Please note, these are the - PowerPoint Presentation

Slide1

Please note, these are the

actual

video-recorded proceedings from the

live

CME event and may include the use of trade names and other raw, unedited content.

Slide2

Consensus OR Controversy?

Clinical Investigators Provide Perspectives on the Treatment of Metastatic Non-Small Cell Lung Cancer in Patients Without Targetable Tumor Mutations March 17, 20177:30 PM – 9:00 PM

Julie R Brahmer, MDCorey J Langer, MDNaiyer Rizvi, MDHeather Wakelee, MD

Faculty

Moderator

Neil Love, MD

Slide3

Disclosures for

Dr BrahmerAdvisory Committee

Bristol-Myers Squibb Company, MerckConsulting AgreementsBristol-Myers Squibb Company, Celgene Corporation, Lilly, MerckContracted Research

AstraZeneca Pharmaceuticals LP, Bristol-Myers Squibb Company, Merck

Slide4

Disclosures for

Dr LangerAdvisory