemcitabine/M6620 arm due to pneumonitisOverall, 2 patients with pneumonitis in gemcitabine alone arm (both G2) and 3 patients with pneumonitis in combination arm (2 G2 and 1 G5)4/36 (11.1%) of patients in Gemcitabine alone arm and 7/34 (20.6%) in combination arm discontinued treatment13 patients in the Gemcitabine alone and 13 patients in the Gemcitabine/M6620 had a dose reductionThrombocytopenia was more common in the Gemcitabine/M6620 arm (24% G3 or G4) compared to 6% in the Gemcitabine alone arm. No clinically significant bleeding was observed in the combination armOther toxicities including neutropenia and anemia were not different in the two arms. White blood cell growth factors were allowed but not mandated by the protocolInfusion related reactions were seen in only 3 patients (2 G1 and1 G2) in the Gemcitabine/M6620 arm

Secondary endpoint - toxicity

Slide28

Including subjects who crossed over

Crossover subjects censored at time of cross over

OS, overall survivalRandomized Phase 2 (RP2) Study of ATR inhibitor M6620 in Combination with Gemcitabine versus Gemcitabine alone in Platinum-Resistant High Grade Serous Ovarian Cancer (HGSOC) Konstantinopoulos PA et al., ESMO 2019, abstract LBA60 (oral presentation)

Secondary endpoint - Overall survival

0.00

1.00

0.75

0.50

0.25

Number at

risk

Am = ARM 1

Am = ARM 2

Weeks

102

108

114

0.00

1.00

0.75

0.50

0.25

Number at

risk

Am = ARM 1

Am = ARM 2

Weeks

102

108

114

Median OS:

49.1 weeks for

Gem

47 weeks for

Gem

/M6620

Gem

/M6620

Gem

: HR 1.17

(90% CI: 0.67-2.05)

One-sided

log-rank

p=0.32

Median OS:

40.4 weeks for

Gem

47 weeks for

Gem

/M6620

Gem

/M6620

Gem

: HR 0.82

(90% CI: 0.46-1.44)

One-sided

log-rank

p=0.278

Survival

probability

Survival

probability

Slide29

Crossover subjects censored at the time of cross over

OS, overall survival; PFI, platinum-free intervalRandomized Phase 2 (RP2) Study of ATR inhibitor M6620 in Combination with Gemcitabine versus Gemcitabine alone in Platinum-Resistant High Grade Serous Ovarian Cancer (HGSOC) Konstantinopoulos PA et al., ESMO 2019, abstract LBA60 (oral presentation)

Secondary endpoint - OS (Pfi ≤3 months stratum)

Gem/M6620 vs Gem: HR 0.36(90% CI: 0.13-1.00)One-sided log-rankp=0.051

812

712

Weeks

0.00

1.00

0.75

0.50

0.25

102

108

114

Number at

risk

Am = ARM 1

Am = ARM 2

Survival

probability

Slide30

HGSOC, high grade serous ovarian cancer; PFS, progression-free survivalRandomized Phase 2 (RP2) Study of ATR inhibitor M6620 in Combination with Gemcitabine versus Gemcitabine alone in Platinum-Resistant High Grade Serous Ovarian Cancer (HGSOC) Konstantinopoulos PA et al., ESMO 2019, abstract LBA60 (oral presentation)

Addition of the ATR inhibitor M6620 to gemcitabine in platinum resistant HGSOC patients met the primary endpoint of this exploratory randomized phase 2 trialWith exception of thrombocytopenia, toxicities were balanced in the two armsThe finding that a PFS benefit was seen solely among the PFI≤3 months stratum may reflect that such tumors are more likely to be enriched for biomarkers of replicative stress (e.g. CCNE1 amplification) that are likely to predispose to response to ATR inhibitionThis hypothesis is being explored in the ongoing studiesFurther evaluation of the gemcitabine plus M6620 combination in platinum resistant HGSOC is warranted

SUMMARY & CONCLUSIONS

Slide31

S. Banerjee, L.-A. Lewsley, A. Clamp, J. Krell, R. Herbertson, R. Glasspool, C. Orbegoso, C. Green, R. Kristeleit, C. Gourley, C. Cambell, U. Banerji, C. Shepherd, W. Brugger, L. Chudleigh, A. Hanif, I. Mcneish, J. Paul

OCTOPUS - A Randomised, Multi-centre Phase II Umbrella Trial of Weekly Paclitaxel +/- Novel Agents in Platinum-Resistant Ovarian Cancer:

vistusertib

(abstract 993O)

Slide32

Study background and methods

OCTOPUS is an umbrella phase II trial, testing the addition of targeted agents to weekly paclitaxel (wP) in recurrent platinum-resistant/refractory ovarian cancer. First agent tested is the dual mTORC1/mTORC2 inhibitor vistusertib (V) Preclinical studies support targeting PI3K/AKT/mTOR signalling. The combination of V and wP showed activity in ovarian high grade serous carcinoma (HGSC) in phase I. This is the first randomised trial of wP and dual mTORC1/2 inhibition in ovarian cancer

Patients with platinum-resistant/refractory HGSC were randomised 1:1 to wP* + oral V (50mg BD) or placebo (P)**. The primary endpoint is progression-free survival (PFS)‡ and response is a key secondary end-point. A mandatory pre-treatment biopsy, archival tumour tissue and serial blood samples were collectedThe study uses a 3-outcome approach: significance at 10% (1-sided) for PFS indicates activity, significance at 20% also requires evidence of an improvement in response. The study has 90% power to detect a hazard ratio (HR) of 0.67

OCTOPUS - A Randomised, Multi-centre Phase II Umbrella Trial of Weekly Paclitaxel+/- Novel Agents in Platinum-Resistant Ovarian Cancer: vistusertibBanerjee S et al., ESMO 2019, abstract 993O (oral presentation)

* 80mg/m2 D1, D8, D15 of 28 day cycle

** D1-3, D8-10, D15-17

‡

RECIST v1.1/GCIG CA125 criteria

Slide33

OCTOPUS STUDY FLOWCHART

FUP, follow up period; HGSOC: high grade serous ovarian (fallopian tube, primary peritoneal) carcinoma; wPxl, weekly paclitaxelOCTOPUS - A Randomised, Multi-centre Phase II Umbrella Trial of Weekly Paclitaxel+/- Novel Agents in Platinum-Resistant Ovarian Cancer: vistusertibBanerjee S et al., ESMO 2019, abstract 993O (oral presentation)

Background - octopus trial

Patients will be followed up for progression-free and overall survival

HYPHOTHESIS:

Addition of novel agents to weekly paclitaxel will improve clinical efficacy compared to paclitaxel alone in patients with platinum-resistant/refractory, HGSOC

OCTOPUS provides an efficient generic framework to screen new trageted agents in the context of a rolling randomised placebo-controlled phase II screening study with wPxl as the control arm

BASELINE

TREATMENT

FUP

Written Informed Consent

Baseline Investigations

Randomisation

Weekly paclitaxel 80mg/m

(d1, 8, 15 q28) +/- Novel agent

Patients will be assessed every 8 weeks with imaging assessment until disease progression. CA125 measurements will be performed every 4 weeks

Study treatment will be continued in the absence of disease progression as per drug specific appendix

Slide34

mTOR – important regulator of cell growthDual inhibition of mTORC1 & 2 could deliver superior efficacy by avoiding feedback via AKT observed with rapaloguesRaised p-P70S6K associated with chemoresistance and poor clinical outcome in ovarian cancer1Additive effect on growth in vitro and in vivo: increased apoptosis and metabolic effects with paclitaxel and vistusertib2TAX-TORC study (phase IB dose-escalation study with dose-expansion cohort in HGSOC)3RP2D mg/m2 paclitaxel with 50 mg vistusertib bd 3/7 days for 6/7 weeksResponse rates* 13/25 (52%) and GCIG CA125 response rate 16/25 (64%)Median PFS 5.8 month (95% CI: 3.28-18.54)

1. Carden CP et al. Mol Cancer Ther 2012; 11(7):1609-1617; 2. Wong Te Fong AC et al. Oncotarget 2017; 8(69): 113874-113884; 3. Basu et al. Ann Oncol. 2018:29(9): 1918-1925GCIG, Gynecologic Cancer Intergroup; RP2D, recommended phase II dose; * RECIST v1.1OCTOPUS - A Randomised, Multi-centre Phase II Umbrella Trial of Weekly Paclitaxel+/- Novel Agents in Platinum-Resistant Ovarian Cancer: vistusertibBanerjee S et al., ESMO 2019, abstract 993O (oral presentation)

Background - Rationale

Dual m-TORC1/2

inhibitor - vistusertib

Rapalog

mTORC1

Vistusertib

Cell survival

Cell

growth

4E-BP1

S6K

T37/46

S235/236

T246

PRAS40

Negative

feedback

mTORC2

AKT

S473

T308

IRS1

RTK

PI3K

PIP3

Slide35

Patients can continue beyond 6 cycles of weekly Pxl +/- vistusertib at discretion of Investigator provided the patient has not progressed and after discussion with Chief Investigator. If weekly Pxl is not continued and patients have completed at least 4 cycles of combination treatment, vistusertib/placebo can continue as maintenance.

Primary Endpoint: PFSSecondary Endpoints: OS, Qol; ORR & toxicity.

Key eligibility criteriaHistologically confirmed HGS ovarian, fallopian tube or primary peritoneal cancerPlatinum-resistant (PROC, including platinum-refractory)Treatment immediately prior to study entry need not be platinumPatients who received prior wPxl for PROC are not eligibleMandatory biopsy pre cycle 1 (disease documented as not biopsiable by a consultant radiologist eligible)Adequate archival tumor tissue available

HGS, high grade serous; PROC, platinum resistant ovarian cancer; PFS, progression free survival; ORR, objective response rate; OS, overall survival; Qol, quality of life; wPxl, weekly PaclitaxelOCTOPUS - A Randomised, Multi-centre Phase II Umbrella Trial of Weekly Paclitaxel+/- Novel Agents in Platinum-Resistant Ovarian Cancer: vistusertibBanerjee S et al., ESMO 2019, abstract 993O (oral presentation)

Octopus study design-vistubertib

Control ArmwPxl 80mg/m2 D1, D8, D15 of 28 day cycle plus oral placebo 50 mg bd (D1-3, D8-10, D15-17) of a 28 day cycle.

Randomisation

Experimental Arm

wPxl 80mg/m2 D1, D8, D15 of 28 day cycle plus AZD2014 50 mg bd (D1-3, D8-10, D15-17) of a 28 day cycle.

AssessmentsRadiological assessment every 8 weeks. CA125 assessment every 4 weeks.

AssessmentsRadiological assessment every 8 weeks.CA125 assessment every 4 weeks.

140 Platinum resistant/refractory high grade serous ovarian cancer(including fallopian tube primary peritoneal)

Slide36

PFS, progression free survival; wPxl, weekly paclitaxelOCTOPUS - A Randomised, Multi-centre Phase II Umbrella Trial of Weekly Paclitaxel+/- Novel Agents in Platinum-Resistant Ovarian Cancer: vistusertibBanerjee S et al., ESMO 2019, abstract 993O (oral presentation)

PRIMARY ENDPOINT – PFS

Patients at riskwPxI + placebo704713520wPxI + vistusertib70512240

Time

from randomisation (months)

0.0

0.2

0.0

0.8

1.0

Survival probability

wPxI

placebo

wPxI

vistusertib

PFS

events

Median PFS

(80% CI) months

Hazard

ratio

(80% CI)

1-sided

p-value

Vistusertib

4.5 (3.9-5.5)

0.84 (0.67-1.07)

0.18

Placebo

4.2 (3.7-4.7)

PFS improvement

significant at 20%

(not 10%)

Slide37

SECONDARY ENDPOINT - OS

OS, overall survival; wPxl, weekly paclitaxelOCTOPUS - A Randomised, Multi-centre Phase II Umbrella Trial of Weekly Paclitaxel+/- Novel Agents in Platinum-Resistant Ovarian Cancer: vistusertibBanerjee S et al., ESMO 2019, abstract 993O (oral presentation)

Time

from

randomisation

(months)

0.0

0.2

0.0

0.8

1.0

Survival

probability

Deaths

Median OS

(80% CI) months

Hazard

ratio

(80% CI)

1-sided

P-

value

Vistusertib

9.7 (8.8-10.5)

1.21 (0.91-1.60)

0.80

Placebo

11.1 (9.2-13.9)

evidence

improvement

Patients at

risk

wPxI

placebo

wPxI

vistusertib

wPxI

placebo

wPxI

vistusertib

Slide38

Hazard ratios with p-values for interaction test

hR for clinical minimisation factors

dependence

effect

on minimisation factors

Progression-free survival

Overall survival

Subgroup

No. of patients

Hazard ratio (80% CI)

Number per arm

Subgroup

No. of patients

Hazard ratio (80% CI)

Number per arm

Vistusertib

Placebo

value

Vistusertib

Placebo

value

Vistusertib

better

Placebo

better

Vistusertib

better

Placebo

better

OCTOPUS - A Randomised, Multi-centre Phase II Umbrella Trial of Weekly Paclitaxel+/- Novel Agents in Platinum-Resistant Ovarian Cancer: vistusertib

Banerjee S et al.,

ESMO 2019, abstract 993O (oral presentation)

Slide39

OCTOPUS is the:First randomised, multicentre, umbrella phase II trial in recurrent (‘platinum-resistant’) ovarian cancer to report.First randomised trial of weekly paclitaxel combined with a dual mTORC1/2 inhibitor (vistusertib) in ovarian cancerThere was no significant improvement in progression-free survival, overall survival or response rates No increased grade 3/4 toxicity was observed with the addition of vistusertib to weekly paclitaxelPTEN loss may predict vistusertib activityTranslational research exploring the influence of PI3K/mTOR signalling on platinum resistance and response to weekly paclitaxel is ongoing

SUMMARY & CONCLUSIONS

Slide40

A. González Martín, B. Pothuri, I. Vergote, R. Christensen, W. Graybill, M.R. Mirza, C. Mccormick, D. Lorusso, P. Hoskins, G. Freyer, F. Backes, K. Baumann, A. Redondo, R. Moore, C. Vulsteke, R. O'Cearbhaill, B. Lund, Y. Li , D. Gupta, B. Monk

Niraparib Treatment in Patients With

Newly Diagnosed Advanced Ovarian Cancer (PRIMA/ENGOT-OV26/GOG-3012 study)

(abstract LBA1)

Slide41

Study background and methods

Niraparib has shown progression-free survival benefit in recurrent ovarian cancer (OC) after platinum-based chemotherapy (CT) in all patients regardless of BRCA status The PRIMA/ENGOT-OV26/GOG-3012 study evaluated the efficacy of niraparib in patients with newly diagnosed advanced OC after completion of first-line (1L) CT regardless of BRCA status1

In this randomized, double-blind, phase 3 trial, patients (n=733) with newly diagnosed advanced ovarian cancer were randomly assigned in a 2:1 ratio to receive niraparib or placebo once daily after a response to platinum-based chemotherapyPrimary end point was PFS in patients who had tumors with homologous-recombination deficiency (HRD+) and in those in the overall population, as determined on hierarchical testing. A prespecified interim analysis for OS was conducted at the time of the primary analysis of PFS

1. González-Martín A et al. New Engl J Med, 2019; DOI: 10.1056/NEJMoa1910962Niraparib Treatment in Patients With Newly Diagnosed Advanced Ovarian Cancer (OC)González Martin A et al., ESMO 2019, abstract LBA1 (oral presentation)

PFS, progression-free survival

, overall survival

Slide42

Hypothesis:

PRIMA/ENGOT-OV26/GOG-3012 was designed to test the efficacy and safety of niraparib therapy after response to platinum-based chemotherapy in patients with newly diagnosed advanced ovarian cancer, including those at high risk of relapse (ClinicalTrials.gov: NCT02655016)

Key Inclusion CriteriaHigh grade serous or endometroid pathologyStage III: PDS with visible residual disease post surgery, NACT, or inoperableStage IV: PDS regardless of residual disease, NACT, or inoperableCR or PR following platinum first-line treatmentTissue for homologous recombination testing was required at screening (Myriad myChoice®)

Key Exclusion CriteriaPatients with Stage III disease who have had complete cytoreduction (i.e., no visible residual disease) after PDS

Prima addresses unmet needs in 1l advanced oc

1L, first-line; CR,

complete

response

; NACT, neoadjuvant

chemotherapy

; OC,

ovarian

cancer

; PDS,

primary

debulking

surgery;

partial

response

Niraparib Treatment in Patients With Newly Diagnosed Advanced Ovarian Cancer (OC)

González Martin

A et al.,

ESMO 2019, abstract LBA1 (oral presentation)

Slide43

1L, first-line; BICR

blinded

independent central review; CR, complete response; OC, ovarian Cancer; PR, partial response PFS2, progression-free survival 2; PR partial response; PRO, patient-reported outcomes; QD, once daily; TFST, time to first subsequent therapy.Niraparib Treatment in Patients With Newly Diagnosed Advanced Ovarian Cancer (OC)González Martin A et al., ESMO 2019, abstract LBA1 (oral presentation)

Niraparib

2:1 Randomization

Patients with

newly-diagnosed

OC at high

risk

for

recurrence

after

response

to 1L platinum-based chemotherapy (independent of BRCA)

Placebo

Endpoint assessmentPrimary Endpoint: Progression-free survival by BICRKey Secondary Endpoint: Overall SurvivalSecondary Endpoints: PFS2, TFST, PRO, Safety

Hierachical PFS TestingPatients with homologous recombination deficient tumors, followed by the overall population.Statistical assumption: hazard ratio benefit in PFS of0.5 in homologous recombination deficient patients0.65 in the overall population>90% statistical power and one-side type I error of 0.025

Stratification FactorsNeoadjuvant chemotherapy administered: Yes or NoBest response to first therapy: CR or PRTissue homologous recombination test status: deficient or proficient/not-determined

Body weight ≥77 kg and platetes ≥150,000/𝜇L started with 300 mg QDBody weight <77 kg and/or platetes <150,000/𝜇L started with 200 mg QD

Patients were treated with niraparib or placebo once daily for 36 months or until disease progression

Prima

trial

design

Slide44

Testing

for Homologous Recombination Deficiency (HRd) and Proficiency (HRp)Next generation sequencing of DNA from tumor tissue (Myriad Genetics myChoice® Test)Provides a score based on algorithmic measurement of 3 tumor factors:Loss of heterozygosity (LOH)Telomeric allelic imbalance (TAI)Large-scale state transitions (LST)Homologous recombination status is determined by the following:HR-deficient tumor: Tissue test score ≥42 OR a BRCA mutationHR-proficient tumors: Tissue test score <42HR-not-determined

MyChoice

Score

Loss of

Heterozygosity (LOH)

Telomeric allelic imbalance (TAI)

Large-scale state transitions (LST)

https://myriadmychoice.com/portfolio/ovariancancer/mychoicehrdovariancancer/#resultNiraparib Treatment in Patients With Newly Diagnosed Advanced Ovarian Cancer (OC)González Martin A et al., ESMO 2019, abstract LBA1 (oral presentation)

TISSUE TEST FOR HOMOLOGOUS RECOMBINATION

Slide45

Patient Characteristics & Demographics

CharacteristicNiraparib(n=487)Placebo(n=246)Overall(N=733)Age, median (range), years62 (32, 85)62 (33, 88)62 (32, 88)Weight, median, kg666666Stage at initial diagnosis, n (%) III318 (65)158 (64)476 (65) IV169 (35)88 (36)257 (35)Prior NACT, N (%) Yes322 (66)167 (68)489 (67) No165 (34)79 (32)244 (33)Best response to platinum-based CT, n (%) CR337 (69)172 (70)509 (69) PR150 (31)74 (30)224 (31)Homologous recombination test status, n (%) HRd247 (51)126 (51)373 (51) BRCAmut152 (31)71 (29)223 (30) BRCAwt95 (20)55 (22)150 (20) HRp169 (35)80 (33)249 (34) HRnd71 (15)40 (16)111 (15)

35% of patients were Stage IV99.6% with Stage III had residual disease post PDS67% received NACT31% achieved a PR to 1L CT51% had HRd tumors30% had BRCAmut tumors34% had HRp tumors

1L, first-line; CR, complete response; CT, chemotherapy;

HRd

, homologous recombination deficient;

HRp

, homologous recombination proficient;

HRnd

, homologous recombination not

determined;

mut

, mutation; NACT, neoadjuvant chemotherapy; PDS, primary debulking surgery; PR, partial response;

, wild-type.

Niraparib Treatment in Patients With Newly Diagnosed Advanced Ovarian Cancer (OC)

González Martin

A et al.,

ESMO 2019, abstract LBA1 (oral presentation)

Slide46

PFS benefit in the HR-deficient population

1. González-Martín A et al. New Engl J Med, 2019; DOI: 10.1056/NEJMoa1910962PD, progressive disease; PFS, progression-free survivalNiraparib Treatment in Patients With Newly Diagnosed Advanced Ovarian Cancer (OC)González Martin A et al., ESMO 2019, abstract LBA1 (oral presentation)

prima - primary endpoint

Niraparib 24723121518918416811176664222191340Placebo 126117997970573421211155410

Initiation of PRIMAafter completion of 1L CT

57% reduction in risk of relapse or death with niraparibNiraparib(n=247)Placebo(n=126)Median PFSmonths(95% CI)21.9(19.3-NE)10.4(8.1-12.1)Patients without PD or death (%)6 months86%68%12 months72%42%18 months59%35%

Months since

Randomization

Progression-free Survival (%)

100

Niraparib

Placebo

Hazard

ratio

: 0.43

(95% CI, 0.31-0.59)

P<0.001

Slide47

PFS benefit in the overall population

prima - primary endpoinT

Niraparib 487454385312295253167111945829211340Placebo 246226177133117906032291766410

38% reduction in risk of relapse or death with niraparibNiraparib(n=487)Placebo(n=246)Median PFSmonths(95% CI)13.8(11.5-14.9)8.2(7.3-8.5)Patients without PD or death (%)6 months73%60%12 months53%35%18 months42%28%

Initiation of PRIMAafter completion of 1L CT

100

Placebo

Niraparib

Hazard

ratio

: 0.62

(95% CI, 0.50-0.76)

P<0.001

Months since

Randomization

Progression-free

Survival

(%)

Slide48

Hazard ratio for PFS (95% CI)Overall0.62 (0.50–0.76)Age group<65 years0.61 (0.47–0.81)≥65 years0.53 (0.38–0.74)Stage of disease at initial diagnosisIII0.54 (0.42–0.70)IV0.79 (0.55–1.12)Neoadjuvant chemotherapyYes0.59 (0.46–0.76)No0.66 (0.46–0.94)Best response to platinum therapyCR0.60 (0.46–0.77)PR0.60 (0.43–0.85)Homologous recombination statusHRd–BRCAmut0.40 (0.27–0.62)HRd–BRCAwt0.50 (0.31–0.83)HRp0.68 (0.49–0.94)HRnd0.85 (0.51–1.43)

* Exploratory analysis; CI, confidence interval; CR, complete response;

HRd, homologous recombination deficient; HRp, homologous recombination proficient; HRnd, homologous recombination not determined; mut, mutation; PFS, progression-free survival; PR, partial response; wt, wild-type.Niraparib Treatment in Patients With Newly Diagnosed Advanced Ovarian Cancer (OC)González Martin A et al., ESMO 2019, abstract LBA1 (oral presentation)

PFS Benefit in pre-specified groups *

1.00

Niraparib

Better

Placebo

Better

.00

Slide49

PFS Benefit in Biomarker Subgroups

CI, confidence interval; HR, homologous recombination; mut, mutation; PFS, progression-free survival; wt, wild-type.Niraparib Treatment in Patients With Newly Diagnosed Advanced Ovarian Cancer (OC)González Martin A et al., ESMO 2019, abstract LBA1 (oral presentation)

Niraparib provided similar clinical benefit in the HRd subgroups (BRCAmut and BRCAwt)Niraparib provide clinically significant benefit in the HR-proficient subgroup with a 32% risk reduction in progression or death

100

Months since

Randomization

Progression-free

Survival

(%)

HRd

BRCA

mut

100

Months since

Randomization

HRd

BRCA

100

Months since

Randomization

HR-proficient

Niraparib

Placebo

Hazard

ratio

: 0.40

(95% CI, 0.27-0.62)

Hazard

ratio

: 0.50

(95% CI, 0.31-0.83)

Hazard

ratio

: 0.68

(95% CI, 0.49-0.94)

Homologous Recombination Deficient (

HRd

)

Niraparib

Placebo

Niraparib

Placebo

p=0.020

p=0.006

p<0.001

Slide50

Overall survival (11% data maturity)

Key Secondary Endpoint

CI, confidence interval; HR, homologous recombination.Niraparib Treatment in Patients With Newly Diagnosed Advanced Ovarian Cancer (OC)González Martin A et al., ESMO 2019, abstract LBA1 (oral presentation)

100

Niraparib

Placebo

Hazard

ratio

: 0.70

(95% Cl, 0.44-1.11)

Months since

Randomization

Overall Survival (%)

Overall

Population

100

Months since

Randomization

HR-deficient

Placebo

Niraparib

Pre-planned

interim

analysis of overall survival numerically favours

niraparib

over

placebo

Overall population 84% vs 77% alive at

years

HR-deficient 91% vs 85% alive at

years

HR-proficient 81% vs 59% alive at

years

100

Months since

Randomization

HR-proficient

Placebo

Niraparib

Hazard

ratio

: 0.61

(95% Cl, 0.27-1.39)

Hazard

ratio

: 0.51

(95% Cl, 0.27-0.97)

p=0.23

p=0.13

p=0.04

Slide51

PARP, poly(ADP-ribose) polymerase; TEAE, treatment-emergent adverse event.Niraparib Treatment in Patients With Newly Diagnosed Advanced Ovarian Cancer (OC)González Martin A et al., ESMO 2019, abstract LBA1 (oral presentation)

Safety Overview

Adverse Event, no. (%)Niraparib(n=484)Placebo(n=244)Any TEAE478 (98.8)224 (91.8) Grade ≥3341 (70.5)46 (18.9)Led to treatment discontinuation58 (12.0)6 (2.5)Led to dose reduction343 (70.9)20 (8.2)Led to dose interruption385 (79.5)44 (18.0)TEAEs leading to death2 (0.4)1 (0.4)

TEAEs

were

manageable

and

consistent

with the PARP

inhibitor

class

Dose

interruptions

were

similar

those

in the

niraparib

trials

Treatment

discontinuation

due to

thrombocytopenia

was 4.3%

TEAEs

leading

death were

determined

to be not treatment-

Slide52

PRIMA Safety & Patient-Reported Outcomes

TEAEs ≥20% incidence in niraparib arm. Note: Hematologic TEAEs are not combined with laboratory results FOSI, FACIT ovarian cancer symptom index; MDS, myelodysplastic syndrome; TEAE, treatment-emergent adverse event.Niraparib Treatment in Patients With Newly Diagnosed Advanced Ovarian Cancer (OC)González Martin A et al., ESMO 2019, abstract LBA1 (oral presentation)

No new safety signals were identified for niraparibMost common TEAE was reversible myelosuppressionOne patient was diagnosed with MDS after 9 months of niraparib treatment

NiraparibAny Grade

Niraparib

Grade  3

Placebo

Any Grade

Placebo

Grade  3

Anemia

Nausea

Thrombocytopenia

Constipation

Fatigue

Platelet

Count

Decreased

Neutropenia

Headache

Insomnia

Vomiting

100

Patients

(%)

Cycle

FOSI Adjusted Health Utility Index Score

No impact in quality of life with niraparib treatment

0 3 5 7 9 11 13 15 18 21 24 27 30

Mean

(±SE) FOSI

Niraparib

Placebo

Slide53

Niraparib Treatment in Patients With Newly Diagnosed Advanced Ovarian Cancer (OC)González Martin A et al., ESMO 2019, abstract LBA1 (oral presentation)

Available therapies and active surveillance do not address the high unmet need for many patients with newly diagnosed advanced ovarian cancer (OC) after platinum-based chemotherapyNiraparib therapy in patients with advanced OC provided a clinically significantly improvement in PFS after response to frontline platinum-based chemotherapy in all patientsPFS overall population: hazard ratio, 0.62; p<0.001PFS homologous recombination deficient: hazard ratio, 0.43; p<0.001PFS homologous recombination proficient: hazard ratio, 0.68; p=0.020Niraparib is the first PARP-inhibitor to demonstrate benefit in patients across biomarkers subgroups after platinum-based chemotherapy in frontline, consistent with prior clinical trials of niraparib in recurrent OC (NOVA, QUADRA)Patients with OC at the highest risk of early disease progression (NACT, partial responders to 1L platinum chemotherapy) had significant benefit with niraparib therapyNo new safety signals were observed, and quality of life was maintained on niraparibNiraparib monotherapy after frontline platinum-based chemotherapy should be considered a new standard of care

SUMMARY & CONCLUSIONS

Slide54

I. Ray-Coquard, P. Pautier, S. Pignata, D. Pérol, A. González-Martín, P. Sevelda, K. Fujiwara, I. Vergote, N. Colombo, J. Mäenpää , F. Selle, J. Sehouli, D. Lorusso, E. Guerra Alia, C. Lefeuvre-Plesse, U. Canzler, A. Lortholary, F. Marmé, E. Pujade-Lauraine, P. Harter

Phase III PAOLA-1/ENGOT-ov25: maintenance

olaparib

with bevacizumab in patients with newly diagnosed, advanced ovarian cancer treated with platinum-based chemotherapy and bevacizumab as standard of care

(abstract LBA2)

Slide55

Study background and methods

PAOLA-1/ENGOT-ov25* is the first randomized, double-blind phase III trial to evaluate the efficacy and safety of a PARP inhibitor with bevacizumab (bev) as first-line (1L) maintenance therapy for advanced ovarian cancer, regardless of BRCA1/2 mutation (BRCAm) status

Eligible patients had newly diagnosed, FIGO stage III–IV, high-grade serous or endometrioid ovarian cancer and had received standard PTCh plus bev and showed CR or PRPatients were randomized (2:1) to olaparib tablets (300 mg bid for up to 24 mo plus bev (15 mg/kg, d1, q3w, for 15 mo including when combined with PTCh) or placebo plus bev, stratified by 1L treatment outcome and tumour BRCAm status The primary endpoint was investigator-assessed PFS in the intent-to-treat population*

Phase III PAOLA-1/ENGOT-ov25 trial: Olaparib plus bevacizumab (bev) as maintenance therapy in patients with newly diagnosed, advanced ovarian cancer (OC) treated with platinum-based chemotherapy plus bev Ray-Coquard IL et al., ESMO 2019, abstract LBA2 (oral presentation)

* NCT02477644

* modified RECIST v1.1

PTCh, platinum-taxane based chemotherapy

CR, complete responsePR, partial response

PFS,

progression-free survival

Slide56

Study design

Newly diagnosed FIGO stage III–IV high-grade serous/endometrioid ovarian, fallopian tube or primary peritoneal cancer*

*Patients with other epithelial non-mucinous ovarian cancer were eligible if they had a germline BRCA1 and/or BRCA2 mutation†Bevacizumab: 15 mg/kg, every 3 weeks for a total of 15 months, including when administered with chemotherapy; ‡By central labs; ¶According to timing of surgery and NED/CR/PRBICR, blinded independent central review; HRQoL, health-related quality of life; PFS2, time to second progression or death; RECIST, Response Evaluation Criteria in Solid Tumours; TFST, time to first subsequent therapy or death; TSST, time to second subsequent therapy or deathPhase III PAOLA-1/ENGOT-ov25 trial: Olaparib plus bevacizumab (bev) as maintenance therapy in patients with newly diagnosed, advanced ovarian cancer (OC) treated with platinum-based chemotherapy plus bev Ray-Coquard IL et al., ESMO 2019, abstract LBA2 (oral presentation)

Maintenance therapy

FIRST LINE

Surgery

(upfront

interval)Platinum–taxane based chemotherapy≥3 cycles of bevacizumab†

Randomization

NED/CR/PR

2:1

N=806

Primary

endpoint

Investigator-

assessed

PFS

(RECIST v1.1)Sensitivity analysisPFS by BICRSecondary endpointsTFSTPFS2, TSSTOS HRQoLSafety and tolerability

Placebo x2

years

+ bevacizumab

†

Stratification

Tumour BRCAm status‡First-line treatment outcome¶

+ bevacizumab†

Olaparib

(300

BID)

years

Slide57

* ECOG performance was missing for six patients in the olaparib arm and four patients in the placebo arm; Two patients had low-grade serous carcinoma with a BRCAm; ǂ Other includes clear cell, undifferentiated and other histology; ¶33 (4%) patients had an unknown tBRCAm status; 26 patients in the olaparib arm and 7 patients in the placebo arm: ECOG, Eastern Cooperative Oncology Group; FIGO, Fédération Internationale de Gynécologie et d'Obstétrique; tBRCAm, tumour BRCA mutationPhase III PAOLA-1/ENGOT-ov25 trial: Olaparib plus bevacizumab (bev) as maintenance therapy in patients with newly diagnosed, advanced ovarian cancer (OC) treated with platinum-based chemotherapy plus bev Ray-Coquard IL et al., ESMO 2019, abstract LBA2 (oral presentation)

Patient characteristics (I)

Olaparib + BEV

(N=537)

Placebo + BEV

(N=269)

Age,

median, years (range)

61 (32-87)

60 (26-85)

ECOG performance*, n (%)

378 (70)

189 (70)

153 (28)

76 (28)

Primary tumour location, n (%)

Ovary

456 (85)

238 (88)

Fallopian tubes

39 (7)

11 (4)

Primary peritoneal

42 (8)

20 (7)

Histology, n (%)

Serous

519 (97)

253 (94)

Endometrioid

12 (2)

8 (3)

Other

6 (1)

8 (3)

BRCA

status

, n (%)

BRCA

mutation

157 (29)

80 (30)

BRCA

mutation/unknown

380 (71)

189 (70)

FIGO stage

, n (%)

III

378 (70)

186 (69)

159 (30)

83 (31)

Slide58

CR, complete responase; NED, no evidence of disease; PR, partial responsePhase III PAOLA-1/ENGOT-ov25 trial: Olaparib plus bevacizumab (bev) as maintenance therapy in patients with newly diagnosed, advanced ovarian cancer (OC) treated with platinum-based chemotherapy plus bev Ray-Coquard IL et al., ESMO 2019, abstract LBA2 (oral presentation)

Patient characteristics (II)

Olaparib + BEV

(N=537)

Placebo + BEV

(N=269)

History of cytoreductive surgery,

n (%)

Upfront

surgery

271 (50)

138 (51)

Residual

macroscopic

disease

111 (41)

53 (38)

No residual

macroscopic

disease

160 (59)

85 (62)

Interval

cytoreductive

surgery

228 (42)

110 (41)

Residual

macroscopic

disease

65 (29)

35 (32)

No residual

macroscopic

disease

163 (71)

75 (68)

No surgery

38 (7)

21 (8)

Response after surgery/ platinum-based chemotherapy

, n (%)

NED

290 (54)

141 (52)

106 (20)

53 (20)

141 (26)

75 (28)

Slide59

*Other includes lost to follow up, surgery, new comorbidities and other; TEAE, treatment-emergent adverse eventPhase III PAOLA-1/ENGOT-ov25 trial: Olaparib plus bevacizumab (bev) as maintenance therapy in patients with newly diagnosed, advanced ovarian cancer (OC) treated with platinum-based chemotherapy plus bev Ray-Coquard IL et al., ESMO 2019, abstract LBA2 (oral presentation)

Patient disposition

Olaparib +BEV

Placebo + BEV

Randomized,

537

269

Treated

, n (%)

535 (99.6)

267 (99.3)

Discontinued

study

treatment

, n(%)

331 (62)

196 (73)

Disease progression per RECIST

182 (34)

155 (58)

Disease progression non-RECIST

14 (3)

13 (5)

TEAE

109 (20)

13 (5)

Patient decision

17 (3)

10 (4)

Death

1 (<1)

3 (1)

Other*

8 (1)

Median

duration

of treatment

, months (

range

)

Olaparib/placebo

17.3 (0.03-33.0)

15.6 (0.07-26.2)

Bevacizumab

11.0 (0.69-21.4)

10.6 (0.69-17.1)

Median

duration

of follow-

months

24.0

22.7

Slide60

By investigator assessment

ITT, intent-to-treat populationPhase III PAOLA-1/ENGOT-ov25 trial: Olaparib plus bevacizumab (bev) as maintenance therapy in patients with newly diagnosed, advanced ovarian cancer (OC) treated with platinum-based chemotherapy plus bev Ray-Coquard IL et al., ESMO 2019, abstract LBA2 (oral presentation)

PFS in the ITT population

Months since randomization

No. at risk

Olaparib53751346143340337427924014111255371230Placebo269252226205172151109835035159110

Olaparib + bevacizumab(N=537)Placebo + bevacizumab(N=269)Events, n (%) [59% maturity]280 (52) 194 (72)Median PFS, months22.1 16.6HR 0.59 (95% CI 0.49–0.72;P<0.0001)

Median time from first cycle of chemotherapy to randomization = 7 months

Patients free from disease progression and death (%)

1009080

7060

504030201000 3 6 9 12 15 18 21 24 27 30 33 36 39 42 45

Slide61

Sensivity

analysis

* These results are immature: PFS2 39% mature and OS 26% mature Phase III PAOLA-1/ENGOT-ov25 trial: Olaparib plus bevacizumab (bev) as maintenance therapy in patients with newly diagnosed, advanced ovarian cancer (OC) treated with platinum-based chemotherapy plus bev Ray-Coquard IL et al., ESMO 2019, abstract LBA2 (oral presentation)

primary & secondary efficacy endpoints

1 HR 0.59 (95% Cl 0.49--0.72, P<0.0001)

HR 0.63 (95% Cl 0.51-0.77, P<0.0001)

HR 0.59 (95% Cl 0.49--0.71, P<0.0001)

HR 0.86 (95% Cl 0.69--1.09)

In the second line, 30/537 (6%) patients in the olaparib arm and 55/269 (20%) patients in the placebo arm received treatment with a PARP inhibitor

Data immature*

HR 0.59

(95% Cl 0.49--0.72, P<0.0001)

Slide62

SubgroupOlaparib + Bev Placebo + BevHR (95% CI)No. of events/no. of patients (%)All 280/537 (52)194/269 (72)0.59 (0.49-0.72)Age group<65 years old171/332 (52)126/182 (69)0.61 (0.49-0.77)≥65 years old109/205 (53)68/87 (78)0.55 (0.41-0.75)FIGO stageIII184/378 (49)125/186 (67)0.64 (0.51-0.80)IV96/159 (60)69/83 (83)0.49 (0.36-0.67)ECOG baseline0193/378 (51)132/189 (70)0.63 (0.50-0.78)185/153 (56)61/83 (83)0.51 (0.37-0.71)Cytoreductive surgery outcomeDebulking surgery with no residual macroscopic disease135/323 (42)104/160 (65)0.54 (0.42-0.71)Debulking surgery with residual macroscopic disease113/176 (64)71/88 (81)0.63 (0.47-0.85)No debulking surgery32/38 (84)19/21 (90)0.56 (0.32-1.01)Timing of cytoreductive surgeryUpfront116/271 (43)92/138 (67)0.52 (0.40-0.69)Interval debulking132/228 (58)83/110 (75)0.66 (0.50-0.87)No debulking surgery32/38 (84)19/21 (90)0.57 (0.32-1.02)Response to first line CTNED119/290(41)92/141 (65)0.53 (0.40-0.70)CR54/106(51)42/53 (79)0.44 (0.29-0.66)PR107/141 (76)60/75 (80)0.86 (0.63-1.19)

PFS

subgroup analysis

Olaparib

+ Bev

better

Placebo+ Bev

better

Slide63

The percentages of patients progression-free at 12 months and 24 months have been calculated based on Kaplan-Meier estimates. *This median is unstable due to a lack of events – less than 50% maturity; †Includes tBRCA unknownPhase III PAOLA-1/ENGOT-ov25 trial: Olaparib plus bevacizumab (bev) as maintenance therapy in patients with newly diagnosed, advanced ovarian cancer (OC) treated with platinum-based chemotherapy plus bev Ray-Coquard IL et al., ESMO 2019, abstract LBA2 (oral presentation)

PFS by tBRCA mutation status

100

0 3

No. at

risk

BRCA

6 9 12 15 18 21

24 27 30

36 39

Olaparib

157

154

150

148

144

138

117

110

380

359

285

259

236

162

130

Placebo

189

174

154

139

113

Non-

BRCA

†

76%

39%

76%

94%

Olaparib

+ bevacizumab

(N=157)

Placebo + bevacizumab

(N=80)

Events, n (%)

[59% maturity

]

(26)

(61)

37.2* 21.7

Median PFS

, months

HR 0.31

(95% CI

0.20–0.47)

Olaparib

+ bevacizumab

(N=380)

Placebo + bevacizumab

(N=189)

Events, n (%)

[59% maturity

]

239

(63)

145

(77)

18.9 16.0

Median PFS

, months

HR 0.71

(95% CI

0.58–0.88)

Patients free from disease

progression and

death

(%)

Months since

randomization

Months since

randomization

0 3

6 9 12 15 18 21 24 27 30 33 36 39

Slide64

PFS by HRD status

The percentages of patients progression-free at 12 months and 24 months have been calculated based on Kaplan-Meier estimates. HRD positive is an HRD score ≥42. *This median is unstable due to a lack of events – less than 50% maturityPhase III PAOLA-1/ENGOT-ov25 trial: Olaparib plus bevacizumab (bev) as maintenance therapy in patients with newly diagnosed, advanced ovarian cancer (OC) treated with platinum-based chemotherapy plus bev Ray-Coquard IL et al., ESMO 2019, abstract LBA2 (oral presentation)

No. at

risk

Olaparib

Placebo

255 252

242

236 223 213

169

155

103 85 46 29

1 3 0

132 128

103 91 79 54 44

28 18 8 5 1

1 0

100

Patients free from disease

progression and death (%)

HRD positive,

including

BRCA

97 96 90 86 79

48 30

16 12

4 2 0

55 54 48 41 37 32 19 15

3 2 0

282 261 219 197 180 161

110

85 38 27

9 8 1

137 124 109 102 81 72 55 39 22

7 4

66%

52%

29%

26%

89%

71%

83%

69%

Months since

randomization

Months since

randomization

Months since

randomization

Olaparib

+ bevacizumab

(N=282)

Placebo + bevacizumab

(N=137)

193

(68)

102

(74)

16.9 16.0

HR 0.92

(95% CI

0.72–1.17)

Olaparib

+ bevacizumab

(N=97)

Placebo + bevacizumab

(N=55)

(44)

(73)

28.1* 16.6

HR 0.43

(95% CI

0.28–0.66)

Olaparib

+ bevacizumab

(N=255)

Events, n (%)

[59% maturity

]

(34)

(70)

37.2* 17.7

Median PFS

, months

HR 0.33

(95% CI

0.25–0.45)

Placebo + bevacizumab

(N=132)

Olaparib

+ bevacizumab

(N=255)

HRD positive,

excluding

BRCA

HRD negative/

unknown

Slide65

Dose interruption, reductions and discontinuations reported are for olaparib and placebo; SAE, serious adverse event Phase III PAOLA-1/ENGOT-ov25 trial: Olaparib plus bevacizumab (bev) as maintenance therapy in patients with newly diagnosed, advanced ovarian cancer (OC) treated with platinum-based chemotherapy plus bev Ray-Coquard IL et al., ESMO 2019, abstract LBA2 (oral presentation)

Summary of Adverse events

Olaparib

+ bevacizumab

(N=535)

Placebo + bevacizumab

(N=267)

All grade TEAEs

, n (%)

531 (99)

256 (96)

Grade ≥3 TEAEs

, n (%)

303 (57)

136 (51)

SAEs

, n (%)

167 (31)

83 (31)

Deaths

, n (%)

1 (<1)

4 (1)

Dose

interruptions

due to AEs

, n (%)

291 (54)

65 (24)

Dose reductions due to AEs

, n (%)

220 (41)

20 (7)

Discontinuations due to AEs

, n (%)

109 (20)

15 (6)

Slide66

Most

common Adverse events

All grades (frequency ≥15%)

Fatigue

asthenia

Nausea

Hypertension

Anaemia

Lymphopenia*

Arthralgia

Vomiting

Abdominal pain

Diarrhoea

Neutropenia*

100

Adverse

events

(%)

Olaparib

+ bevacizumab (N=535)

Placebo + bevacizumab (N=267)

Leukopenia

Urinary

tract

infection

Grade ≥3

All grades (

frequency

≥15%)

Grade ≥3

*Grouped terms. All-grade thrombocytopenia (grouped term) occurred in 8% of patients in the

olaparib

group and 3% of patients in the placebo group, grade ≥3 thrombocytopenia occurred

in 2% of patients in the

olaparib

group and <1% of patients in the placebo group.

Phase III PAOLA-1/ENGOT-ov25 trial:

Olaparib

plus bevacizumab (

bev

) as maintenance therapy in patients with newly diagnosed, advanced ovarian cancer (OC) treated with platinum-based chemotherapy plus

bev

Ray-

Coquard

IL et al.,

ESMO 2019, abstract LBA2 (oral presentation)

Slide67

AA, aplastic anaemia; AML, acute myeloid leukaemia; ILD, interstitial lung disease; MDS, myelodysplastic syndrome Phase III PAOLA-1/ENGOT-ov25 trial: Olaparib plus bevacizumab (bev) as maintenance therapy in patients with newly diagnosed, advanced ovarian cancer (OC) treated with platinum-based chemotherapy plus bev Ray-Coquard IL et al., ESMO 2019, abstract LBA2 (oral presentation)

Summary of Adverse events

Olaparib

+ bevacizumab

(N=535)

Placebo + bevacizumab

(N=267)

MDS/AML/AA

, n (%)

6 (1.1)

1 (0.4)

New primary malignancies

, n (%)

7 (1.3)

3 (1.1)

Acute lymphocytic leukaemia

Breast cancer

Lung cancer

Myeloma

Pancreatic cancer

Squamous

skin

cancer

Thyroid cancer

Pneumonitis/lLD

, n (%)

6 (1.1)

Slide68

Health-

quality of life

Mean change from baseline in GHS/QoL score

-5

-10

-15

Weeks since

randomization

Olaparib

Placebo

508

249

458

228

432

207

396

199

393

185

352

171

342

166

308

151

252

123

No. al

risk

Olaparib

+ bevacizumab

Placebo +

bevacizumab

498

246

Adjusted mean

-1.33

-2.89

95% CI,

value

-2.47 to -0.19,

=0.022

-4.52 to -1.26,

=0.0005

Estimated difference

1.56

95% CI,

value

-0.42 to 3.55,

=0.123

A minimal

clinically

important

difference

defined

points

(

Cocks

et a/.

Eur

Cance,2012;48:1713-21)

GHS, global

health

score;

Qol

, Quality

life

Phase III PAOLA-1/ENGOT-ov25 trial:

Olaparib

plus bevacizumab (

bev

) as maintenance therapy in patients with newly diagnosed, advanced ovarian cancer (OC) treated with platinum-based chemotherapy plus

bev

Ray-

Coquard

IL et al.,

ESMO 2019, abstract LBA2 (oral presentation)

Slide69

PAOLA-1/ENGOT-ov25 included a broad frontline population of advanced ovarian cancer patients which was not restricted by surgical outcome or BRCA mutation statusPAOLA-1/ENGOT-ov25 met its primary objective, demonstrating a statistically significant improvement in PFS in the ITT population when olaparib compared with placebo was added to first-line standard-of-care bevacizumab maintenance treatmentPrespecified subgroup analyses showed that patients with tBRCA mutations and patients with a positive HRD status had the greatest PFS benefitsThe results reveal a patient population beyond tBRCAm patients, who are HRD positive that experiences substantial benefit from maintenance treatment with olaparib plus bevacizumabThe safety profile of olaparib in combination with bevacizumab was generally consistent with previous trials of each drug and the addition of olaparib did not impact on bevacizumab tolerability and HRQoL

Conclusions

HRQoL Health

quality

life

Phase III PAOLA-1/ENGOT-ov25 trial:

Olaparib

plus bevacizumab (

bev

) as maintenance therapy in patients with newly diagnosed, advanced ovarian cancer (OC) treated with platinum-based chemotherapy plus

bev

Ray-

Coquard

IL et al.,

ESMO 2019, abstract LBA2 (oral

presentation

)

Slide70

R. Coleman, G. Fleming, M. Brady, E. Swisher, K. Steffensen, M. Friedlander, A. Okamoto, K. Moore, N. Ben-Baruch, T. Werner, A. Oaknin, J.-H. Nam, C. Leath, S. Nicum, D. Cella, D. Sullivan, P. Ansell, M. Dinh, C. Aghajanian, M. Bookman

VELIA/GOG-3005: Integration of veliparib (V) with front-line chemotherapy and maintenance in women with high-grade serous carcinoma of ovarian, fallopian tube, or primary peritoneal origin (HGSC)

(abstract LBA3)

Slide71

Study background and methods

VELIA/GOG-3005 is phase III randomized placebo controlled multinational trial evaluating whether progression-free survival (PFS) is increased when Veliparib is added to front-line carboplatin and paclitaxel (CP) and continued as maintenance in newly diagnosed stage III-IV HGSOC patients considering BRCA mutations (m), homologous recombination deficiency (HRD), and neoadjuvant chemotherapy (NACT) utilization

Patients received 6 cycles (21-d interval) of CP using 3-wkly or wkly paclitaxel, following primary cytoreduction or NACT with interval cytoreduction. Veliparib or PL was administered during CP (150 mg BID PO) and as maintenance (400 mg BID for 30 cycles). Randomization was 1:1:1, stratified by Stage III vs IV, residual disease and regimen, region, and gBRCA status - see study design slide for detailsPrimary endpoints were PFS* in arm 3 vs 1 using hierarchical testing in BRCAm, HRD (incl. BRCAm), and whole populations by log-rank tests. Secondary endpoints were PFS (arm 2 vs 1), overall survival, and disease related symptom scores. Germline and tissue BRCAm and HRD were determined by central testing

VELIA/GOG-3005: Integration of veliparib (V) with front-line chemotherapy and maintenance in women with high-grade serous carcinoma of ovarian, fallopian tube, or primary peritoneal origin (HGSC)Coleman RL et al., ESMO 2019, abstract LBA3 (oral presentation)

HGSOC, high-grade serous ovarian carcinoma

* Kaplan-Meier

Slide72

High-grade serous cancerFIGO stage III or IVNo prior systemic therapyECOG 0 to 2No CNS metastases

Stage of diseaseRegionPrimary vs Interval CytoreductionResidual diseaseChemotherapy regimen*gBRCA status**

Patient population

Stratification factors

Primary endpoint: PFS for Veliparib-throughout vs. ControlPFS includes combination and maintenance phase

Carboplatin

(Q3W) +

Paclitaxel (QW or Q3W) +

Combination: Cycles 1-6

Maintenance: Cycles 7-36

Veliparib- combination-only (n=383)

Veliparib150mg BID

Placebo

Veliparib

- throughout (n=382)

liparib

150mg BID

liparib

400mg BID

Control

(n=375)

Placebo

1:1:1

Randomizationn=1140

* Carboplatin AUC 6 Q3W + Paclitaxel 80 mg/m2 QW or 175 mg/m2 Q3W** Added as stratification factor ~14 months after trial initiation due to noted imbalanceVELIA/GOG-3005: Integration of veliparib (V) with front-line chemotherapy and maintenance in women with high-grade serous carcinoma of ovarian, fallopian tube, or primary peritoneal origin (HGSC)Coleman RL et al., ESMO 2019, abstract LBA3 (oral presentation)

Study Design: VELIA/GOG-3005 (NCT02470585)

Slide73

Characteristic, no. (%)Veliparib-throughout(n=382)Control therapy(n=375)Age, yearsMedian (Range)62 (30-85)62 (33-86)FIGO StageStage III295 (77%)292 (78%)Stage IV87 (23%)82 (22%)Surgery received (% complete gross resection)Primary (69%)261 (68%)250 (67%) Interval (71%)99 (26%)107 (29%)None22 (6%)18 (5%)Paclitaxel regimenWeekly190 (50%)193 (52%)Every 3 weeks189 (50%)179 (48%)

Patient Characteristics

VELIA/GOG-3005: Integration of veliparib (V) with front-line chemotherapy and maintenance in women with high-grade serous carcinoma of ovarian, fallopian tube, or primary peritoneal origin (HGSC)

Coleman RL et al.,

ESMO 2019, abstract LBA3 (oral presentation)

Slide74

Characteristic, no. (%)Veliparib-throughout(n=382)Control therapy(n=375)BRCAm statusDeleterious Mutation (n=200)108 (31%)92 (27%)BRCA1 vs. BRCA2 (% of BRCAm)78 (72%) + 30 (28%)59 (64%) + 31 (36%)*gBRCA vs. tBRCA (% of study arm)80 (23%) + 28 (8%)63 (18%) + 29 (8%)No deleterious mutation245 (69%)254 (73%)Missing2929HRD statusHRD (includes BRCAm) (n=421)214 (63%)207 (63%)Non-HRD (n=249)125 (37%)124 (38%)Missing (n=87)4344

*2 patients had both BRCA1 and BRCA2 mutations; BRCA assessed via Myriad BRACAnalysis CDx®. HRD assessed via Myriad myChoice HRD CDx®. gBRCA, germline BRCA; HRD, homologous recombination deficiency; tBRCA, tissue-based BRCA.VELIA/GOG-3005: Integration of veliparib (V) with front-line chemotherapy and maintenance in women with high-grade serous carcinoma of ovarian, fallopian tube, or primary peritoneal origin (HGSC)Coleman RL et al., ESMO 2019, abstract LBA3 (oral presentation)

Patient

Characteristics

Slide75

No. at riskControl 929089888480746357504638292419136420Veliparib-throughout1081029997959088828076736553453830211495110

aintenan

Combination

BRCA

population

Median

duration

of follow-

was 28 months at the time of

database

lock.VELIA/GOG-3005: Integration of veliparib (V) with front-line chemotherapy and maintenance in women with high-grade serous carcinoma of ovarian, fallopian tube, or primary peritoneal origin (HGSC)Coleman RL et al., ESMO 2019, abstract LBA3 (oral presentation)

PFS by Investigator Assessment

BRCAmVeliparib- throughoutControlEvents(%)34/108(31.5)51/92(55.4)Median PFS,months (95% CI)34.7(31.8, -)22.0(17.8, 29.1)

BRCAm

HRD

Non-HRD

0.44

95% CI [0.28-0.68],

p<0.001 n=200

Slide76

No. at riskControl 207199196191183170158134119104977955473422119420Veliparib-throughout214203195191182167161150140130121109827258443019145110

HRD population

Median

duration of follow-up was 28 months at the time of database lock.VELIA/GOG-3005: Integration of veliparib (V) with front-line chemotherapy and maintenance in women with high-grade serous carcinoma of ovarian, fallopian tube, or primary peritoneal origin (HGSC)Coleman RL et al., ESMO 2019, abstract LBA3 (oral presentation)

PFS by Investigator Assessment

aintenan

Combination

HRD

Veliparib- throughout

Control

Events

(%)

87/214

(40.7)124/207(59.9)Median PFS,months (95% CI)31.9(25.8, 38.0)20.5(17.8, 22.8)

Non-HRD

HRD

HR 0.5795% CI [0.43-0.76], p<0.001 n=421

BRCA

HRD

Slide77

No. at riskControl 3753563403282972602362021721531431198470553621161030Veliparib-throughout3823523373293082752532282081921721531119576553826197210

PFS by Investigator Assessment

Median

duration

of follow-up was 28 months at the time of database lock.VELIA/GOG-3005: Integration of veliparib (V) with front-line chemotherapy and maintenance in women with high-grade serous carcinoma of ovarian, fallopian tube, or primary peritoneal origin (HGSC)Coleman RL et al., ESMO 2019, abstract LBA3 (oral presentation)

aintenan

Combination

ITT

Veliparib

throughout

Control

Events(%)191/382(50.0)237/375(63.2)Median PFS,months (95% CI)23.5(19.3, 26.3)17.3(15.1, 19.1)

HR 0.68

95% CI [0.56-0.83], p<0.001 n=757

ITT population

BRCA

HRD

Non-HRD

Slide78

*Stratification factor. Values reported as collected in electronic data capture system.Disease stage by International Federation of Gynecology and Obstetrics (FIGO) stage III or IV disease.VELIA/GOG-3005: Integration of veliparib (V) with front-line chemotherapy and maintenance in women with high-grade serous carcinoma of ovarian, fallopian tube, or primary peritoneal origin (HGSC)Coleman RL et al., ESMO 2019, abstract LBA3 (oral presentation)

SubgroupVeliparibControlHazard ratio for disease progression or death (95% CI)No. of patients with events/totalAll patients191/382237/3750.70 (0.58, 0.84)Age group<65 years old110/228155/2330.65 (0.50, 0.82)≥65 years old81/15482/1420.77 (0.57, 1.05)RaceWhite158/300194/2990.70 (0.57, 0.86)Asian21/5635/590.50 (0.29, 0.87)Other12/268/171.57 (0.63, 3.97)ECOG status0113/224135/2260.72 (0.56, 0.93)≥178/153102/1450.66 (0.49, 0.89)Disease stageStage III142/295183/2920.67 (0.54, 0.84)Stage IV49/8754/820.79 (0.54, 1.17)Paclitaxel regimenWeekly92/190125/1930.65 (0.50, 0.85)Every 3 weeks99/189112/1790.73 (0.55, 0.90)Surgery receivedPrimary surgery126/261149/2500.72 (0.57, 0.92)Interval surgery56/9978/1070.64 (0.45, 0.90)Residual disease after primary surgeryMacroscopic residual disease42/8350/760.60 (0.40, 0.91)No macroscopic residual disease84/17899/1740.77 (0.58, 1.04)Residual disease after interval surgeryMacroscopic residual disease23/2723/311.12 (0.62, 2.00)No macroscopic residual disease33/6953/720.52 (0.34, 0.81)

PFS

subgroup analysis

FavorsVeliparib-throughout

FavorsControl

0.1

Slide79

Favors Veliparib-throughout

By mutational status

Missing BRCA status: 29 in each arm; Missing HRD status: 43 in veliparib-throughout, 44 in control. gBRCA, germline BRCA; HRD, homologous recombination deficiency; tBRCA, tissue-based BRCA.VELIA/GOG-3005: Integration of veliparib (V) with front-line chemotherapy and maintenance in women with high-grade serous carcinoma of ovarian, fallopian tube, or primary peritoneal origin (HGSC)Coleman RL et al., ESMO 2019, abstract LBA3 (oral presentation)

PFS Subgroup Analysis

Subgroup

VeliparibControlHazard Ratio for disease progression or death (95% CI)No. of patients with events/totalAll patients191/382237/3750.70 (0.58, 0.84)BRCAm34/10851/920.45 (0.29, 0.70)Mutational status:BRCA126/7836/590.38 (0.23, 0.63)BRCA28/3013/310.64 (0.27, 1.56)gBRCA27/8036/630.50 (0.30, 0.82)tBRCA7/2815/290.35 (0.14, 0.87)

0.1

Favors

Veliparib-throughout

Favors

Control

Slide80

PFS: Non-HRD Population

*Exploratory Analysis

No. at

riskControl 1241181111058766554936353329191614964310Veliparib-throughout1251101031029481685748433529181311754310

aintenan

Combination

Non-HRD*

Veliparib

throughout

Control

Median PFSmonths (95% CI)15(12.7, 18.0)11.5(10.1, 14.9)HR vs. Control [95% CI]0.81[0.60-1.09]-

BRCA

HRD

Non-HRD

Months

from

randomization

Slide81

PFS: BRCAwt/HRD Population

*Exploratory Analysis

No. at

riskControl 1151091071039990847162545141262315955220Veliparib-throughout10610196948777736860544844292720149550

aintenan

Combination

BRCA

Non-HRD*

Veliparib

- throughoutControlMedian PFSmonths (95% CI)22.9(18.2, 37.5)19.8(16.7, 22.2)HR vs. Control [95% CI]0.74[0.52-1.06]-

HRD

BRCA

HRD

Non-HRD

Slide82

PFS: BRCAwt/NON-HRD Population

*Exploratory Analysis

No. at

riskControl 254242232221196165147125103938874494333211411730Veliparib-throughout245224212208191168151134117106908053453422149810

aintenan

Combination

BRCA

Veliparib

throughoutControlMedian PFSmonths (95% CI)18.2(15.9, 21.7)15.1(12.6, 17.5)HR vs. Control [95% CI]0.80[0.64-0.997]-

HRD

BRCA

HRD

Non-HRD

Slide83

Differences in mean change from baseline in scores between treatment arms and within all subgroups were small (range: 0-2.1) and not considered clinically significant

NFOSI-18: Disease-Related Symptom – Physical Score

Health-Related Quality of Life:

Veliparib-

throughoutVeliparib-combo-onlyControl

DRS-P Scores in ITT Population

-1

Comb

Maintenance

mean

change

from

baseline

Cycle

Patients at

each

visit

Vel-throughout

319

301

287

277

249

225

207

202

178

174

153

145

130

135

118

111

Vel

-combo-

only

332

311

300

290

267

25422520217116013912712011310810089Control33331030129126925422420417717015014412912311110191

Least

squares

mean

change

from

baseline

of DRS-P

scores

using

mixed

-models

repeated

measures

method

bars

are

shown

. For

comparisons

versus

control

: *

indicates

p≤0.05.

Slide84

PFS for Veliparib-combo-only vs. Control

ITT PFS

Veliparib- combo-onlyControlHR 1.0795% CI (0.90-1.29)

Across BRCAm, HRD, and ITT, the veliparib-combo-only arm and the control arm demonstrated similar PFSVELIA/GOG-3005: Integration of veliparib (V) with front-line chemotherapy and maintenance in women with high-grade serous carcinoma of ovarian, fallopian tube, or primary peritoneal origin (HGSC)Coleman RL et al., ESMO 2019, abstract LBA3 (oral presentation)

No. at

riskControl 3753563403282972602362021721531431198470553621161030Veliparib-combo-only38335934834131626624119316414513111589705034241396110

aintenan

Combination

Slide85

84 83 91

84 84 90

92 93 98

Relative Dose

Intensity

Chemotherapy

Relative dose

intensity

: Mean % of

actual

planned

doses

Dosing

veliparib

placebo

during

combination

phase

(

Cycles

1-6)

Veliparib-throughout

Veliparib

-combo-

only

Control

Median cycles

6 cycles

cycles6 cyclesDose reductions5%6%3%

Carboplatin AUC 6

Paclitaxel QW 80 mg/m2

Paclitaxel Q3W 175 mg/m2

Slide86

Veliparib-throughout (n=377)Veliparib-combo-only(n=376)Control (n=371)Any treatment-emergent AE 377 (100)376 (100)371 (100)Grade 3 or 4 AEs 332 (88)329 (88)285 (77)Serious AEs 141 (37)129 (34)141 (38)AEs leading to discontinuation of Veliparib/Placebo97 (26)49 (13)43 (12)Related to disease progression6 (2)11 (3)18 (5)Not related to disease progression(Combination: cycles 1-6)40 (11)29 (8)22 (6)Not related to disease progression (Maintenance: cycles 7-36) *53 (14)9 (3)3 (1)AEs Leading to Death8 (2)7 (2)6 (2)

Summary of Adverse Events

*Most

discontinuations

veliparib

occurred

during

cycles

7-8; AE, adverse

event

VELIA/GOG-3005: Integration of veliparib (V) with front-line chemotherapy and maintenance in women with high-grade serous carcinoma of ovarian, fallopian tube, or primary peritoneal origin (HGSC)

Coleman RL et al.,

ESMO 2019, abstract LBA3 (oral presentation)

Slide87

Grade

All

rades

100

Veliparib-

oughout

Veliparib

-combo-

only

Control

Neutropenia

Nausea

Fatigue

Anemia

Peripheral

neuropathy

Thrombocytopenia

Alopecia

Constipation

Diarrhea

Vomiting

Leukopenia

Decreassed

appetite

Abdominal

pain

Insomnia

Headache

Hypomagnesemia

Combination phase (Cycles 1-6)

VELIA/GOG-3005: Integration of veliparib (V) with front-line chemotherapy and maintenance in women with high-grade serous carcinoma of ovarian, fallopian tube, or primary peritoneal origin (HGSC)

Coleman RL et al.,

ESMO 2019, abstract LBA3 (oral presentation)

Adverse Events

Slide88

100

Grade

All

rades

Neutropenia

Nausea

Fatigue

Anemia

Peripheral

neuropathy

Thrombocytopenia

Diarrhea

Abdominal

pain

Vomiting

Arthralgia

Veliparib-

oughout

Veliparib

-combo-

only

Control

VELIA/GOG-3005: Integration of veliparib (V) with front-line chemotherapy and maintenance in women with high-grade serous carcinoma of ovarian, fallopian tube, or primary peritoneal origin (HGSC)

Coleman RL et al.,

ESMO 2019, abstract LBA3 (oral presentation)

Maintenance phase (Cycles 7-36)

Adverse Events

Slide89

Veliparib added to chemotherapy and continued as maintenance significantly extended PFS in all patient cohorts with newly diagnosed high-grade serous ovarian carcinoma, regardless of biomarker, choice of surgery, or paclitaxel regimenReduction of hazard for recurrence or progression was 56% in patients with BRCA mutations, 43% in patients with HRD, and 32% in the ITT populationVeliparib given only during the chemotherapy cycles did not demonstrate increase in PFS, though numerically higher ORR was observed for both veliparib-containing armsVeliparib could be safely administered with carboplatin and paclitaxelPatients received a similar number of chemo cycles with veliparib as they did with placebo and relative dose intensity of carboplatin and paclitaxel were not significantly impacted by addition of veliparibAdverse events with veliparib were consistent with chemotherapy during combination phase and consistent with veliparib safety profile during maintenance phase

SUMMARY & CONCLUSIONS

VELIA/GOG-3005: Integration of veliparib (V) with front-line chemotherapy and maintenance in women with high-grade serous carcinoma of ovarian, fallopian tube, or primary peritoneal origin (HGSC)

Coleman RL et al.,

ESMO 2019, abstract LBA3 (oral presentation)

Slide90

LBA 1, LBA 2, LBA3

Diskussion der 3 Studien mit

PARP-Inhibitoren in der

Erstlininentherapie

des fortgeschrittenen Ovarialkarzinoms

Slide91

Tissue

test to segregate the population according to HRD - „MyCoice by Myriad“

*HR deficient tumors( HRD):HR Score ≤ 42 or a BRCAmut;HR proficient tumors( HRP/HRD neg):HR Score≤ 42Mansoor Mirza, ESMO 2019, Presidential Symposium 1 discussion

Homologous Recombination status

HRD- (34%)

HRD

unknown

(15%)

PRIMA

HRD- (34%)

HRD+

(48%)

BRCA

mut

(29%)

HRD

unknown

(18%)

PAOLA

PRIMA population

(100%)

HRD+

(51%)HRD- (34%)HRD unknown (15%)

BRCAmut (30%)BRCAwt (21%)

PAOLA

population

(100%)

HRD+ (48%)HRD- (34%)HRD unknown (18%)

BRCAmut (29%)BRCAwt (19%)

HRD+

(51%)

BRCA

mut

(30%)

Slide92

Comparative overview

Gonzalez, ESMO 2019; (2) Moore, NEJM 2018; (3) Ray-Coquard ESMO 2019; (4) Coleman ESMO 2019; (5) Burger NEJM 2011; (6) Perren NEJM 2011Mansoor Mirza, ESMO 2019, Presidential Symposium 1 discussion

PARPi & BEVACIZUMAB TRIALS IN FIRST-LINE

PRIMA

Niraparib

SOLO-1

Olaparib

PAOLA-1

Olaparib

VELIA

Veliparib

GOG-218

Bevacizumab

ICON7

Bevacizumab

Patients

, N

733

391

806

1873

1528

Stage

III: Visible

residual

disease

required

after

PDS

YES

Stage

IV:

Inoper

ble disease

YES

NACT

permitted

YES

BRCA

mut

ONLY

YES

Slide93

Hazard ratio of PFS

Gonzalez, ESMO 2019; (2) Moore, NEJM 2018; (3) Ray-Coquard ESMO 2019; (4) Coleman ESMO 2019; (5) Burger NEJM 2011; (6) Perren NEJM 2011Mansoor Mirza, ESMO 2019, Presidential Symposium 1 discussion

PARPi & BEVACIZUMAB TRIALS IN FIRST-LINE

PRIMA

Niraparib

SOLO-1

Olaparib

PAOLA-1

Olaparib

VELIA

Veliparib

GOG-218

Bevacizumab

ICON7

Bevacizumab

Patients

733

391

806

1140

1873

1528

Overall

popu

lati

0.62

0.59

0.68

0.73

0.87

deficient

BRCA

mut

0.40

0.30

0.31

0.44

0.95

deficient

BRCAwt

0.50

0.43

0.74

proficient

BRCA

0.68

0.92

0.81

0.71

Slide94

Die Integration

eines PARP-Inhibitors in die Erstlinientherapie von Patientinnen mit einem high-grade epithelialen Ovarialkarzinom führte in 3 Phase III-Studien unabhängig vom Mutationsstatus zu einer signifikanten Verbesserung der progressionsfreien Überlebens in der ITT-PopulationKlinisch relevant ist die Optimierung der Patientenselektion - die Selektion durch einen prädiktiven Biomarker erscheint sinnvoll, wenngleich zu diskutieren bleibt, ob mit dem HRD-Test bereits die besten Testmethode etabliert istDie drei Studien unterscheiden sich deutlich in ihrem Design und/oder Ein-/Ausschlusskriterien, daher sollten nicht die absoluten Überlebensdaten, sondern die jeweilige Hazard Ratio zur Orientierung herangezogen werdenDie simultane/kombinierte Anwendung von Veliparib zur Chemotherapie zeigte keine therapeutische Verbesserung, allerdings eine Zunahme der ToxizitätDie überzeugenden Daten aus den Phase III Studien werden die Hinzunahme eines PARP-Inhibitors in der Erstlinientherapie nicht nur bei BRCAm Tumoren erfordern. Dies ist als “practice changing” zu bezeichnen

Fazit der Experten

Slide95

K. Moore, A. Oza, N. Colombo, A. Oaknin, G. Scambia, D. Lorusso, R. Farias-Eisner, S. Banerjee, C. Murphy, J. Tanyi, H. Hirte, J. Konner, P. Lim, M. Prasad Hayes, B. Monk, S. Kim, J. Wang, P. Pautier, I. Vergote, M. Birrer

FORWARD I (GOG 3011): A Phase III study of

mirvetuximab

soravtansine

, a folate receptor alpha (

FRa

)-targeting antibody-drug conjugate (ADC),

versus chemotherapy in patients with

platinum-resistant ovarian cancer

(abstract 992O)

Slide96

Study background and methods

Mirvetuximab soravtansine (MIRV) is an antibody-drug conjugate comprising a folate receptor alpha (FRα)-binding antibody, cleavable linker, and the maytansinoid DM4, a potent tubulin-targeting agentFORWARD I is a phase III study evaluating the safety and efficacy of MIRV compared to chemotherapy in patients with platinum-resistant ovarian cancer (PROC)

Patients with PROC *were enrolled and randomized 2:1 to MIRV (6 mg/kg, adjusted ideal body weight) once every 21 days or investigators’ choice chemotherapy**The primary endpoint was progression-free survival (PFS) by blinded independent review committee, in both the intention-to-treat (ITT) population (medium & high FRα expression) and, separately, in patients with high FRαSecondary endpoints included objective response rate (ORR) and overall survival (OS). Median follow-up time was 12.5 months

FORWARD I (GOG 3011): A Phase III study of mirvetuximab soravtansine, a folate receptor alpha (FRa)-targeting antibody-drug conjugate (ADC), versus chemotherapy in patients (pts) with platinum-resistant ovarian cancer (PROC)Moore KN et al., ESMO 2019, abstract 992O (oral presentation)

* 1-3 prior lines of therapy, and FRα positivity by immunohistochemistry (stratified by predefined medium or high expression)

** paclitaxel, pegylated liposomal doxorubicin, or topotecan

Slide97

Incorporation

of PARPi and anti-angiogenic agents throughout the treatment course of ovarian cancer has contributed to the increasing prevalence of women living with their diseaseDespite these advances, most patients will eventually develop platinum resistant disease, with limited options characterized by poor efficacy and tolerabilityMirvetuximab soravtansine is an antibody–drug conjugate that targets folate receptor-α (FRα) to deliver the microtubule-disrupting agent DM4 directly to the tumorFORWARD I is a randomized Phase III study to compare the safety and efficacy of mirvetuximab soravtansine versus investigator’s choice chemotherapy in FRα-positive, platinum-resistant ovarian cancer (PROC)

BACKGROUND

Slide98

Platinum-resistant ovarian cancerFRα-positive tumor expressionMedium (50-74% cells positive)High (≥75% cells positive)ECOG performance status 0 or 11-3 prior therapies

Primary Endpoint

Progression-free survival (PFS; by BICR*) for ITT and high FRα populations

Secondary

Endpoints

Overall response rate (ORR) Overall survival (OS)Patient reported outcomes (PRO)

Paclitaxel: 80 mg/m2 weeklyPLD: 40 mg/m2 once every 4 weeksTopotecan: 4 mg/m2 on Days 1, 8, and 15every 4 weeks; or 1.25 mg/m2 on Days 1-5 every 3 weeks

Mirvetuximab Soravtansine (n=248)

Investigator’s Choice (IC)ChemotherapyPaclitaxel, PLD†, or Topotecan(n=118)

6 mg/kg (adjusted ideal body weight) once every 3 weeks2:1 RandomizationStratification Factors:FRα expression (medium or high) Prior therapies (1 and 2, or 3) Choice of chemotherapy

Statistical

Assumptions

Hochberg procedureα=0.05 (two-sided), power = 90% HR=0.58; control arm mPFS 3.5 mos

*BIRC, Blinded Independent Central;Review analyzed by Hochberg procedure†Pegylated liposomal doxorubicin; ClinicalTrials.gov Identifier: NCT02631876FORWARD I (GOG 3011): A Phase III study of mirvetuximab soravtansine, a folate receptor alpha (FRa)-targeting antibody-drug conjugate (ADC), versus chemotherapy in patients (pts) with platinum-resistant ovarian cancer (PROC)Moore KN et al., ESMO 2019, abstract 992O (oral presentation)

STUDY DESIGN

Slide99

Disease Characteristics

Stratification Factors

Mirvetuximab soravtansine (n=248)IC Chemo (n=118)FRα Status Medium42 %42 % High58 %58 %No. Prior Lines 1 or 265 %65 % 335 %35 %IC Chemotherapy Paclitaxel32 %31 % PLD44 %46 % Topotecan23 %23 %

Baseline Characteristics

Mirvetuximab

soravtansine

(n=248)

IC Chemo

(n=118)

Primary Diagnosis

Ovarian

83 %

89 %

Fallopian Tube

6 %

4 %

Primary Peritoneal

11 %

7 %

Histology

High Grade Serous

99 %

97 %

Other

1 %

3 %

ECOG

57 %

51 %

43 %

48 %

Prior Therapy

Bevacizumab

49 %

47 %

PARPi

11 %

10 %

Any

BRCA

Mutation

Yes

9 %

7 %

Platinum-Free Interval

0-3 months

39 %

38 %

3-6 months

57 %

58 %

≥

6 months

4 %

Slide100

*Five and nine patients randomized into the mirvetuximab soravtansine and chemotherapy arms, respectively, did not receive any allocated intervention and were not included in the safety analysesFORWARD I (GOG 3011): A Phase III study of mirvetuximab soravtansine, a folate receptor alpha (FRa)-targeting antibody-drug conjugate (ADC), versus chemotherapy in patients (pts) with platinum-resistant ovarian cancer (PROC)Moore KN et al., ESMO 2019, abstract 992O (oral presentation)

SAFETY SUMMARY

Mirvetuximab

soravtansine

(n=243*)

IC Chemotherapy

(n=109*)

Any TEAE

>99%

98%

Grade 3+ TEAEs

46%

61%

SAEs

28%

Deaths on study drug or within 30 days of last dose

Dose reductions due to related TEAEs

20%

30%

Dose delays due to related TEAEs

29%

28%

Discontinuations due to related TEAEs

Slide101

Mirvetuximab soravtansine has a different safety profile

*Grade 2+ peripheral neuropathy events were observed in 12% and 28% of patients that received mirvetuximab soravtansine or paclitaxel, respectively.FORWARD I (GOG 3011): A Phase III study of mirvetuximab soravtansine, a folate receptor alpha (FRa)-targeting antibody-drug conjugate (ADC), versus chemotherapy in patients (pts) with platinum-resistant ovarian cancer (PROC)Moore KN et al., ESMO 2019, abstract 992O (oral presentation)

MOST COMMON TEAEs (> 20%)

Mirvetuximab

Chemotherapy

Grade

All

Hematologic

General

Gastrointestinal

Ocular

Mirv

Pac

PLD

Topo

Mirv

Pac

PLD

Topo

Mirv

Pac

PLD

Topo

Mirv

Pac

PLD

Topo

Mirv

Pac

PLD

Topo

Mirv

Pac

PLD

Topo

Mirv

Pac

PLD

Topo

Mirv

Pac

PLD

Topo

Mirv

Pac

PLD

Topo

Mirv

Pac

PLD

Topo

Mirv

Pac

PLD

Topo

Neutropenia

Anemia

Thromobocytopenia

Peripheral

Neuropathy

Alopecia

Diarrhea

Nausea

Stomatitis

Blurred

Vision

Keratopathy

Dry Eye

Slide102

ITT Population

FR High Population

*Nominal p-value^Not significant based on Hochberg Procedure†≥15-point improvement in the EORTC QLQ-OV28 Abdominal/GI Symptom SubscaleUnless otherwise noted, data cut January 2019FR, folate receptor; mPFS, median progression-free survival; mOS, median overall survivalFORWARD I (GOG 3011): A Phase III study of mirvetuximab soravtansine, a folate receptor alpha (FRa)-targeting antibody-drug conjugate (ADC), versus chemotherapy in patients (pts) with platinum-resistant ovarian cancer (PROC)Moore KN et al., ESMO 2019, abstract 992O (oral presentation)

EndpointTreatment effect size[Mirv (n=248) vs IC Chemo (n=118)]P value*PFS by BICR(months)HR: 0.981 (0.734, 1.310)mPFS: 4.1 vs 4.40.897^ORR by BICR95% Cis22% vs 12%(17%, 28%) vs (7%, 19%)0.015OS (August 2019)HR: 0.846 (0.625, 1.145)mOS: 15.6 vs 13.90.278PRO†32% vs 14%0.011

EndpointTreatment effect size[Mirv (n=147) vs IC Chemo (n=71)]P value*PFS by BICR(months)HR: 0.693 (0.480, 1.000)mPFS: 4.8 vs 3.30.049^ORR by BICR95% CIs24% vs 10%(17%, 32%) vs (4%, 19%)0.014OS (August 2019)HR: 0.678 (0.460, 0.999)mOS: 16.4 vs 12.00.048PRO†28% vs 13%0.096

EFFICACY RESULTS

Slide103

PS2+ Scoring Positive: ≥ 50% of tumor cells with FR membrane staining with ≥ 2+ intensity

intensity

intensity 3+ intensity

10X Scoring Positive: ≥ 50% of tumor cells with FRα membrane staining visible at 10X microscope objective

PS2+ Scoring

In all prior studies, PS2+ scoring was used to assess FR expressionEligibility determined by staining intensity and percentage of tumor cells staining at 0, 1+, 2+, or 3+

10X Scoring

In FORWARD I, a simplified scoring method to assess FR expression was implementedEligibility was determined by scoring just the percentage of cells with membrane staining by ≤10X magnification, without regard to intensity

FR, folate receptor FORWARD I (GOG 3011): A Phase III study of mirvetuximab soravtansine, a folate receptor alpha (FRa)-targeting antibody-drug conjugate (ADC), versus chemotherapy in patients (pts) with platinum-resistant ovarian cancer (PROC)Moore KN et al., ESMO 2019, abstract 992O (oral presentation)

FR SCORING IN THE MIRV. SORAVTANSINE PROGRAM

Bridging

study

indicated

that

10X

scoring

was

sufficient

for patient

selection

Exploratory

analyses

suggest

that

the

change

scoring

method

from PS2+ to 10X

introduced

population

patients

into FORWARD I with

lower

levels

of FR

expression

than

intended

Slide104

FRα expression below intended inclusion cut-off

Intended FRα expression (medium/high)

FORWARD I 10x scoring vs exploratory PS2+ scoring

Rescoring

of the FORWARD I

samples

using

PS2+

indicates

:34% of patients enrolled in FORWARD I had low FRα levels that should have precluded enrollment; andThe protocol defined FRα high subset contained patients with a mixture of FRα expression levels

FR, folate receptorFORWARD I (GOG 3011): A Phase III study of mirvetuximab soravtansine, a folate receptor alpha (FRa)-targeting antibody-drug conjugate (ADC), versus chemotherapy in patients (pts) with platinum-resistant ovarian cancer (PROC)Moore KN et al., ESMO 2019, abstract 992O (oral presentation)

Scoring comparison

Slide105

Efficacy

Parameter/PS2+ Level

Hazard Ratio

P Value

HR: 0.549 P=0.015mPFS: 5.6 vs 3.2 months

PFS Hazard Ratio Plot

PFS (by BICR) - FRα High (n=116)

mPFS, median progression-free survival; P values from unstratified log-rank test; BICR, blinded independent central reviewFORWARD I (GOG 3011): A Phase III study of mirvetuximab soravtansine, a folate receptor alpha (FRα)-targeting antibody-drug conjugate (ADC), versus chemotherapy in patients (pts) with platinum-resistant ovarian cancer (PROC)Moore KN et al., ESMO 2019, abstract 992O (oral presentation)

0.2

0.5

1.0

1.5

2.0

2.5

Mirvetuximab

better

CI Chemo

better

0.545

50%

0.343

Medium

0.037

Hight

PFS (INV)

0.143

50%

0.954

Medium

0.015

High

PFS (BICR)

1.0

0.8

0.6

0.4

0.2

0.0

Survival

Probability

No. at

risk

Mirvetuximab

IC Chemo

Time in months

PS2+ RE-SCORING: PFS TRENDS ACROSS SUBGROUPS

Mirvetuximab

Chemotherapy

Slide106

HR: 0.678 (0.410, 1.119) P=0.126mOS: 16.4 vs 11.4 months

Overall survival in FR high (n=116)

mOS; median overall survivalFORWARD I (GOG 3011): A Phase III study of mirvetuximab soravtansine, a folate receptor alpha (FRa)-targeting antibody-drug conjugate (ADC), versus chemotherapy in patients (pts) with platinum-resistant ovarian cancer (PROC)Moore KN et al., ESMO 2019, abstract 992O (oral presentation)

PS2+ RE-SCORING

1.0

0.8

0.6

0.4

0.2

0.0

Survival

Probability

Time in months

Mirvetuximab

IC Chemo

No. al

risk

Mirvetuximab

Chemotherapy

Slide107

EndpointFRα < 50% (n=114)(Mirv vs IC Chemo)FRα Medium (n=103)(Mirv vs IC Chemo)FRα High (n=116)(Mirv vs IC Chemo)PFS by BICR(mo.)HR: 1.458 (0.878, 2.420)mPFS: 3.8 vs 5.5HR: 1.015 (0.611, 1.687)mPFS: 4.3 vs 5.6HR: 0.549 (0.336, 0.897)mPFS: 5.6 vs 3.2ORR by BICR95% CIs16% vs 16%(8%, 26%) vs (6%, 31%)28% vs 18%(18%, 40%) vs (7%, 35%)29% vs 6%(20%, 40%) vs (1%, 20%)OS (August 2019) (months)HR: 0.923 (0.548, 1.554)mOS: 14.0 vs 13.4HR: 0.936 (0.542, 1.616)mOS: 15.9 vs 20.7HR: 0.678 (0.410, 1.119)mOS: 16.4 vs 11.4PFS by INV(months)HR: 1.149 (0.732, 1.803)mPFS: 4.0 vs 4.5HR: 0.810 (0.523, 1.254)mPFS: 5.1 vs 2.8HR: 0.619 (0.394, 0.975)mPFS: 5.6 vs 3.7ORR by INV95% CIs18% vs 21%(11%, 29%) vs (10%, 37%)36% vs 24%(25%, 49%) vs (11%, 41%)38% vs 9%(27%, 49%) vs (2%, 24%)

Trends across subgroups

BICR; blinded independent central review; OS, overall survival; PFS, progression-free survivalFORWARD I (GOG 3011): A Phase III study of mirvetuximab soravtansine, a folate receptor alpha (FRa)-targeting antibody-drug conjugate (ADC), versus chemotherapy in patients (pts) with platinum-resistant ovarian cancer (PROC)Moore KN et al., ESMO 2019, abstract 992O (oral presentation)

PS2+ RE-SCORING

Slide108

Next phase 3 registration trial for mirvetuximab soravtansine using PS2+scoring in FRα-high patients

BICR; blinded independent central review; PLD; pegylated liposomal doxorubicinFORWARD I (GOG 3011): A Phase III study of mirvetuximab soravtansine, a folate receptor alpha (FRa)-targeting antibody-drug conjugate (ADC), versus chemotherapy in patients (pts) with platinum-resistant ovarian cancer (PROC)Moore KN et al., ESMO 2019, abstract 992O (oral presentation)

Data support the initiation of the MIRASOL STUDY

430 patients/330 events for PFS by INVPlatinum resistant disease (<6 months PFI)Prior Bev and PARP allowedBRCAmut patients allowed

Primary Endpoint

Progression-free survival by INVBICR* for sensitivity analysis

Secondary

Endpoints

Overall response rate by INVOverall survivalPatient reported outcomes

Paclitaxel: 80 mg/m2 weeklyPLD: 40 mg/m2 once every 4 weeksTopotecan: 4 mg/m2 on Days 1, 8, and 15every 4 weeks; or 1.25 mg/m2 on Days 1-5 every 3 weeks

Mirvetuximab Soravtansine

Investigator’s Choice (IC)ChemotherapyPaclitaxel, PLD†, or Topotecan

6 mg/kg (adjusted ideal body weight) once every 3 weeks1:1 RandomizationStratification Factors:STRATIFICATION FACTORSIC Chemotherapy Choice(Paclitaxel, PLD, Topotecan)Prior therapies (1 vs 2 vs 3)

Statistical

Assumptions

α=0.05 (two-sided), Power = 90%,HR=0.7; control arm mPFS 3.5 mo

Enrollment

and Key Eligibility

Slide109

FORWARD I did not meet the PFS primary endpoint in the ITT or folate receptor (FR) high populationsIn the FR high population (by 10X scoring), consistent efficacy signals were observed with mirvetuximab soravtansineMirvetuximab soravtansine was well tolerated with a differentiated safety profile: fewer grade 3+ adverse events, fewer drug-related dose reductions/discontinuations, but more patients with improved abdominal/GI symptoms compared to chemotherapyExploratory analyses suggest that the change in scoring method from PS2+ to 10X introduced a population of patients into FORWARD I with lower levels of FRα expression than intendedRe-analysis of the FR high population (by PS2+ scoring) demonstrates improved outcomes correlated with FRα expression, with the strongest treatment effects for all efficacy endpoints in this populationData presented support the design of MIRASOL, the next phase III trial in PS2+ high FR patients, which is expected to begin by end of 2019

SUMMARY & CONCLUSIONS

Slide110

A. Oaknin, K. Moore, N. Colombo, G. Scambia, B.-G. Kim, M. Friedlander, A. Lisyanskaya, A. Floquet, A. Leary, G. Sonke, C. Gourley, S. Banerjee, A. Oza, A. González-Martín, C. Aghajanian, W. Bradley, E. Lowe, R. Bloomfield, P. Disilvestro

Time to second progression (PFS2) and second subsequent therapy (TSST) for patients with newly diagnosed, advanced ovarian cancer and a

BRCA

mutation (

BRCA

) treated with

maintenance

olaparib

– Phase III SOLO1 trial

(abstract 995PD)

Slide111

Study background and methods

SOLO1* patients with newly diagnosed, advanced OC and a BRCA mutation treated with maintenance olaparib had a substantial progression-free survival benefit vs placebo (HR 0.30 [95% CI 0.23–0.41], P < 0.001)1 The impact of first line use of PARP inhibitors on subsequent therapy is of clinical interest Secondary objectives included PFS2 and TSST, which indicate the effect of treatment beyond first progression

Patients were randomized 2:1 to olaparib 300 mg bid or placebo for up to 2 years or until disease progression. After first progression, PFS2 was assessed every 12 weeks (radiological, CA125 or clinical progression)

1. Moore et al. NEJM 2018Time to second progression (PFS2) and second subsequent therapy (TSST) for patients with newly diagnosed, advanced ovarian cancer (OC) and a BRCA mutation (BRCAm) treated with maintenance olaparib – Phase III SOLO1 trialOaknin A et al., ESMO 2019, abstract 995PD (poster discussion presentation)

* NCT01844986; GOG-3004

PFS2, progression-free survival 2

TSST,

time to

second

subsequent therapy

Slide112

Time to second progression (PFS2) and second subsequent therapy (TSST) for patients with newly diagnosed, advanced ovarian cancer (OC) and a BRCA mutation (BRCAm) treated with maintenance olaparib – Phase III SOLO1 trialOaknin A et al., ESMO 2019, abstract 995PD (poster discussion presentation)

SOLO1 study design

Olaparib 300 mg bid (n=260)

Placebo(n=131)

Study treatment continued until disease progressionPatients with no evidence of disease at 2 years stopped treatmentPatients with an ongoing partial response at2 years could continuetreatment

2:1 randomizationStratified by response to platinum- based chemotherapy

Rationale for this analysis: PFS2 and TSST are recommended by the EMA and GCIG ovarian cancer consensus guidelines to reflect treatment effect beyond first progression; impact of first-line use of PARPi on response to subsequent therapy is of clinical interest and should be evaluated.

Newly

diagnosed,

FIGO

stage III–IV, high-grade serous or endometrioid ovarian, primary peritoneal or fallopian tube cancerGermline or somatic BRCAmECOG performance status 0-1Cytoreductive surgeryIn clinical complete response or partial response after platinum-based chemotherapy

Primary endpointInvestigator-assessed PFS (modified RECIST 1.1)

Secondary endpointsPFS using BICRPFS2Overall survivalTime from randomization to first subsequent therapy or deathTime from randomizationto second subsequent therapy or death (TSST)HRQoL (FACT-O TOI score)

years’ treatment if no evidence of

disease

Slide113

Methods: After first progression, PFS2 was assessed every 12 weeks and based on radiological, CA-125 or clinical evidence ofprogression; PFS2 and TSST were analysed at the time of data cut-off for the primary analysis (17 May 2018)

PFS2 and tsst

Time

from randomization

(months)

Proportion

of patients

event-free

0.0

0.1

0.2

0.3

0.4

0.5

0.6

0.7

0.8

0.9

1.0

Olaparib

300

bid

Placebo

bid

Number at

risk

Olaparib 300 mg bid

260

246

239

231

229

225

216

204

194

177

168

163

140

111

Placebo bid

131

126

122

113

108

100

Time

from randomization

(months)

Proportion

of patients

event-free

0.0

0.1

0.2

0.3

0.4

0.5

0.6

0.7

0.8

0.9

1.0

Olaparib

300

bid

Placebo

bid

Number at

risk

Olaparib 300 mg bid

260

251

245

241

238

234

226

215

203

192

186

178

171

143

Placebo bid

131

129

126

120

117

109

100

PFS2:

50%

lower

risk

second

progression or death in the

olaparib

group

than

in the

placebo

group

(HR 0.50, 95% CI 0.35, 0.72; p=0.0002)

TSST:

HR for the

use

of a

second

subsequent therapy or death for

olaparib

versus

placebo

was 0.45 (95% CI 0.32, 0.63)

Conclusion:

Maintenance

olaparib

in newly diagnosed ovarian cancer increases both PFS2 and TSST versus placebo,

with patients receiving maintenance

olaparib

in the first-line setting continuing to derive benefit beyond first progression.

36%

Data

maturity

31%

Data

maturity

Slide114

PD, progressive diseaseTime to second progression (PFS2) and second subsequent therapy (TSST) for patients with newly diagnosed, advanced ovarian cancer (OC) and a BRCA mutation (BRCAm) treated with maintenance olaparib – Phase III SOLO1 trialOaknin A et al., ESMO 2019, abstract 995PD (poster discussion presentation)

Subsequent therapies in patients with PD

Of 198 patients with progression, 91/102 in the olaparib arm and 94/96 in the placebo arm had any subsequent therapy or therapies

Most common subsequent therapies, n (%)Olaparib(n=91)Placebo(n=94)Platinum-based chemotherapy58 (64)50 (53)Platinum with bevacizumab22 (24)15 (16)PARPi, including platinum followed by PARPi20 (22)49 (52)Non-platinum chemotherapy (excluding regimens with Bev)35 (38)26 (28)

Olaparib arm10/91 (11%) patients received a PARPi as their first subsequent therapy (n=1 monotherapy; n=9 maintenance therapy following platinum-based chemotherapy)3 had progression for a second time; the remaining patients were on treatment at data cut-off

Placebo arm

49/94

patients received subsequent

PARPi

therapy

(35%) patients received

PARPi

(including

olaparib

)

as their

first subsequent

therapy

(47%) patients

had

olaparib

as any

subsequent

therapy

Slide115

Maintenance olaparib in newly diagnosed ovarian cancer patients with a BRCA-mutation increases both PFS-2 and time to 2nd subsequent therapy (TSST) vs. placeboOlaparib provided benefit beyond first progression, with a statistically significant and clinically meaningful 50% reduction in the risk of PFS-2The delay in TSST was clinically meaningful and consistent with the benefit observed in the analysis of PFS-2These results suggest that olaparib does not diminish patients’ ability to receive and respond to subsequent therapy. This benefit was observed despite a higher proportion of patients in the placebo group receiving a PARP inhibitor as subsequent therapy, which may potentially explain the median PFS-2 of 42 months seen in this arm

SUMMARY & CONCLUSIONS

Slide116

F. Tinquaut, G. Freyer, F. Pommeret, L. Gladieff, D. Lorusso, M.A. Mouret Reynier, V. D'Hondt, D. Mollon-Grange, A. Floquet, S. Abadie Lacourtoisie, P.E. Brachet, L. Stefani, F. Rousseau, J.-S. Frenel, F. Del Piano, J. Herrstedt, T. Warkus, O. Tredan, E. Pujade-Lauraine, C. Falandry

Validation of the Geriatric Vulnerability Score (GVS)

in older ovarian cancer patients: an analysis from the GCIG-ENGOT-GINECO EWOC-1 study

(abstract 997PD)

Slide117

Study background and methods

The geriatric vulnerability score (GVS) was previously developed to identify geriatric vulnerability in older ovarian cancer (oOC) patients (Falandry, 2013)The derivation cohort was EWOT-3 database of 111 oOC patients treated with 1st line carboplatin. The GVS combines albumin (≥ or < 35g/l), lymphocyte (< or ≥ 1x109/L) levels, and activities of daily living (ADL; ≥ or < 6), Instrumental ADL (≥ or < 25), HADS (< or ≥ 14) scoresWith a cut-off ≥3, GVS delineated a population with significantly decreased OS (HR(95%CI)=2.94 (1.79–4.84), P <.0001). EWOC-1 international study included an external validation of the GVS as a secondary endpoint

Patients ≥70 years diagnosed with FIGO stage III/IV epithelial OC and no organ failure were screened for GVS. Those with GVS≥3 were proposed EWOC-1 randomized trial, evaluating 3 treatment regimens in the vulnerable patients. Other patients’ data were collected in the “EWOC-1 registry”. External validation of GVS was performed in the whole population (V1), in the EWOC-1 registry subgroup (V2), and in the subgroup of patients treated with carboplatin paclitaxel regimens (V3). Cross-validation analyses (calibration, discrimination, and performance analysis) were performed according current recommendations (Steyerber, 2014).

Validation of the Geriatric Vulnerability Score (GVS) in older ovarian cancer (oOC) patients: an analysis from the GCIG-ENGOT-GINECO EWOC-1 studyTinquaut F et al., ESMO 2019, abstract 997PD (poster discussion presentation)

OS,

overall survival

Slide118

Gineco has developed a geriatric vulneability score to discriminate vulnerable from fit older patients1

1. Falandry et al. Annals Oncol 2013.Validation of the Geriatric Vulnerability Score (GVS) in older ovarian cancer (oOC) patients: an analysis from the GCIG-ENGOT-GINECO EWOC-1 studyTinquaut F et al., ESMO 2019, abstract 997PD (poster discussion presentation)

geriatric vulneability score (gvs)

GVS ≥ 3 defines vulnerable older patients (≥ 70 years old)

Need for a prospective external validation of GVS score on a larger cohort, in patients treated with the current standard of care (carboplatin paclitaxel association)

Derivation cohort

GVS

items

EWOT3

study

111

pts

≥ 70

treated

with carboplatin

monotherapy

France, 08/2007 – 01/2010

Activity

of Daily Living (ADL-Katz) score < 6

Instrumental

Activities

of Daily Living (IADL-

Lawton

) score < 25

Hospital

Anxiety

and Depression score (HADS) > 14

Albuminemia

< 35g/L

Lymphocyte

count

< 1G/L

Slide119

Results

of EWOC-1

randomized trial presented at ASCO 20191

3 GVS validation cohortsV1Total population: EWOC-1 trial + EWOC-1 registryV2EWOC-1 registry onlyV3Carboplatin-Paclitaxel treated patients

1. Falandry et al. EWOC-1: A randomised trial to evaluate the feasibility of three different first-line chemotherapy regimens for vulnerable elderly women with ovarian cancer (OC): A GCIG-ENGOT-GINECO study. ASCO oral presentation 2019.Validation of the Geriatric Vulnerability Score (GVS) in older ovarian cancer (oOC) patients: an analysis from the GCIG-ENGOT-GINECO EWOC-1 studyTinquaut F et al., ESMO 2019, abstract 997PD (poster discussion presentation)

EWOC-1 study: a 2-steps design

GVS ≥ 3

Eligible

for EWOC-1

trial

Other case

EWOC-1 registry

Eligibility criteria

Arm A: 3-weekly carboplatin-paclitaxel

Arm C: weekly carboplatin-paclitaxel

Arm-B: 3-weekly carboplatin

Informed consent for GVS assessment

Informed

consent

for GVS

assessment

Slide120

Overall survival By GVS Score (V1)

1.0

0.0

Survival

probability

Time in months

0.8

0.6

0.4

0.2

GVS = 0

GVS = 1

GVS = 2

GVS = 3

GVS = 4

GVS = 5

Results

New

aspects

from the additional

EWOC-1

analyses

Proper patient assessment important in clinical trials

Age alone cannot classify elderly ovarian cancer patients regarding vulnerability

GVS can provide a reproducible and robust prediction model of vulnerability in this context

Slide121

The geriatric vulnerability score (GVS) provides a reproducible and robust prediction model of vulnerability in older and often frail ovarian cancer patientsFindings were independent of geographic and historic effect (V1), as well as treatment patterns (V3), and validated on an international population

SUMMARY & CONCLUSIONS

Slide122

Y. Drew, B. Kaufman, S. Banerjee, A. Lortholary, S.H. Hong, Y.H. Park, S. Zimmermann, P. Roxburgh, M. Ferguson, R.H. Alvarez, S. Domchek, C. Gresty, H.K. Angell, V. Rocher Ros, K. Meyer, M. Lanasa, P. Herbolsheimer, M. De Jonge

Phase II study of

olaparib

durvalumab

(MEDIOLA): Updated results in germline

BRCA

-mutated

platinum-sensitive relapsed (PSR) ovarian cancer

(abstract 1190PD)

Slide123

Study background and methods

Olaparib is PARP inhibitor approved as maintenance treatment of platinum sensitive ovarian cancer (PSROC). MEDIOLA assessed olaparib in combination with the anti-PD-L1 antibody durvalumab in patients with germline BRCA1 and/or BRCA2 mutated PSROC* The 12-week disease control rate (DCR) = complete response [CR] + partial response + stable disease was presented at SGO 2018**

Patients had PSROC, gBRCA1/2 mutation, and had received at least one prior line of platinum. Patients received olaparib 300 mg BID for a 4-week run-in, then olaparib 300 mg BID and durvalumab 1.5 g IV q 4 weeks until progressive diseaseTumours were assessed‡ at baseline, 4 weeks, then every 8 weeksPrimary endpoints were 12week DCR and safety. Secondary endpoints were 28-week DCR, objective response rate (ORR), duration of response (DoR), progression-free survival (PFS), overall survival (OS), and biomarker analyses

Phase II study of olaparib + durvalumab (MEDIOLA): Updated results in germline BRCA-mutated platinum-sensitive relapsed (PSR) ovarian cancer (OC)Drew Y et al., ESMO 2019, abstract 1190PD (poster discussion presentation)

* NCT02734004

** SGO 2018 late-breaker abst. 4

‡

by RECIST 1.1

Slide124

Study design

bid, twice daily; PARP, poly(ADP-ribose) polymerase; PD-L1, programmed cell death ligand 1; ClinicalTrials.gov identifier: NCT02734004Phase II study of olaparib + durvalumab (MEDIOLA): Updated results in germline BRCA-mutated platinum-sensitive relapsed (PSR) ovarian cancer (OC)Drew Y et al., ESMO 2019, abstract 1190PD (poster discussion presentation)

MEDIOLA BRCAm ovarian cohort

N=34*Platinum-sensitive relapsed ovarian cancer†Germline mutation in BRCA1 or BRCA2≥1 previous platinum-based therapyPARP inhibitor and immunotherapy naive

*34 patients were assessed for safety; 32 patients were assessed for efficacy†Relapsed ≥ 24 weeks after administration of last platinum treatment

then

Olaparib 300 mg bid PO plusdurvalumab IV 1.5 g every4 weeks

Treatment until disease progression or intolerable toxicity

MEDIOLA is a multi-cohort, phase I/II studyThe design of the BRCAm ovarian cohort is presented below; other ovarian cancer cohorts are ongoing

Primary endpointDisease control rate at 12 weeksSafety and tolerability

Secondary endpointsDisease control rate at 28 weeksObjective response rateDuration of responseProgression-free survivalOverall survivalPD-L1 expression in tumour samples

Olaparib

monotherapy

300 mg bid PO for 4 weeks

Slide125

DCR, disease control rate; mPFS, median progression-free survival; ORR, objective response ratePhase II study of olaparib + durvalumab (MEDIOLA): Updated results in germline BRCA-mutated platinum-sensitive relapsed (PSR) ovarian cancer (OC)Drew Y et al., ESMO 2019, abstract 1190PD (poster discussion presentation)

MEDIOLA BRCAm ovarian cohort - Efficacy

DCR at 12 weeks: 81.3%(90% CI 66.3, 91.5)

Unconfirmed ORR: 71.9%(95% CI 53.3, 86.3)

DCR at 28 weeks: 65.6%(90% CI 49.6, 79.4)

Greater clinical activity was seen in earlier- versus later-line patients

mPFS: 11.1 months(95% CI 8.2, 15.6)

Best change (%)

Best percentage change in target lesion size†Number of prior lines of chemotherapy:1 prior line 2 prior lines ≥3 prior lines

100

Time to

progression

treatment

discontinuation

Number

of prior

lines

SD PD

Treatment discontinued

due

to clinical progression

Treatment discontinued

due

Treatment discontinued

due

to patient

decision

Treatment discontinued

because of

Last known

date

alive On

treatment

Death

-20

-30

-40

-50

-60

-70

-80

-90

-100

Slide126

AE, adverse eventPhase II study of olaparib + durvalumab (MEDIOLA): Updated results in germline BRCA-mutated platinum-sensitive relapsed (PSR) ovarian cancer (OC)Drew Y et al., ESMO 2019, abstract 1190PD (poster discussion presentation)

MEDiola BRCAm ovarian cohort - Safety

Patients(n=34)Grade ≥ 3 AEs, n(%)20 (58.8)Aneamia6 (17.6)Lipase increased4 (11.8)Neutropenia3 (8.8)Amylase increased3 (8.8)Lymphocyte count decreased3 (8.8)Hyponatraemia2 (5.9)Neutralgia2 (5.9)Fatigue2 (5.9)

Patients(n=34)Immune-mediated AEs, n(%)17 (50.0)Hypothyroidism5 (14.7)Rash4 (11.8)Adrenal insufficiency2 (5.9)Hyperthyroidism2 (5.9)Dyspnoea2 (5.9)Myalgia2 (5.9)Lipase increased2 (5.9)

9 patients (26.5%) had a serious AE. 14 (41.2%) had an

olaparib

dose reduction caused by an AE, 19 (55.9%) had an

olaparib

dose

interruption

caused by an AE, and 7 (20.6%) had a

durvalumab

dose

delay

due

an AE. Six

patients

(17.6%)

discontinued

study treatment

because

AE.

Slide127

Combination of olaparib and durvalumab continues to show promising activityCombination of olaparib and durvalumab continues to be well toleratedOne additional year of follow-up, one patient discontinued treatment due to an AEHighlights the importance of currently ongoing trials with different combination therapies

SUMMARY & CONCLUSIONS

Slide128

J. Grabowski, J. Glajzer, E.I. Braicu, J. Sehouli

Niraparib initial dose and its’ management in patients with recurrent high-grade serous ovarian cancer

(abstract 1006P)

Slide129

Study background and methods

PARP inhibitor niraparib is indicated as maintenance therapy in patients with relapsed, platinum sensitive high-grade serous ovarian cancerThe initial dose, especially after presentation of RADAR analysis remains a subject of discussionThe aim of this study was to evaluate the initial dose management

All subsequent patients who started niraparib maintenance therapy were eligible to be included in this analysisData collection included body weight of patients, the initial dose and its modifications within the therapy period

Niraparib initial dose and its’ management in patients with recurrent high-grade serous ovarian cancer

Grabowski J et al.,

ESMO 2019, abstract 1006P (poster presentation)

Slide130

nPrior to RADARAfter RADARPatient number722052Age (Median)65 (27 – 82 y.o.)65 (49 – 81 y.o.)65 (27 – 82 y.o.)Baseline weight<57kg57-77kg>77 kg23 (31.9%)41 (56.9%)8 (11.2%)7 (35%)11 (55%)2 (10%)16 (30.8%)30 (57.7%)6 (11.5%)Baseline platelets count100-150> 15014 (26.9%)58 (73.1%)5 (25%)15 (75%)9 (17.3%)43 (82.7%)Therapy-line2nd≥3rd40 (55.6%)32 (44.3%)9 (45%)11 (55%)31 (59.6%)21 (40.4%)

Niraparib initial dose and its’ management in patients with recurrent high-grade serous ovarian cancerGrabowski J et al., ESMO 2019, abstract 1006P (poster presentation)

Patients characteristics

Slide131

Initial niraparib dose prior and after RADAR analysis publication

Niraparib dose reduction within first three cycles in subgroups prior and after RADAR Analysis publication

Niraparib initial dose and its’ management in patients with recurrent high-grade serous ovarian cancerGrabowski J et al., ESMO 2019, abstract 1006P (poster presentation)

Patients characteristics

Slide132

Niraparib initial dose and its’ management in patients with recurrent high-grade serous ovarian cancerGrabowski J et al., ESMO 2019, abstract 1006P (poster presentation)

The present study is the first analysis on niraparib initial dose managementDose adjustment of niraparib according to RADAR analysis data resulted in more frequent 200mg application from the beginning of the therapyMoreover, significantly less patients needed dose adjustment in the first three months of the therapyThe initial dose reduction seems to be a reasonable and well tolerated option in patients who are going to start niraparib maintenance therapyFurther potential factors influencing dose tolerability should be investigated in prospective multicenter trials

SUMMARY & CONCLUSIONS

Slide133

J. Sehouli, F. Hilpert, M. Welslau, J. Grabowski , J. Seitz, A. El-Balat, A. Hartkopf, R. Glowik, F. Marmé

Results of the 3rd interim analysis of C-Patrol:

A non-interventional study on

olaparib

German routine clinical practice

(abstract 1007P)

Slide134

Study background and methods

Olaparib (50 mg hard capsules, HC) was the first PARP inhibitor approved in the EU in 12/2014 as monotherapy for maintenance treatment of patients with platinum-sensitive relapsed BRCA-mutated ovarian cancer (PSR-OC) who are in response to platinum-based chemotherapy. In 05/2018, film-coated tablets of olaparib (FT, 100/150 mg) were approved in 05/2018 regardless of BRCA statusThe present study reports for the first time data on real-world olaparib treatment from patients who switched from HC to FT

The German prospective non-interventional study C-PATROL* collects routine clinical and patient-reported outcome data in BRCA-mutated PSR-OC patients treated according to label with olaparib with the recommended total daily dose of 800 mg (HC) or 600 mg (FT)The 3rd interim analysis‡ for patients treated with olaparib (HC/FT) reflects data on patient characteristics and safety by using descriptive statistics focussing on “switcher” (here patients can be treated with FT since 08/2018)

Results of the 3rd interim analysis of C-Patrol: A non-interventional study on olaparib in German routine clinical practiceSehouli J et al., ESMO 2019, abstract 1007P (poster presentation)

*NCT02503436

‡

cut-off: 1

April 2019

Slide135

NIS, non-interventional study

Results of the 3rd interim analysis of C-Patrol: A non-interventional study on

olaparib in German routine clinical practiceSehouli J et al., ESMO 2019, abstract 1007P (poster presentation)

Overall study design

Patients with platinum-sensitive relapsed BRCA-mutated (germline and / or somatic) high grade epithelial ovarian, fallopian tube, or primary peritoneal cancer*

Decision to initiate olaparib treatment by the treating physician

Prior to NIS inclusion

Inclusion of patients until 14 days after treatment initiation with olaparib

Treatment with OLAPARIB

Follow-up and documentation until end of study**

NIS Phase

C ● PATROL

*at least 2 prior lines of platinum-based chemotherapy and documented platinum-sensitivity

**Last

Subject

Last

Visit

(LSLV), death or

other

reason

for

study

discontinuation

Slide136

Patient distribution

Reasons for olaparib discontinuation (n=147*)

FT, film-coated tablets; HC, hard capsules

Results of the 3rd interim analysis of C-Patrol: A non-interventional study on olaparib in German routine clinical practiceSehouli J et al., ESMO 2019, abstract 1007P (poster presentation)

Patient distribution

28 (11%)

FT group

177 (69%)HC group

264 patients registered until data cut-off (April 1st, 2019)

47 (18%)Switcher group

255 patients with a documented start of olaparib therapy*

108 patients (42%) on olaparib treatment at data cut-off**

22 (79%)FT group

41 (23%)HC group

42 (89%)Switcher group

HC group: patients who received solely olaparib hard capsules; FT group: patients who started therapy with olaparib film-coated tablets; Switcher group: patients who switched from olaparib hard capsules to olaparib film-coated tablets. *Three patients have switched the formulation multiple times. This subgroup of patients is not further described. **147 patients (58%) have discontinued treatment.

*147 of a total of 255

patients

have

discontinued

olaparib

treatment. Other

reasons

include

death (n=2), withdrawal of

informed

consent (n=3),

missing

(n=2) and

other

(n=3). 5

patients

of the

switcher

group

have

discontinued

, all due to progression. 6

patients

of FT

group

have

discontinued

, due to progression (n=4), non-

hematological

tox

. (n=1) and

other

(n=1).

Slide137

AE, adverse event; FT, film-coated tablets; HC, hard capsulesResults of the 3rd interim analysis of C-Patrol: A non-interventional study on olaparib in German routine clinical practiceSehouli J et al., ESMO 2019, abstract 1007P (poster presentation)

Patient distribution

Switcher (n=47)Total (n=255)HC(n=177)FT (n=28)Switcher (n=47)Before switch (HC)After switch (FT)Treatment duration [month], median (range)9.2 (0.03-35.3)9.0 (0.03-35.3)2.9 (0.1-7.1)17.4 (3.0-34.8)13.4 (0.5-29.8)4.4 (0.03-8.5)Number of patients with…, n (%)Any adverse event (AE)222 (87.1)157 (88.7)19 (67.9)44 (93.6)41 (87.2)26 (55.3)≥ Grade 387 (34.1)67 (37.9)5 (17.9)15 (31.9)12 (25.5)3 (6.4)Serious AE54 (21.2)43 (24.3)2 (7.1)8 (17.0)5 (10.6)3 (6.4)Drug-related AE*184 (72.2)128 (72.3)16 (57.1)38 (80.9)37 (78.7)16 (34.4)≥ Grade 346 (18.0)37 (20.9)2 (7.1)7 (14.9)6 (12.8)1 (2.1)Serious drug-related AE15 (5.9)14 (7.9)0 (0)1 (2.1)0 (0)1 (2.1)AE leading to reduction of olaparib dose49 (19.2)32 (18.1)6 (21.4)11 (23.4)9 (19.1)2 (4.3)AE leading to interruption of olaparib74 (29.0)54 (30.5)6 (21.4)14 (29.8)11 (23.4)6 (12.8)AE leading to discontinuation of olaparib**21 (8.2)19 (10.7)2 (7.1)0 (0)0 (0)0 (0)

Relationship

to study

treatment assessed

treating

physician.

for

patients following reasons for

olaparib

discontinuation

was

given

Treatment

Discontinuation

form

(eCRF):

other, patient´s

wish, progress, missing, withdrawal

informed

consent

Slide138

CTCAE, Common Terminology Criteria for Adverse EventsResults of the 3rd interim analysis of C-Patrol: A non-interventional study on olaparib in German routine clinical practiceSehouli J et al., ESMO 2019, abstract 1007P (poster presentation)

The interim results of the C-PATROL non-interventional study (NIS) represent the first reported German real-world evidence data on patients switching from the olaparib capsule (HC) formulation to the new tablet (FT) formulationOlaparib HC and FT treatment discontinuations were mainly related to progression (76%); treatment interruptions and dose modifications mainly occurred due to various adverse event (AEs) during treatment. Only 8% discontinued olaparib HC and FT treatment due to AEsOlaparib HC and FT treamtent was well tolerated with a manageable toxicity profile. 34% of patients had AEs of CTCAE Grade 3 or higher. The safety profile observed in this NIS is in line with data from previous clinical trials with olaparib in patients with ovarian cancerThese data indicate that switching from olaparib capsules to tablets during treatment was well tolerated by patients under routine conditions

SUMMARY & CONCLUSIONS

Slide139

ESMO 2019

Fazit der Autoren

Abstract LBA58Bei platin-resistentem Ovarialkarzinom (PROC) sind die bisherigen Therapieoptionen limitiert und das Tumoransprechen, wie auch das PFS fallen gering aus. In vorangegangen Zellmodellen und kleineren Kohorten zeigten sich vielversprechende Ansätze zur Kombination eines PARP-Inhibitors mit einer Angiogenese-Inhibition. Diese Hypothese konnte in der BAROCCO-Studie (Kombination von Cediranib-Olaparib vs Paclitaxel) statistisch nicht belegt werden. Hinweise für einen Therapieeffekt zeigten sich zwar für die Kombination von Cediranib-Olaparib (kontinuierliche Gabe), allerdings war dieser Effekt nicht signifikant. In künftigen Studien sollten prädiktive Biomarker integriert werden, um Patientinnen mit einem PROC zu identifizieren, die von dieser Behandlung profitieren könnten.Abstract LBA60Patientinnen mit platin-resistentem Ovarialkarzinom (PROC/HGSOC) erhielten in dieser Phase II Studie den ATR Inhibitor M6620 (ATRi) in Kombination mit Gemcitabine vs. Gemcitabine Monotherapie.Beim PROC wird von einer genetischer Instabilität wegen hohem replikativem Stress ausgegangen, bei dem der ATRi das Potential hat, eine Outcome-Verbesserung zu erzielen. In der Studie konnte dies auch gezeigt werden, wobei ein PFS Benefit nur in der Gruppe mit einem PFI (Platin-freies Intervall) von ≤3 Monaten erreicht werden konnte.Biomarker für replikativen Stress (z.B. CCNE1) könnten daher prädiktiv für den Einsatz von ATRi’s sein und in Zukunft eine bessere Selektion der Patientinnen ermöglichen.

Ovarian cancer

Slide140

ESMO 2019

Fazit der Autoren

Ovarian cancer

Abstract 993O

Beim OCTOPUS Trial handelt es sich um ein „

Umbrella

-Trial“, in dessen Rahmen mehrere Biomarker/innovative Substanzen an einem Krankheitsbild evaluiert werden. Das hierbei im Fokus stehende Krankheitsbild ist das platin-resistente/refraktäre

Ovariakarzinom

(HGSOC) und der therapeutische Ansatz ist die Gabe von wöchentlichem Paclitaxel +/- neue Substanzen.

Diese therapeutisch sehr schwierige Patientinnen-Population wird in der hier präsentierten Auswertung unter Einsatz von

Vistusertib

betrachtet. Obgleich das Ergebnis der Studie mit dem dualen mTORC1/mTORC2 Inhibitor

Vistusertib

, der in den PI3K/AKT/

mTOR

Signalweg eingreift negativ ist, sind diese neuen Studienansätze von großer Bedeutung und haben das Potential, bei den sich immer weiter differenzierenden Patientinnen-Populationen rasch wichtige Ergebnisse zu generieren.

Weitere Auswertungen mit anderen neuen Substanzen sind zu erwarten.

Abstract LBA1

In die PRIMA-Studie wurden neu diagnostizierte Patientinnen mit fortgeschrittenem Ovarialkarzinom und hohem Progressionsrisiko eingeschlossen (FIGO III mit obligatem Tumorrest, FIGO IV).

Die Erstlinien-Erhaltungstherapie mit

Niraparib

führte zu einer signifikanten Verbesserung der PFS in allen Subgruppen und unabhängig von

BRCA

-Status bzw. HRD-Testergebnis.

Der größte therapeutische Benefit zeigte sich in der

BRCA

-mut und HRD-positiven Population.

Slide141

ESMO 2019

Fazit der Autoren

Ovarian cancer

Abstract LBA2

Die Patientinnen der PAOLA-Studie spiegeln mehr die klinische Realität in Deutschland wieder: z.B. Tumorfreiheit nach

Debulking

>60%, Erhaltungstherapie mit

Bevacizumab

. Durch die Hinzunahme von

Olaparib

zur Erhaltungstherapie mit

Bevacizumab

wurde zwar der primäre Studienendpunkt erreicht, allerdings zeigte sich in den geplanten Subgruppen-Analysen kein Effekt der

Bev+Ola

Kombination in der HRD-negativen Population.

Welchen Zusatznutzen die Kombination von

Bev+Ola

grundsätzlich bewirkt, kann nicht spezifiziert werden, da es keinen Kontrollarm ohne

Bevacizumab

gab.

Abstract LBA3

In dieser Studie wurde der Biomarker (

myChoice

) mit einem unterschiedlichen Cut-off Wert zur Definition von HRD-positiv

HRD-negativ verwendet. Die gleichzeitige Kombination von

Veliparib

mit der Chemotherapie scheint keinen zusätzlichen Therapievorteil zu bringen, aber mehr Toxizität.

Subgruppen-Analysen zeigten keinen therapeutischen Benefit durch eine

Veliparib

-Erhaltungstherapie für

BRCA

-Patientinnen unabhängig vom HRD-Test (

cut

-off Wert 33).

Slide142

ESMO 2019

Fazit der Autoren

Abstract 992OMit Mirvetuximab Soravtansin ist zum ersten Mal ein “Antibody-Drug-Conjugate” beim platin-resistenten Ovarialkarzinom innerhalb einer Phase III-Studie (FORWARD I) getestet worden.Der primäre Endpunkt wurde in FORWARD I weder in der ITT noch in der “Folate Receptor (FR)α high”-Gruppe erreicht.Das Ergebnis der explorativen Analysen rechtfertigt jedoch eine erneute klinische Prüfung dieser prinzipiell gut verträglichen Substanz mit abgeänderter Methodik bzgl. der Messung des Expressionslevels des Folatrezetors FRα innerhalb einer neuen Phase III-Studie (MIRASOL, Beginn Ende 2019). Abstract 995PDBei Patientinnen mit primärem BRCA positiven Ovarialkarzinom, die in Rahmen der SOLO 1 Studie eine Erhaltungstherapie mit Olaparib bekommen haben, wird eine Verlängerung des PFS-2 und TSST im Vergleich zu Placebo Gruppe beobachtet.Olaparib verschlechtert das Ansprechen auf die folgende Therapie nicht.

Ovarian cancer

Slide143

ESMO 2019

Fazit der Autoren

Abstract 997PDEine Klassifikation von älteren Patientinnen mit Ovarialkarzinom in „geeignet“ oder „nicht-geeignet“ für eine Chemotherapie nach dem chronologischen Alter ist nicht angemessen. Der Geriatric Vulnerability Score (GVS) ist deutlich besser geeignet, diese Zuordnung vorzunehmen. Dabei muss ein komplexerer Evaluationsprozess in Kauf genommen werden, der jedoch zu einem besseren Outcome der Patientinnen führt und daher sinnvoll ist. Möglicherweise kann der Score mit einem vergleichbaren Ergebnis bei älteren Patienten mit anderen Tumoren angewendet werden.Abstract 1190PDAus dieser Phase I/II Studie lassen sich durchaus positive Signale für eine Kombination aus PARP-Inhibitor und Checkpoint-Blockade (hier Olaparib + Durvalumab) ableiten. Die Kombination scheint adäquat verträglich zu sein. Ob sich eine solche Kombination tatsächlich in einen Benefit für die Patientinnen übersetzt, müssen allerdings weitere Studien zeigen.

Ovarian cancer

Slide144

ESMO 2019

Fazit der Autoren

Abstract 1006PDie mediane Niraparib Startdosis nach Publikation der RADAR Analyse beträgt 200mg in Real-Life Setting. Bei Patientinnen, die nach Publikation der RADAR Analyse die Erhaltungstherapie mit Niraparib begonnen haben, beträgt die Dosisreduktionsrate in den ersten 3 Zyklen 28.8% versus 90% bei Patientinnen, die ihre Therapie vor RADAR begonnen haben.Es wird deutlich, dass sich die Daten bzgl. einer zu bevorzugenden Erhaltungsdosis von Niraparib von 200mg bei Patientinnen mit niedriger Thrombozytenzahl und/oder Körpergewicht <77 kg in die Anwendung übersetzt haben. Dadurch mussten weniger Dosisadjustierungen stattfinden und die Verträglichkeit verbesserte sich.Abstract 1007PDie absolute Mehrheit der Patientinnen haben mit der empfohlenen Olaparib Startdosis begonnen (Kapsel 800mg täglich / Tabletten 600mg täglich). Nach Umstellung auf die Tablettenformulierung begann die Mehrheit der Patientinnen (68%) mit der Startdosis von 600mg. Eine Progression war der häufigste Grund (76%) für die Beendigung der Therapie mit Olaparib (Kapseln/Tabletten).Die Therapie mit Olaparib wird gut toleriert, das Nebenwirkungsprofil in Real-Life Setting reflektiert die Daten klinischer Studien.

Ovarian cancer

Slide145

OVERVIEW OF ESMO 2019 ORAL & POSTER PRESENTATIONS

Endometrial, cervical & rare gyn. CANCER

A Randomized Phase II/III Study to Assess the Efficacy of Trametinib in Patients with Recurrent or Progressive Low-Grade Serous Ovarian or Peritoneal Cancer

(

Gershenson

DM et al. ESMO 2019, abstract LBA61)

Efficacy and safety of nivolumab + ipilimumab in patients with recurrent/metastatic (R/M) cervical cancer: Results from

CheckMate

358

(

Oaknin

A et al. ESMO 2019, abstract LBA62)

Lenvatinib

(LEN) and Pembrolizumab (PEMBRO) in Advanced Endometrial Cancer (EC)

(

Makker

V et al. ESMO 2019, abstract 994O)

Molecular classification of the PORTEC-3 trial for high-risk endometrial cancer: impact on adjuvant therapy

(

Creutzberg

CL et al. ESMO 2019, abstract LBA63)

Immune-related gene expression signatures (irGES) in patients (pts) with ovarian clear cell carcinomas (OCCC) – a multicenter analysis

(

Heong

V et al. ESMO 2019, abstract 999PD)

Baseline IPI (Immune Prognostic Index) predicts survival in patients with advanced cervical cancer treated with immune checkpoint inhibitors

(Blanc-Durand F et al. ESMO 2019, abstract 1025P)

Pembrolizumab in Patients with MSI-H Advanced Endometrial Cancer from the KEYNOTE-158 Study

(

Omalley

D et al. ESMO 2019, abstract 1044P)

Primary results from CECILIA, a global single-arm phase 2 study evaluating bevacizumab (BEV), carboplatin (C) and paclitaxel (P) for advanced cervical cancer

(Redondo A et al. ESMO 2019, abstract 1053P)

Slide146

D. Gershenson, A. Miller, W. Brady, J. Paul, K. Carty, W. Rodgers, D. Millan, R. Coleman, K. Moore, S. Banerjee, K. Connolly, A. Secord, D. O'Malley, O. Dorigo, S. Gaillard, H. Gabra, P. Hanjani, H. Huang, L. Wenzel, C. Gourley

A Randomized Phase II/III Study to Assess

the Efficacy of Trametinib in Patients with

Recurrent or Progressive Low-Grade

Serous Ovarian or Peritoneal Cancer

(abstract LBA61)

Slide147

Study background and methods

Low-grade serous ovarian carcinoma (LGSOC) is a rare subtype, accounting for 5-10% of all serous cancers, and is characterized by alterations in the MAPK pathway, relative chemoresistance, and prolonged overall survival (OS) compared to high-grade serous carcinomaNRG Oncology in the US and the National Cancer Research Network (NCRN) in the UK collaborated on a phase II/III trial to assess the efficacy of a MEK inhibitor trametinib (TRAM) compared to physician’s choice standard of care (SOC) in recurrent LGSOC

LGSOC patients were randomized 1:1 to receive either TRAM 2 mg daily or 1 of 5 SOC options* until disease progression. Patients who progressed on SOC were allowed to crossover to TRAM. The primary objective tested the PFS superiority of TRAM vs SOC. Secondary objectives included toxicity, QoL, and objective response rate (ORR) by RECIST 1.1. Exploratory objectives were OS and PFS and ORR after crossover

A Randomized Phase II/III Study to Assess the Efficacy of Trametinib in Patients with Recurrent or Progressive Low-Grade Serous Ovarian or Peritoneal CancerGershenson DM et al., ESMO 2019, abstract LBA61 (oral presentation)

* weekly paclitaxel, pegylated liposomal doxorubicin, topotecan, letrozole, or tamoxifen

PFS, progression-free survival

QoL,

quality of life

Slide148

LGSOC, Low-grade serous ovarian carcinoma; PLD, pegylated liposomal doxorubicin; SOC, Standard of CareA Randomized Phase II/III Study to Assess the Efficacy of Trametinib in Patients with Recurrent or Progressive Low-Grade Serous Ovarian or Peritoneal CancerGershenson DM et al., ESMO 2019, abstract LBA61 (oral presentation)

Study design

Eligibility CriteriaRecurrent LGSOC Prospective digital path review Measurable disease by RECIST 1.1 At least 1 prior platinum regimenUnlimited no. prior therapies No prior MEKi, BRAFiCannot have received all 5 SOC

Trametinib 2 mg/d continuously until disease progression

Standard of Care

Letrozole 2.5 mg daily

PLD 40-50 mg IV Q. 28d

Weekly Paclitaxel 80 mg/m

3/4 weeks

Tamoxifen 20 mg bid daily

Topotecan 4.0 mg/m2 on days 1, 8, 15 Q. 28dUntil disease progression

Cross-over allowed

Trametinib 2 mg/d continuously until progression

Primary endpoint:

rogression-free survival (investigator-assessed)

n=260

Slide149

Most common treatment-emergent adverse events (%)

Adverse events of special interest

AE, adverse event A Randomized Phase II/III Study to Assess the Efficacy of Trametinib in Patients with Recurrent or Progressive Low-Grade Serous Ovarian or Peritoneal CancerGershenson DM et al., ESMO 2019, abstract LBA61 (oral presentation)

Safety

0 60

100

Skin

rash

Diarrhea

usea

omi

ing

Abdominal

pain

Constipation

Hypertension

15.0

7.9

10.2

9.4

12.6

7.1

5.5

2.4

11.8

92.1

72.5

72.4

60.6

51.9

45.7

44.0

42.6

38.6

All

AEs

≥

Grade

Adverse

event

Trametinib

(n=130)

Standard of Care (n=130)

Retinal

tear

1 (0.8%)

Retinal

vascular

disorder

2 (1.6%)

systolic

dysfunction

2 (1.6%)

1 (0.8%)

Decreased

ejection

fraction

10 (7.9%)

1 (08%)

QTc

prolongation

2 (1.6%)

Pneumonitis

3 (2.4%)

Slide150

Compared to standard of care (SOC) treatment, MEK-inhibitor trametinib was associated with improved:median progression-free survival: 13.0 vs 7.2 months [HR=0.48] (p<0.0001)objective response rate: 26.2% vs 6.2% [OR=5.4] (p<0.0001)response duration: 13.6 vs 5.9 monthsmedian overall survival: 37.0 vs 29.2 months [HR=0.75] (p=0.054)Principal ≥ Grade 3 adverse events for trametinib vs SOC were:hematologic (13.4% vs 9.4%)gastrointestinal (27.6% vs 29%)skin (15% vs 3.9%)vascular toxicities (18.9 vs 8.6%)Trametinib may represent a new SOC treatment option for women with recurrent low-grade serous carcinoma

ummary

of efficacy results

Slide151

What to do with “hard-to-treat” ovarian cancer? (J. Lederman, UK)

PFS, progression-free survival; PLD, pegylated liposomal doxorubicin; RR, response rateWhat to do with “hard-to-treat” ovarian cancerJonathan Lederman., ESMO 2019, Profered Paper 2 discussion

Comment by the invited discussant

Gershenson et al….Control arm

DrugResponse rate (%)Letrozole13.6Tamoxifen0Paclitaxel9.1PLD2.5Topotecan0

Low response rate to chemotherapyHighest response rate in patients on letrozoleStable disease rate (8 weeks) 70.8 %Med duration of response 5.9 ( 2.8-12.2) monthsMedian PFS 7.2 (5.6-9.9) months48% ≥ 3 prior lines of treatment

Despite the poor response rate, progression is relatively slowThis disease has a long natural history - Where in the pathway of disease were these patients treated?

How would trametinib have compared to a letrozole control arm - the drug with the highest RR?

Slide152

A. Oaknin, R. Naumann, T. Meyer, J.M. Lopez-Picazo, C. Lao, Y.-J. Bang, V. Boni, W. Sharfman, J.C. Park, L. Devriese, K. Harano, C. Chung, S. Topalian, K. Zaki, T. Chen, J. Gu, B. Li, A. Barrows, A. Horvath, K. Moore

Efficacy and safety of nivolumab + ipilimumab

in patients with recurrent/metastatic (R/M)

cervical cancer: Results from

CheckMate

358

(abstract LBA62)

Slide153

Study background and methods

There is a high unmet medical need in patients with R/M cervical cancer; median overall survival (OS) is < 17 months after 1L therapy with few options in 2L. Per current guidelines, patients whose tumors express PD-L1 are eligible for pembrolizumab in the 2L settingCheckMate 358* is an ongoing open-label, multi-cohort, phase I/II study of nivolumab +/- ipililumab (Nivo/Ipi) in virus-associated cancers regardless of PD-L1 expressionHere we report an interim analysis of pts with R/M cervical cancer, with or without prior systemic therapies (PST), receiving nivolumab + ipilimumab

Eligible patients had R/M cervical cancer treated with 0-2 PST. Patients were randomized to Nivo 3mg/kg Q2W + Ipi 1mg/kg Q6W (Combo A), or Nivo 1mg/kg + Ipi 3mg/kg Q3W for 4 doses followed by Nivo 240mg Q2W (Combo B), for ≤24 months until progression or unacceptable toxicityPrimary endpoint: investigator-assessed objective response rate (ORR) by RECIST 1.1; secondary endpoints: OS, progression-free survival (PFS) and duration of response

Efficacy and safety of nivolumab (Nivo) + ipilimumab (Ipi) in patients (pts) with recurrent/metastatic (R/M) cervical cancer: Results from CheckMate 358Oaknin A et al., ESMO 2019, abstract LBA62 (oral presentation)

R/M, recurrent / metastatic

PD-L1, programmed death ligand 1

* NCT02488759

Slide154

ORR, objective response rate; OS, overall survival; PFS, progression-free survival; PST, prior systemic therapy; SCC, squamous cell carcinoma

Efficacy and safety of nivolumab (

Nivo) + ipilimumab (Ipi) in patients (pts) with recurrent/metastatic (R/M) cervical cancer: Results from CheckMate 358Oaknin A et al., ESMO 2019, abstract LBA62 (oral presentation)

Study Design and Current Analysis

Imaging every 8 weeks for year 1 of treatmentImaging every 12 weeks beyond year 1

Histologically confirmed SCC of the cervixR/M disease≤2 PSTs for R/M disease≥1 target lesionECOG PS 0–1HPV: positive or unknown

Database lockJune 26, 2019Median follow-up (range) NIVO3+IPI1:10.7 mo (0.8–32.1) NIVO1+IPI3:13.9 mo (0.5–29.3)

Primary endpoint: Investigator-assessed ORR by RECIST 1.1Secondary endpoints: OS, PFS, duration of response

Study start date: October 2015Estimated completion date: December 2019

Randomized cervical cancer cohorts of CheckMate 358 (NCT02488759) testing 2 combination regimens of nivolumab + ipilimumab for recurrent and/or metastatic (R/M) disease

Screening

Treatment

(until toxicity or

progression or a maximum of 24 months)

Follow-up

Current

nal

sis

NIVO + IPI Regimen

NIVO3 + IPI1

(n=45):

NIVO

3 mg/kg q2w + IPI 1 mg/kg q6w

NIVO1 + IPI3

(n=46)

NIVO

mg/kg + IPI

mg/kg

q3w x 4 followed by

NIVO 240 mg

q2w

Slide155

Patient Characteristics

* Tumor cell PD-L1 expression was defined as the percentage of tumor cells exhibiting plasma membrane staining at any intensity. † Assessed in pretreatment (archival or fresh) tumor biopsy specimens with the use of a validated, automated immunohistochemical assay using the rabbit antihuman PD-L1 clone 28-8 (Phillips T, et al. Appl Immunohistochem Mol Morphol 2015;23:541-549).AJCC, American Joint Committee on Cancer.

Baseline characteristicsNIVO3 + IPI1(n=45)NIVO1 + IPI3(n=46)Age, median (range), y48.0 (32–76)44.5 (26–74)ECOG PS, n (%)0123 (51.1)22 (48.9)26 (56.5)20 (43.5)AJCC stage, n (%)(A–B)(A–C)(A–B)3 (6.6)1 (2.2)41 (91.1)0 (0.0)8 (17.4)38 (82.6)Tumor cell PD-L1 expression, *† n (%)Evaluable≥1%37 (82.2)23 (62.2)34 (73.9)23 (67.6) <1%Not evaluable/not reported14 (37.8)8 (17.8)11 (32.4)12 (26.0)

Prior

therapiesNIVO3 + IPI1 (n=45)NIVO1 + IPI3 (n=46)Prior therapy, n (%) PlatinumBevacizumab39 (86.7)24 (53.3)42 (91.3)25 (54.3)Prior radiotherapy, n (%)38 (84.4)39 (84.8)Prior systemic therapy in the R/M setting, n (%)0≥119 (42.2)26 (57.8)24 (52.2)22 (47.8)

Slide156

Tumor Response

* Responses could not be determined in 1 patient with PST in NIVO3 + IPI1 and in 1 patient each with and without PST in NIVO1 + IPI3. ‡ Tumor cell PD-L1 expression was defined as the percentage of tumor cells exhibiting plasma membrane staining at any intensity. CI, confidence interval; NR, not reached; PST, prior systemic therapy.

NIVO3 + IPI1NIVO1 + IPI3Response in all treated patientsNo PST for R/Mdisease, n = 19PST for R/M disease, n = 26No PST for R/M disease, n = 24PST for R/Mdisease, n = 22ORR,* % (95% CI)31.6 (12.6–56.6)23.1 (9.0–43.6)45.8 (25.6–67.2)36.4 (17.2–59.3)Duration of response, median, mo (95% CI)NR (6.6–NR)14.6 (7.5–NR)NR (4.6–NR)9.5 (1.9–NR)ORR by tumor cell PD-L1 expression,‡PD-L1 ≥1%, # responders/# treated (%)[95% CI]4/13 (30.8)[9.1–61.4]4/10 (40.0)[12.2–73.8]4/11 (36.4)[10.9–69.2]2/12 (16.7)[2.1–48.4]PD-L1 <1%, # responders/# treated (%)[95% CI]1/3 (33.3)[0.8–90.6]1/11 (9.1)[0.2–41.3]0/4 (0)[0.0–60.2]4/7 (57.1)[18.4–90.1]

Slide157

PFS, progression-free survival; PST, prior systemic therapyEfficacy and safety of nivolumab (Nivo) + ipilimumab (Ipi) in patients (pts) with recurrent/metastatic (R/M) cervical cancer: Results from CheckMate 358Oaknin A et al., ESMO 2019, abstract LBA62 (oral presentation)

Progression-free Survival

NIVO3 + IPI1Median PFS, months (95% CI)No PST for R/M disease13.8 (2.1–NR)PST for R/M disease 3.6 (1.9–5.1)

NIVO1 + IPI3Median PFS, months (95% CI)No PST for R/M disease8.5 (3.7–NR)PST for R/M disease 5.8 (3.5–17.2)

Owing

the

high percentage of censored responses, median and rate estimators may be misleading.

Probability

of PFS,

100

Time

months

No. at

risk

No PST

PST

Probability

of PFS,

100

No. at risk

No PST

PST

Time,

months

Slide158

NR, not reached; OS, overall survival; PST, prior systemic therapyEfficacy and safety of nivolumab (Nivo) + ipilimumab (Ipi) in patients (pts) with recurrent/metastatic (R/M) cervical cancer: Results from CheckMate 358Oaknin A et al., ESMO 2019, abstract LBA62 (oral presentation)

Overall Survival

Owing to the high percentage of censored responses, median and rate estimators may be misleading.

Probability

of OS, %

100

No. at risk

No PST

PST

Time,

months

Probability

of OS,

100

Time,

months

No. at

risk

No PST

PST

NIVO3

IPI1

Median

OS,

months

(95%

CI)

PST

for R/M

disease

(17.4–NR)

PST

for R/M

disease

3.6

(7.9–15.2)

NIVO1

IPI3

Median

nths

(95%

CI)

PST

for R/M

disease

(

–NR)

PST

for R/M

disease

(

.5–

)

Slide159

SAE; serious adverse event; TRAE, treatment-related adverse eventEfficacy and safety of nivolumab (Nivo) + ipilimumab (Ipi) in patients (pts) with recurrent/metastatic (R/M) cervical cancer: Results from CheckMate 358Oaknin A et al., ESMO 2019, abstract LBA62 (oral presentation)

Safety Summary

No new safety signalsHigher incidence of TRAEs and treatment-related SAEs leading to treatment discontinuation in NIVO1 + IPI3 compared with NIVO3 + IPI1No treatment-related deaths

Event, n (%)NIVO3 + IPI1 (n=45)NIVO1 + IPI3 (n=46)Any gradeGrade 3-4Any gradeGrade 3-4TRAEs36 (80.0)13 (28.9)38 (82.6)17 (37.0)Treatment-related SAEs12 (26.7)8 (17.8)16 (34.8)10 (21.7)TRAEs leading to treatment discontinuation6 (13.3)2 (4.4)9 (19.6)6 (13.0)Treatment-related SAEs leading to treatment discontinuation2 (4.4)1 (2.2)5 (10.9)5 (10.9)

Slide160

The results suggest a clinical benefit with both regimens of nivolumab + ipilimumab in patients with recurrent / metastatic (R/M) cervical cancerWhile patient subgroups were small, responses were noted regardless of tumor cell PD-L1 expressionAcross both regimens (Nivo3 + Ipi1, Nivo1 + Ipi3), efficacy was better in patients without prior systemic therapy vs. with prior systemic therapy Responses were durable; at median follow-up >10 months, median duration of response was not reached for either regimen in patients without prior systemic therapyBoth treatment regimens had a manageable safety profile; no new safety signals were detectedGiven the limited treatment options for patients with R/M cervical cancer, these data with nivolumab + ipilimumab are of strong clinical interest and warrant further investigation in this patient populationCheckMate 358 is continuing to enrol patients with R/M cervical cancer

SUMMARY & CONCLUSIONS

Slide161

Take home message (N. Colombo, Italy)

Nicoletta Colombo, ESMO 2019, Profered Paper 2 discussion

Comment by the invited discussant

The Good*:The combination of ipilimumab and nivolumab confirmed a strong activity in cervical cancer as seen in other tumor typesHigh response rate and prolonged survival particularly in no prior systemic therapy (PST) populationActivity seen regardless of tumor cell PD-L1 expressionChemotherapy-sparing regimen!The Bad*:Toxicity is not trivial: probably NIVO3 + IPI1 preferredThe Ugly*:No control arm!

referring

famous western

movie

Sergio Leone

Slide162

V. Makker, M. Taylor, C. Aghajanian, A. Oaknin, J. Mier, A. Cohn, M. Romeo Marin, R. Bratos Lorenzo, M. Brose, C. Disimone, M. Messing, D. Stepan, C. Dutcus, J. Wu, E. Schmidt, R. Orlowski, P. Sachdev, R. Shumaker, A. Casado Herraez

Lenvatinib

(LEN) and Pembrolizumab (PEMBRO)

in Advanced Endometrial Cancer (EC)

(abstract 994O)

Slide163

Study background and methods

Lenvatinib (LEN) is a multikinase inhibitor of VEGFR 1–3, FGFR 1–4, PDGF-Rα, RET, and KIT; Pembrolizumab (pembro) is an anti-PD-1 antibody.Here, final results* are reported of a cohort of patients with metastatic endometrial cancer (EC) as part of an ongoing phase 1b/2 study evaluating LEN + PEMBRO in patients with selected solid tumours.

In this cohort of a multicenter, open-label study, patients confirmed metastatic EC and measurable disease who received ≤ 2 prior line of CT were administered LEN (20 mg PO QD) plus PEMBRO (200 mg IV Q3W). Tumour assessments for the primary phase 2 endpoint‡ and secondary endpoints were evaluated by investigators per immune-related (ir)RECIST. Secondary endpoints included ORR, PFS, OS, and DoR Tumour responses were also assessed by independent imaging reviewers per irRECIST, RECIST 1.1, and modified RECIST 1.1, and by investigators per mRECIST 1.1.

Lenvatinib (LEN) and Pembrolizumab (PEMBRO) in Advanced Endometrial Cancer (EC)Makker V et al., ESMO 2019, abstract 994O (oral presentation)

* data cutoff, Jan. 10, 2019

‡ objective response rate at 24 weeks [ORRWK24]

RR,

objective response rate

PFS,

progression-free survival

OS,

overall survival

DoR,

duration of response

Slide164

Phase 2, open-label, single-arm study (NCT02501096)

PFS, progression-free survival; OS, overall survival; CBR, clinical benefit rate; DCR, disease control rate; DOR, duration of response; ORR, objective response rate; OS, overall survival*Tumor responses for primary and secondary endpoints were assessed by the investigator per irRECIST (immune-related RECIST).Lenvatinib (LEN) and Pembrolizumab (PEMBRO) in Advanced Endometrial Cancer (EC)Makker V et al., ESMO 2019, abstract 994O (oral presentation)

Study design

Primary endpointORR at Week 24

Key

eligibility criteria

Aged ≥ 18 yearsPathologically confirmed and metastatic endometrial carcinoma≤ 2 prior systemic therapiesMeasurable disease by irRECISTECOG performance status ≤ 1Life expectancy ≥ 12 weeks

Prespecified exploratory endpointsIndependent imaging review per irRECIST and RECIST v1.1Antitumor activity by PD-L1 status

Post hoc exploratory analysisAntitumor activity by tumor histologyAntitumor activity by MSI status

Lenvatinib20 mg/day (oral)+Pembrolizumab200 mg Q3W (IV)

Key secondary endpoints*

Overall ORR

DOR

PFS

DCR

CBR

Safety and tolerability

Slide165

Independent Imaging Review, RECIST version 1.1

a. The MSI or MMR status was not available for 3 patients; b. As found in the United States Prescribing

lnformation; c. 95%CIs were calculated with the Clopper-Pearson method; d. Duration of response was estimated with the Kaplan-Meier methodMSI-H, microsatellite instability high; dMMR, deficient mismatch repairLenvatinib (LEN) and Pembrolizumab (PEMBRO) in Advanced Endometrial Cancer (EC)Makker V et al., ESMO 2019, abstract 994O (oral presentation)

Tumor Response

Response categoryTotal(n=108)aNot MSI-Hor dMMR (n=94)MSI-H/dMMR(n=11)Best overall response, n (%) Complete response11 (10.2)10 (10.6)1 (9.1) Partial response33 (30.6)26 (27.7)6 (54.5) Stable disease42 (38.9)38 (40.4)3 (27.3) Progressive disease14 (13.0)12 (12.8)1 (9.1) Not evaluable8 (7.4 )8 (8.5)0Objective response rate(complete response + partial response), n(%)44 (40.7)36 (38.3)b7 (63.6) 95% CIc31.4, 50.628.5, 48.930.8 , 89.1Duration of response (months),median (range)d 14.8(1.2+, 35.6+)NE(1.2+, 33.1+)NE(2.1+, 35.6+)

Slide166

Kaplan-Meier plot (independent imaging review, RECIST version 1.1)

Lenvatinib

(LEN) and Pembrolizumab (PEMBRO) in Advanced Endometrial Cancer (EC)Makker V et al., ESMO 2019, abstract 994O (oral presentation)

Progression-Free Survival

Number of patients at risk:Total in EC 2l+1081048373635748483631201814131212111111987777777766542211110Not MSI-H or dMMR949071625449404029251514111099888765555555555431100000MSI-H/dMMR11111010988876543333333222222222211111111110

Median of overall survival (and median follow-up times) were estimated with the Kaplan-Meier method, and 95% CIs were calculated with a generalized Brookmeyer and Crowley method.

Progression-

free survival, %

100

Time (months)

Total

Failed

Censored

Median (months) 95% CI

108

7.5 (5.0-8.3)

5.4 (4.4-7.6)

18.9 (3.9-NE)

Slide167

Lenvatinib

(LEN) and Pembrolizumab (PEMBRO) in Advanced Endometrial Cancer (EC)Makker V et al., ESMO 2019, abstract 994O (oral presentation))

Overall Survival

Number of patients at risk:Total in EC 2l+108106101999591878481766659514541393327252318151312121211111111111111654221110Not MSI-H or dMMR94928785827875737167575245403634292321191613111010109999999543110000MSI-H/dMMR11111111101010109887655544442222222222222111111110

100

151617181920212223242526272829303132333435363738394041

Median duration of follow-up:18.7 months (95% CI 13.1-20.3)

TotalFailedCensoredMedian (months) 95% CI108495916.7 (15.0, NE)94445016.4 (13.5, 25.9)1138NE (7.4, NE)

Median of overall survival (and median follow-up times) were estimated with the Kaplan-Meier method, and 95% CIs were calculated with a generalized Brookmeyer and Crowley method.

Lenvatinib

(LEN) and Pembrolizumab (PEMBRO) in Advanced Endometrial Cancer (EC)

Makker

V et al.,

ESMO 2019, abstract 994O (oral presentation)

Time (months)

Progression-

free

survival, %

Slide168

TEAEs, treatment emergent adverse eventsLenvatinib (LEN) and Pembrolizumab (PEMBRO) in Advanced Endometrial Cancer (EC)Makker V et al., ESMO 2019, abstract 994O (oral presentation)

Overview of Treatment-related TEAEs

Previously treated EC (n=108)n (%)Patients with any treatment-related TEAEs150 (97.2)Patients with treatment-related TEAEs leading to study drug discontinuationa20 (18.5) Both lenvatinib and pembrolizumab 10 (9.3) Lenvatinibb17 (15.7) Pembrolizumabc14 (13.0)Patients with treatment-related TEAEs leading to study-drug dose reduction of lenvatinib70 (64.8)Patients with treatment-related TEAEs leading to study-drug interruptiona78 (72.2) Both lenvatinib and pembrolizumab30 (27.8) Lenvatinibb73 (67.6) Pembrolizumabc43 (39.8)

a) Drug

action

taken

for

lenvatinib

and/

pembrolizumab

; b) Drug

action

taken

for

lenvatinib

regardless

action

taken

for

pembrolizumab

; c) Drug

action

taken

for

pembrolizumab

regardless

action

taken

for

lenvatinib

Slide169

TEAEs, treatment emergent adverse events; AEOSI, adverse events of special interestLenvatinib (LEN) and Pembrolizumab (PEMBRO) in Advanced Endometrial Cancer (EC)Makker V et al., ESMO 2019, abstract 994O (oral presentation)

Immune-related teaEs

AEOSI category, n(%)Previously treated EC (n=108)Any gradeGrade ≥ 3Any AESOI62 (57.4)14 (13.0)Hypothyroidism51 (47.2)1 (0.9)Hyperthyroidism7 (6.5)0 Severe skin reactions5 (4.6)5 (4.6)Colitis5 (4.6)2 (1.9)Pancreatitis5 (4.6)2 (1.9)Adrenal insufficiency4 (3.7)3 (2.8)Thyroiditis4 (3.7)0Nephritis3 (2.8)2 (1.9)Hepatitis2 (1.9)1 (0.9)Hypophysitis1 (0.9)1 (0.9)Pneumonitis1 (0.9)0

Preferred term, n (%)Previously treated EC (n=108)Any gradeGrade 3/4Patients with any treatment-related TEAEs105 (97.2)75 (69.4)Hypertension65 (60.2)35 (32.4)Diarrhea57 (52.8)7 (6.5) Decreased appetite51 (47.2)0Fatique56 (51.9)9 (8.3)Hypothyroidism47 (43.5)1 (0.9)Nausea43 (39.8)3 (2.8)Stomatitis36 (33.3)0Arthralgia34 (31.5)1 (0.9)Dysphonia30 (27.8)0Vomiting29 (26.9)0Palmar-plantar erythrodysesthesia syndrome28 (25.9)3 (2.8)Weight decreased28 (25.9)2 (1.9)Proteinuria24 (22.2)4 (3.7)Headache22 (20.4)0

Treatment-related TEAEs (≥ 20%)

treatment-related

deaths were reported per investigator assessment. Patients are counted in the worst grade experienced of grade 3 or 4.

Slide170

1. Ott PA et al. J Clin Oncol. 2017,35:2535-2541; 2. Vergote et al. J Clin Oncol. 2013,31(15 Suppl):Abstract 5520; 3. Motzer RJ et al. Lancet Oncol. 2015,16:1473-1482; 4. Robert C et al. N Engl J Med. 2015,372:2521-2532; 5. Schlumberger M et al. N Engl J Med. 2015,372:621-630.Lenvatinib (LEN) and Pembrolizumab (PEMBRO) in Advanced Endometrial Cancer (EC)Makker V et al., ESMO 2019, abstract 994O (oral presentation)

Multikinase inhibitor lenvatinib plus pembrolizumab showed compelling activity in patients with advanced endometrial cancer and progressive disease following prior therapy, regardless of MSI status, PD-L1 status, or histologyLenvatinib plus pembrolizumab demonstrated deep and durable responsesThe safety profile of lenvatinib plus pembrolizumab was similar to previously reported profiles of each monotherapy1-5Incidence of hypothyroidism was higher in this study than previous reports of each monotherapy3,4A phase 3 trial of lenvatinib plus pembrolizumab versus doxorubicin or weekly paclitaxel in advanced endometrial carcinoma is ongoing (NCT03517449)

Conclusions

Slide171

The FDA, the Australian Therapeutic Goods Administration, and Health Canada granted simultaneous review decisions in all 3 countries on September 17, 2019

Lenvatinib plus pembrolizumab was granted accelerated approval for the treatment of advanced endometrial carcinoma that is not MSI-H or dMMRPatients must have had disease progression following prior systemic therapy and must not be candidates for curative surgery or radiation

Lenvatinib (LEN) and Pembrolizumab (PEMBRO) in Advanced Endometrial Cancer (EC)Makker V et al., ESMO 2019, abstract 994O (oral presentation)

Accelerated Approval

Slide172

Take home message (N. Colombo, Italy)

The Good:*The combination of pembrolizumab and lenvatinib led to unprecedented results in patients with advanced/recurrent previously treated endometrial cancer, MSSFor the first time, a chemotherapy-free regimen demonstrated a high rate and durable responses in this clinical setting with a high unmet needThe Bad:*Toxicity was as remarkable as activityThe Ugly:*No control arm!

MSS, microsatellite stableNicoletta Colombo, ESMO 2019, Profered Paper 2 discussion

Comment by the invited discussant

referring

famous western

movie

Sergio Leone

Slide173

C. Creutzberg, A. Leon-Castillo, S. De Boer, M. Powell, L. Mileshkin, H. Mackay, A. Leary, H. Nijman, N. Singh, P. Pollock, A. Fyles, C. Haie-Meder, V. Smit, R. Edmondson, H. Putter, H. Kitchener, E. Crosbie, M. De Bruyn, R. Nout, T. Bosse

Molecular classification of the PORTEC-3 trial

for high-risk endometrial cancer:

impact on adjuvant therapy

(abstract LBA63)

Slide174

Study background and methods

The PORTEC-3 trial investigated the benefit of combined adjuvant chemotherapy and radiotherapy (CTRT) versus radiotherapy alone (RT) for women with stage I-III endometrial cancer with high-risk features (HREC)Since the TCGA defined 4 molecular subgroups of EC with strong prognostic value, we investigated outcomes and impact of chemotherapy for each molecular subgroup using tissue samples from PORTEC-3 trial participants

Paraffin-embedded tissues of 423 consenting patients (64% of 660) were collected. IHC for p53 and mismatch repair (MMR) proteins, and DNA sequencing for POLE pathogenic exonuclease domain mutations were done to classify tumours as p53 mutant staining (p53abn), POLE ultramutated (POLEmut), MMR deficient (MMRd), or no specific molecular profile (NSMP) The Kaplan-Meier method, log-rank test and Cox model were used for analysis

Molecular classification of the PORTEC-3 trial for high-risk endometrial cancer: impact on adjuvant therapyCreutzberg CL et al., ESMO 2019, abstract LBA63 (poster discussion presentation)

TGCA, The Cancer Genome Atlas program

IHC,

immunohistochemistry

Slide175

Molecular classification of the PORTEC-3 trial for high-risk endometrial cancer: impact on adjuvant therapyCreutzberg CL et al., ESMO 2019, abstract LBA63 (poster discussion presentation)

Molecular Subclassification of EC (Endometrial cancer)

MSI high

cluster 4

POLE (ultramutated) (17)7%

MSI (hypermutated) (65)28%

Copy-number low(endometrioid) (90)39%

Copy-number high(serious-like) (60)26%

Spectrum*

*(%[CA] > 0.2) AND (%[CG] < 0.03) AND (SNV count > 500)

(232)

(215)

(150)

Progression-free survival, %

Months

Log-rank

=0.02

Pole

MSI

Copy-number low (endometrioid)

Copy-number high (serous-like)

Cancer Genome Atlas Research Network, et al.

Nature

.2013;497(7447):67-73

Slide176

RT, radiotherapyMolecular classification of the PORTEC-3 trial for high-risk endometrial cancer: impact on adjuvant therapyCreutzberg CL et al., ESMO 2019, abstract LBA63 (poster discussion presentation)

PORTEC-3 Trial Design and Results

High

risk:Stage I G3, Stage II-IIISerous and clear cell

de Boer Lancet Oncol 2018

Pelvic RT 48.6 Gy +

2x Cisplatin 50mg/m

4x Carboplatin AUC5Paclitaxel 175mg/m2

5 weeks

12 weeks

2 wks

5 weeks

RT alone

Slide177

MMR, mismatch repair; NSMP, no specific molecular profileMolecular classification of the PORTEC-3 trial for high-risk endometrial cancer: impact on adjuvant therapyCreutzberg CL et al., ESMO 2019, abstract LBA63 (poster discussion presentation)

Outcomes (I)

423/660 (65%) endometrial cancers from PORTEC-3 participants were analysed by immunohistochemistry for p53 and mismatch repair proteins and by DNA sequencing for POLE pathogenic exonuclease domain mutationsMolecular analysis was successful in 410 cases (97%)Sought to evaluate outcomes in PORTEC-3 based on mutation classification in treatment cohorts

Slide178

Outcomes (II)

Recurrence-free survival

Years since randomisation

423/660 (65%) endometrial cancers from PORTEC-3 participants were analysed by immunohistochemistry

for p53 and mismatch repair proteins and by DNA sequencing for POLE pathogenic exonuclease domain mutations

Molecular analysis was successful in 410 cases (97%)

Sought to evaluate outcomes in PORTEC-3 based on mutation classification in treatment cohorts

Slide179

CTRT, combined adjuvant chemotherapy and radiotherapy; RT, radiotherapyMolecular classification of the PORTEC-3 trial for high-risk endometrial cancer: impact on adjuvant therapyCreutzberg CL et al., ESMO 2019, abstract LBA63 (poster discussion presentation)

RFS by treatment arm for p53abn and MMRd EC

Recurrence-free survival (RFS)

p53abn

Recurrence-free survival

Recurrence-free survival (RFS)

MMR-deficient

Recurrence-free survival

Years since randomisation

Slide180

Molecular endometrial cancer classification has a strong prognostic value in high-risk endometrial cancer (HREC)Population-informed treatment response by mutational profile may help to better refine treatment at the patient levelSerous – chemotherapyMMRd/POLE – immune checkpointNSMP/MMRd – radiation or chemotherapyCurrent trials are incorporating the molecular classifications as eligibility and stratification factorsOngoing effort is the development of predictive biomarkers for treatment

SUMMARY & CONCLUSIONS

Slide181

V. Heong, T.Z. Tan, J. Ye, M. Miwa, D. Lim, C. Herrington, Y. Iida, A. Okamoto, J. Low, J. Ng, S.E. Lim, Y.W. Lim, C. Gourley, K. Hasegawa, D.S. Tan, R. Huang

Immune-related gene expression signatures

(irGES) in patients with ovarian clear cell

carcinomas (OCCC) – a multicenter analysis

(abstract 999PD)

Slide182

Study background and methods

It was shown previously that ovarian clear cell carcinoma (OCCC) can be classified into 4 molecular subgroups based on their immune-related gene expression signatures (irGES) profiles with distinct clinicopathological characteristics and prognostic outcomes A combined analysis of samples from 3 independent centres was performed to investigate the prognostic relevance of the irGES profiles in a larger OCCC cohort

Immune-related gene profiling was performed on 255 FFPE OCCC samples collected from 3 centres (NUH, Singapore, Saitama, Japan, and Edinburgh, UK) using the nanoString nCounter PanCancer Immune Profiling PanelUnsupervised hierarchical clustering analysis was performed and correlated with clinical outcome MMR protein levels were assessed by immunohistochemistry

Immune-related gene expression signatures (irGES) in patients (pts) with ovarian clear cell carcinomas (OCCC) – a multicenter analysisHeong V et al., ESMO 2019, abstract 999PD (poster discussion presentation)

FFPE, formalin-fixed paraffin-embedded

MMR

, mismatch repair

Slide183

Immune-related gene expression signatures (irGES) in patients (pts) with ovarian clear cell carcinomas (OCCC) – a multicenter analysis

Heong V et al., ESMO 2019, abstract 999PD (poster discussion presentation)

Based

on irGES, four distinct subgroups of OCCC were identified: G1 – Subgroup enriched in NK cell markers and PD-1 expression G2 – Subgroup with high CTLA-4 expressionG3 – Up-regulation of genes associated with Ag presentation G4 – Subgroup with increased pro-angiogenic genes

G1 - PD1 high G2 - CTLA4 highG3 - Antigen-Presentation G4 - Pro-angiogenic

Using signatures derived from the discovery cohort (left), unsupervised clusteringwas performed on the Saitama and Edinburgh cohort (above)

PD1 high CTLA4 highAntigen-Presentation Pro-angiogenic

OCCC CLASSIFIED INTO 4 MOLECULAR SUBTYPES

Ovarian clear cell carcinoma (OCCC) can be classified into 4 molecular subgroups based on their

immune-related gene expression signatures (

irGES) profiles with distinct clinicopathological characteristics and prognostic outcomes

Using gene signatures derived from our discovery cohort, unsupervised clustering was subsequently performed on the Saitama and Edinburgh cohort independently and correlated with clinical outcome

Slide184

OCCC, ovarian clear cell carcinomaImmune-related gene expression signatures (irGES) in patients (pts) with ovarian clear cell carcinomas (OCCC) – a multicenter analysisHeong V et al., ESMO 2019, abstract 999PD (poster discussion presentation)

PATIENT DEMOGRAPHICS

ParameterSingaporeSaitamaEdinburghNo patients968484Failed samples081Final number967683Agemedian525761StageIA,IB15 (15.6%)9 (11.8%)15 (18.1%)IC30 (31.3%)41 (54%)28 (33.7%)IC-1NA20 (26.3%)7 (8.4%)IC-2NA5 (6.6%)3 (3.6%)IC-3NA16 (21.1%)18 (21.7%)II,III,IV46 (47.9%)26 (34.2%)40 (48.2%)missing5 (5.2%)00HistologyOCCC96 (100%)NA75 (90.36%)Mixed0NA8 (9.64%)

Parameter

Singapore

Saitama

Edinburgh

Debulking

residual

disease

(86.8%)

(72.3%)

optimal (< 1

cm)

(13.2%)

(16.9%)

Suboptimal >=

1cm

(10.8%)

Adjuvant

Therapy

yes

(68.8%)

(84.2%)

(80.7%)

(10.4%)

(15.8%)

(19.3%)

missing

(20.8%)

platinum-containing

(68.8%)

(81.6%)

(73.5%)

taxol-containing

(61.5%)

(59.2%)

(39.8%)

radiotherapy

(7.2%)

Overall

survival

median

follow-

(

month

)

33.5

41.6

event

(30.2%)

(26.3%)

(63.9%)

Progression-Free

median

follow-

(

month

)

29.2

31.7

#event

(43.8%)

(31.6%)

(48.2%)

Slide185

DFS, disease-free survival; OS, overall survivalImmune-related gene expression signatures (irGES) in patients (pts) with ovarian clear cell carcinomas (OCCC) – a multicenter analysisHeong V et al., ESMO 2019, abstract 999PD (poster discussion presentation)

CLINICAL OUTCOMES – 3-YeaR OS AND DFS

Binary 3-year disease-free and overall survival

Overall Survival

Disease-Free Survival

Slide186

MMR protein assessed by immunohistochemistryIncidence of MMR deficient protein levels in OCCC was similar across the 3 cohorts (~5%)

MMR, mismatch repairImmune-related gene expression signatures (irGES) in patients (pts) with ovarian clear cell carcinomas (OCCC) – a multicenter analysisHeong V et al., ESMO 2019, abstract 999PD (poster discussion presentation)

MMR Proteins By Molecular Subgroup And Cohort

MMRSingapore, NUHSaitama, JapanEdingburgh, UKProficient76 (79.17%)72 (94.74%)81 (95.29%)Deficient6 (6.25%)4 (5.06%)4 (4.71%)Missing14 (15.58%)--

PD1

CTLA4

APre

ProA

Frequency

100

Deficient

Retained

PD1 = PD1-high

CTLA4 = CTLA4-high

Apre = Antigen-

presentation

ProA

= Pro-

angiogenic

P-

value

chi-square

test

p=0.0149

Slide187

Ovarian clear cell has been uniquely identified to have an ethnic distribution raising the question as to whether the disease is the same in different patient cohortsCurrent trial supports homologyBased on immune-related gene expression signatures (irGES), it appears that sub-categories can be identifiedSuspected immune-escape in ovarian clear cell carcinoma (OCCC) is supporting ongoing immunotherapeutic trials

SUMMARY & CONCLUSIONS

Slide188

F. Blanc-Durand, M. Richardson, P. Vuagnat, P. Pautier, A. Hollebecque, A. Varga, C. Massard, A. Leary

Baseline IPI (Immune Prognostic Index) predicts survival in patients with advanced cervical cancer treated with immune checkpoint inhibitors

(abstract 1025P)

Slide189

Study background and methods

Treatment response to immune checkpoint inhibitors in cervical cancer remains modest and predictive biomarkers to select patients are neededAn immune prognostic index (IPI) score combining lactate dehydrogenase (LDH) level and the derived neutrophils/(leucocytes minus neutrophils) ratio (dNLR) has been shown to correlate with ICI outcome in melanoma and lung cancerThis study aimed to assess the predictive value of baseline IPI for advanced cervical cancer treated with immune checkpoint inhibitors (ICI)

Pre-ICI treatment dNLR and LDH levels were retrospectively collected for all patients with advanced cervical cancer (n=48) treated with PD-1 / PD-L1 inhibitors Patients were divided into three groups: (1) IPI-0 (normal LDH, dNLR<3); (2) IPI-1 (LDH>upper limit or dNLR>3); and (3) IPI-2 (LDH>upper limit and dNLR>3) The primary endpoint was overall survival (OS) and the secondary objective was progression free survival (PFS) analyzed by Kaplan Meyer and log-rank (PFS)

Baseline IPI (Immune Prognostic Index) predicts survival in patients with advanced cervical cancer treated with immune checkpoint inhibitorsBlanc-Durand F et al., ESMO 2019, abstract 1025P (poster presentation)

PD-L1, Programmed cell death ligand 1

PD-1,

Programmed

cell death 1

Slide190

Patient baseline characteristicsn=48Age – yearn=48Median47Range21-77Tumor histologic subtypen=48Squamous N (%)37 (77)Adenocarcinoma N (%)6 (12.5)Other5 (10.4)Performance statusn=48ECOG 022 (46)ECOG 124 (50)ECOG 2+2 (4)

Patient baseline characteristics

Patient

baseline

characteristics

n=48

HPV

testing

n=14

HPV+

14 (100)

PD-L1

expression

n=13

≥1% expression

9 (69%)

systemic

therapy

n=48

4 (8.4)

22 (45.8)

Type of treatment

n=48

Monotherapy

23 (47.9)

Combo with

another

ICI

19 (39.6)

Combo with

antiangiogenic

therapy

6 (12.5)

Slide191

IPI, immune prognostic index;

mPFS, median progression-free survival; mOS, median overall survivalBaseline IPI (Immune Prognostic Index) predicts survival in patients with advanced cervical cancer treated with immune checkpoint inhibitorsBlanc-Durand F et al., ESMO 2019, abstract 1025P (poster presentation)

Results

100

Percent

survival

100

Combo

Mono

Percent

survival

Months

100

Percent

survival

IPI 0

IPI 1

IPI 2

Months

IPI 0

IPI 1

IPI 2

P-val

mOS

p=0.028

19.0

months

10.3

months

0.9

months

p=0.0003

mPFS

p=0.004

4.9

months

2.6

months

0.6

months

p=0.001

Months

Median OS and PFS

for the cohort

were

14.5

and

3.4

months

respectively

Median OS for

patients

treated

with ICI

monotherapy

was 8.8 months

whereas

in the

combo

group

was not

reached

(p=0.017)

Overall survival

Progression-free survival

Slide192

A high correlation has been shown between baseline immune prognostic index (IPI score) and clinical outcome in patients with cervical cancer treated with immune checkpoint inhibitors Patients with higher IPI scores had poorer survival and are likely worse candidates for checkpoint inhibitors, particularly as monotherapyIPI scores should be considered in addition to PD-L1 expression status before introducing checkpoint inhibitors in patients with advanced cervical cancer

SUMMARY & CONCLUSIONS

Slide193

D. Omalley, A. Marabelle, A. De Jesus-Acosta, S. Piha-Paul, A. Arkhipov, F. Longo, D. Motola-Kuba, R. Shapira-Frommer, R. Geva, B. Rimel, J. Lopez-Martin, A. Hansen, J. Mehnert, X. Chen, F. Jin, K. Norwood, P. Ott

Pembrolizumab in Patients with MSI-H Advanced Endometrial Cancer from the KEYNOTE-158 Study

(abstract 1044P)

Slide194

Study background and methods

Pembrolizumab (anti-PD-1) provides durable responses in patients with MSI-H cancers and is approved in the US/Japan for the treatment of MSI-H advanced solid tumors MSI-H is expressed in ∼25% of endometrial cancers (EC) An analysis of patients with MSI-H advanced EC enrolled in cohort D (advanced EC) and cohort K (pan-tumor MSI-H) of the phase 2 KEYNOTE-158 basket study1 is presented

Eligible patients had advanced EC; progression on or intolerance to ≥ 1 line of standard therapy; measurable disease per RECIST v1.1; ECOG PS ≤ 1; and an MSI-H tumor sample determined retrospectively by centrally performed PCR (cohort D) or prospectively by IHC or PCR (cohort K)Patients received pembro 200 mg Q3W for up to 2 years or until PD or unacceptable toxicity. Tumor imaging was performed every 9 weeks for the first 12 months, and every 12 weeks thereafterResponse was assessed* by independent central radiologic review. The primary endpoint was ORR; secondary endpoints included DOR, PFS, OS and safety. Data cut off was Dec 6, 2018

1. clinicaltrials.gov: NCT02628067 Pembrolizumab in Patients with MSI-H Advanced Endometrial Cancer from the KEYNOTE-158 Study Omalley D et al., ESMO 2019, abstract 1044P (poster presentation)

MSI-H, microsatellite instability‒high

* per RECIST v1.1

PCR, polymerase chain reaction

IHC, immunohistochemistry

PD, disease progression

ORR, objective response rate

DOR

duration of response

Slide195

Summary of confirmed responses for participants with endometrial cancer*

a ORR was 45.5% (95% CI, 16.8–76.6) in the 11 participants from cohort D and 60.5% (95% CI, 43.4–76.0) in the 38 participants from cohort K.b Participants for whom not all target lesions were captured on ≥1 postbaseline imaging assessment.c Participants for whom no postbaseline tumor assessment was performed.MSI-H, microsatellite instability high; ORR, objective response rate; * assed per RECIST v 1.1 by independent central reviewPembrolizumab in Patients with MSI-H Advanced Endometrial Cancer from the KEYNOTE-158 Study Omalley D et al., ESMO 2019, abstract 1044P (poster presentation)

Efficacy Results

MSI-H,

(Cohorts

D +

Cohort

107

(Biomarker

Unselected)

ORR,

(95%

CI)

57.1

(42.2–71.2)

11.2

(5.9–18.8)

Best

overall response,

(%)

Complete

response

(16.3)

Partial response

(40.8)

(11.2)

Stable

disease

(16.3)

(24.3)

Progressive

disease

(22.4)

(52.3)

Not

evaluable

(2.0)

(1.9)

Not

assessed

(2.0)

(10.3)

Slide196

Duration of response (DOR) for participants with MSI-H endometrial cancer*

* assed per RECIST v 1.1 by independent central review; MSI-H, microsatellite instability highPembrolizumab in Patients with MSI-H Advanced Endometrial Cancer from the KEYNOTE-158 Study Omalley D et al., ESMO 2019, abstract 1044P (poster presentation)

Efficacy Results

100

DOR %

Time (

months

)

92%

89%

Median (95% CI), months

(2.9-27.0+)

No. at

risk

Slide197

PFS and OS results for participants with MSI-H endometrial cancer*

* assed per RECIST v 1.1 by independent central review; MSI-H, microsatellite instability high; PFS, progression-free survival; OS, overall survivalPembrolizumab in Patients with MSI-H Advanced Endometrial Cancer from the KEYNOTE-158 Study Omalley D et al., ESMO 2019, abstract 1044P (poster presentation)

Efficacy Results

100

PFS, %

Time (

months

)

64.6%

58.4%

Median (95% CI), months

25.7

(4.9-NR)

No. at

risk

Median (95% CI), months

(27.2-NR)

73.5%

69.1%

100

OS, %

Time (

months

)

No. at

risk

Slide198

Treatment-related adverse events in participants with MSI-H endometrial cancer

MSI-H, microsatellite instability high Pembrolizumab in Patients with MSI-H Advanced Endometrial Cancer from the KEYNOTE-158 Study Omalley D et al., ESMO 2019, abstract 1044P (poster presentation)

Safety results

Event, n (%)MSI-H n = 49Any AE39 (79.6)Led to death0AEs that occurred in ≥5 participants, n (%)Fatigue13 (26.5)Diarrhea12 (24.5)Nausea8 (16.3)Pruritus8 (16.3)Arthralgia7 (14.3)Hypothyroidism7 (14.3)Decreased appetite6 (12.2)Dry mouth5 (10.2)Myalgia5 (10.2)Rash5 (10.2)

Event,

(%)

-H

n =

Any

Grade

3–4

(16.3)

Led

death

Lymphocyte

count

decreased

(4.1)

Acute

respiratory

distress

syndrome

(2.0)

Drug-induced

liver

injury

(2.0)

Enterocolitis

(2.0)

Fulminant

type 1

diabetes

mellitus

(2.0)

Hyperglycemia

(2.0)

Hypophosphatemia

(2.0)

Neutrophil

count

decreased

(2.0)

Primary

adrenal

insufficiency

(2.0)

Rash

generalized

(2.0)

Transaminases

increased

(2.0)

White

blood cell count

decreased

(2.0)

There

were

grade

AEs.

Slide199

MSI-H, microsatellite instability high Pembrolizumab in Patients with MSI-H Advanced Endometrial Cancer from the KEYNOTE-158 Study Omalley D et al., ESMO 2019, abstract 1044P (poster presentation)

Pembrolizumab is associated with robust, durable antitumor activity, a promising survival benefit, and manageable safety in women with heavily pretreated MSI-H advanced endometrial cancerObjective response rate (ORR) was 57.1%Median duration of response (DOR) was not reached (95% CI, 2.9–27.0+ months)89% of participants had estimated response duration ≥12 months12-month PFS rate was 58.4%12-month OS rate was 73.5%ORR was substantially higher in participants with MSI-H advanced endometrial cancer vs. biomarker-unselected participantsThe safety profile of pembrolizumab was consistent with that previously observed in patients with advanced solid tumorsData support the use of pembrolizumab in women with previously treated MSI-H endometrial cancer

SUMMARY & CONCLUSIONS

Slide200

A. Redondo, N. Colombo, L. Dreosti, M. Mccormack, A. Nogueira Rodrigues, G. Scambia, A. Roszak, M. Donica, B. Ulker, A. González Martín

Primary results from CECILIA, a global single-arm phase 2 study evaluating bevacizumab, carboplatin and paclitaxel for advanced cervical cancer

(abstract 1053P)

Slide201

Study background and methods

The addition of Bevacizumab (BEV) to paclitaxel + cisplatin/topotecan for advanced cervical cancer (aCC) significantly improved overall survival (OS) and progression-free survival (PFS) in the phase III GOG240 trial1CECILIA* evaluated BEV with a more widely used carboplatin / paclitaxel (CP) backbone

Primary objective: Safety of BEV + CP for aCC, defined by the frequency /severity of (GI) perforation/fistula, GI-vaginal fistula and genitourinary (GU) fistula. Eligible patients had metastatic/recurrent/persistent CC not amenable to curative surgery and/or radiotherapy (RT)‡. Patients received BEV 15 mg/kg, P 175 mg/m2 and C AUC 5 q3w until disease progression, unacceptable toxicity or consent withdrawal. If BEV, C or P was stopped for adverse events, the remaining drug(s) could be continued alone

1. Tewari KS et al. Lancet. 2017 Oct 7;390(10103):1654-1663Primary results from CECILIA, a global single-arm phase 2 study evaluating bevacizumab (BEV), carboplatin (C) and paclitaxel (P) for advanced cervical cancerRedondo A et al., ESMO 2019, abstract 1053P (poster presentation)

* NCT02467907

GI, gastrointestinal

‡ Patients with ongoing bladder/rectal involvement, prior cobalt RT, history of fistula/GI perforation, or bowel resection ≤6 wk or chemoRT ≤3 mo before first dose were excluded

Slide202

CECILIA design and patient population

Primary results from CECILIA, a global single-arm phase 2 study evaluating bevacizumab (BEV), carboplatin (C) and paclitaxel (P) for advanced cervical cancerRedondo A et al., ESMO 2019, abstract 1053P (poster presentation)

Study design

Most patients (73%) had squamous cell carcinoma; 22% had adenocarcinomaThe majority of patients (71%) had received prior radiation, including chemo-radiation in 58%88 patients (59%) had received prior platinum

Measurable or non-measurable biopsy-confirmed metastatic, recurrent or persistent squamous cell carcinoma, adeno-squamous carcinoma or adenocarcinoma of the cervix not amenable to curative treatment with surgery and/or radiation therapy

Patients were ineligible if they had:

Ongoing bladder/rectal involvementaPreviously received cobalt radiotherapyA history of fistula/GI perforationUndergone bowel resection ≤6 weeks before the first doseReceived chemoradiation ≤3 months before the first dose

AUC = area under the curve; q3w = every 3 weeks.aAbsence of tumour in the bladder or rectal mucosa had to be demonstrated by MRI (or endoscopy/cystoscopy if MRI not easily accessible) in patients with pelvic disease.

Carboplatin AUC 5 q3w +paclitaxel 175 mg/m2 q3w +bevacizumab 15 mg/kg q3w

If bevacizumab, carboplatin orpaclitaxel was stopped for toxicity, the remaining drug(s) could be continued alone

Treatment continued until investigator or patient decision, disease progression, death, unacceptable

toxicity

consent withdrawal

Slide203

Treatment exposure

Overall, 17 patients (11.3%; 95% CI 6.7–17.5%) experienced at least one perforation / fistula event:GI perforation/fistula in 4.7% (1.9–9.4%), comprisingGI perforation in 2.0% (0.4–5.7%)GI fistula in 2.7% (0.7–6.7%)GI-vaginal fistula in 4.0% (1.5–8.5%)GU fistula in 4.7% (1.9–9.4%).

Total number of cycles initiated

160

No. of

patients

140

120

100

Bevacizumab

Paclitaxel

Carboplatin

Slide204

Grouped terms, grade ≥3a (n=150)

Adverse events of special interest

aNo grade ≥3 cases of congestive heart failure, cardiac disorders excluding arterial thromboembolism, pulmonary hypertension, posterior reversible encephalopathy syndrome or wound-healing complications.

Overview of safety:comparison with GOG-240

AE of special interestNo. of patients (%)Grade 3Grade 4Grade 5Neutropenia 22 (15)17 (11)1(1)Hypertension21 (14)00Bleeding 14 (9)1 (1)0Thrombocytopenia 16 (11)5 (3)0Fistula/abscess5 (3)00Thromboembolic events 2 (1)1 (1)0Proteinuria4 (3)00GI perforation1 (1)3 (2)1 (1)

AE,

No. of

patients

(%)

CECILIA (

=150)

GOG-0240

chemotherapy

+ bevacizumab arm (n=218)

2,6

Any perforation/

fistula

event

17 (11.3)

29 (13.3)

GI perforation

3 (2.0)

7 (3.2)

GI fistula

4 (2.7)

GI-vaginal fistula

6 (4.0)

18 (8.3)

GU fistula

7 (4.7)

Non-GI-vaginal,

vesical

female

genital

tract

fistulae

4 (1.8)

Slide205

Progression-free survival

Efficacy

PFS, progression-free survivalPrimary results from CECILIA, a global single-arm phase 2 study evaluating bevacizumab (BEV), carboplatin (C) and paclitaxel (P) for advanced cervical cancerRedondo A et al., ESMO 2019, abstract 1053P (poster presentation)

No.At risk150168124113947959524337272417151286430

PFSn=150Events, n (%)115 (77)12-months PFS rate, % (95% CI)46.2 (37.6-54.4)18-months PFS rate, % (95% CI)29.0 (21.5-36.9)

Estimated probability

Time (months)

0.0

0.1

0.2

0.3

0.4

0.5

0.6

0.7

0.8

0.9

1.0

10.9 months

(95% CI 10.1-13.7)

Slide206

Overall survival

Efficacy

OS, overall survivalPrimary results from CECILIA, a global single-arm phase 2 study evaluating bevacizumab (BEV), carboplatin (C) and paclitaxel (P) for advanced cervical cancerRedondo A et al., ESMO 2019, abstract 1053P (poster presentation)

No. at risk15014513812411610710189817570675942312621171320

OSn=150Events, n (%)73 (49)12-months OS rate, % (95% CI)77.8 (70.0-83.9)24-months OS rate, % (95% CI)51.9 (42.8-60.3)

Time (months)

0.0

0.1

0.2

0.3

0.4

0.5

0.6

0.7

0.8

0.9

1.0

25.0 months

(95% CI 20.9-30.4)

Estimated

probability

Slide207

The CECILIA study results (after a median follow-up of 27.8 months) demonstrate that bevacizumab can be combined with carboplatin + paclitaxel in patients with advanced cervical cancer based on the studied populationNo new safety signals were observedThe incidence of fistula / GI perforation is in line with rates reported in GOG-240, acknowledging the challenges of cross-trial comparisonAll but one patient with fistula had previously received chemoradiation and several had evidence of radiation effectsEfficacy results (median PFS of 10.9 months, median OS of 25.0 months and 61% objective response rate) are encouragingContinuation of bevacizumab after stopping chemotherapy in a large proportion of patients may have contributed to median OS exceeding 2 yearsResults from CECILIA provide reassurance that combining bevacizumab with a more widely used carboplatin-based regimen is a reasonable option in the studied population

SUMMARY & CONCLUSIONS

Slide208

Endometrial, cervical &

rare gynaegological cancer

ESMO 2019 Fazit der Autoren

Abstract LBA61

Die GOG 0281- Studie ist als erste positive Phase II/III Studie zum

low

grade serösen Ovarialkarzinom besonders hervorzuheben. Sie begründet die Anwendung des MEK-inhibitors

Trametinib

als neue Standard-Therapieoption beim Rezidiv dieser Entität. Nebenwirkungen führten bei einem nennenswerten Anteil der Probanden zum Therapieabbruch.

Abstract LBA62

In der Phase I/II-Studie

CheckMate

358 wurden die Kombination der beiden Checkpoint-Inhibitoren Nivolumab und

Ipilimumab

beim rezidivierenden oder metastasierten Zervixkarzinom getestet. Die beobachteten Ansprechraten und das Gesamtüberleben rechtfertigen weitergehende Studien.

Abstract 994O

In der Phase Ib/II-Studie KEYNOTE-146 führte die Kombination des Multikinase-Inhibitors

Lenvatinib

dem PD1-Antikörper

Pembrolizumab

zu einer unerwartet hohen Ansprechrate und Ansprechdauer bei der Behandlung des fortgeschrittenen, systemisch vorbehandelten, mikrosatelliten-stabilen & nicht MMR-defizienten Endometrium-karzinoms. Die Ergebnisse begründeten die beschleunigten Zulassung in den USA, Kanada & Australien. Phase-III-Studien rekrutieren aktuell.

Slide209

ESMO 2019

Fazit der Autoren

Abstract LBA63Die molekulare Subgruppen Klassifikation der Hochrisiko-Endometriumkarzinome hat einen starken prognostischen Wert hinsichtlich Recurrence-Free Survival (RFS) in der PORTEC 3-Studie gezeigt. Weiterhin hat der Nutzen der zusätzlichen Chemotherapie zwischen den unterschiedlichen molekularen Subgruppen zum Teil stark variiert, so dass diese eventuell zukünftig zur Auswahl der optimalen adjuvanten Therapie beitragen könnten.Abstract 999PDDas klarzellige Ovarialkarzinom kann in vier molekularen Subgruppen (PD1-high, CTLA4-high, Antigen-Präsentation und pro-angiogenic) klassifiziert werden. Die Verteilung der molekularen Subgruppen scheint vom ethnischen Herkunft unabhängig zu sein, deren prognostische Rolle ist aktuell allerdings noch unklar. Abstract 1025PDie Bestimmung des Immune-Prognostic-Index (IPI)-Scores scheint für die weitere Selektion zwischen den PDL1-positiven Zervixkarzinomen, welche für eine Monotherapie mit einem Immun-Checkpoint Inhibitor geeignet sind, ein versprechender prognostischer und prädiktiver Faktor zu sein. Prospektive Validierung in größeren Patienten-kollektiven ist dennoch erforderlich.

Endometrial, cervical &

rare gynaegological cancer

Slide210

ESMO 2019

Fazit der Autoren

Abstract 1044PDie offene Phase III CECILIA-Studie überprüfte bei Patientinnen (n=150) mit fortgeschrittenem Zervixkarzinom die Sicherheit der Kombination Carboplatin/Paclitaxel + Bevacizumab im Hinblick auf Anzahl und Schweregrad von Fisteln - gastrointestinal, urogenital, GI-Trakt) im Vergleich zur GOG 0240 Studie.*Im Ergebnis zeigten sich mit 11,3 % vergleichbare viele Ereignisse wie in der GOG 0240 (13,3%) und damit keine neuen Sicherheitsaspekte. Das mediane PFS betrug 10,9 Monate, das mediane OS 25 Monate, die ORR 61 %. Die Kombination Carboplatin/Paclitaxel+Bev könnte deshalb im klinischen Alltag eine Alternative darstellen zur derzeit zugelassenen Therapie mit Bev in Kombination mit Cisplatin/Paclitaxel oder Topotecan+Paclitaxel, ist allerdings derzeit ohne aktuelle Zulassung.Abstract 1053PIn der Keynote158 Basket -Studie zeigte Pembrolizumab bei Patientinnen (n=49) mit MSI-H, fortgeschrittenem Endometrium-karzinom ein gutes, lang anhaltendes Ansprechen (ORR 57,1%), ein 12 Monats-PFS von 58,4 % und ein 12 Monats-OS von 73,5 %. Bei 89 % der Patienten wurde ein Ansprechen ≥ 12 Monate beobachtet. Die häufigsten Nebenwirkungen waren Fatigue, Diarrhoe, Nausea und Pruritus (alle Grade).Pembrolizumab ist somit eine vielversprechende Option für Patientinnen mit MSI-H fortgeschrittenem Endometriumkarzinom.

Endometrial, cervical & rare gynaegological cancer

* GOG 0240:

Cisplatin+Paclitaxel+Bevacizumab

bzw.

Topotecan+Paclitaxel+Bevacizumab

)

Slide211

Legal Disclaimer

This slide-kit is intended for healthcare professionals only The authors of this report were supported by TESARO Bio Germany GmbH, their participation at the ESMO 2019 was in agreement with legal and ethical guidelinesThe content presented here corresponds to opinions and impressions of the authors and does not necessarily reflect the views of TESARO Bio Germany GmbHTESARO BIO Germany GmbH is not responsible for the content of this report

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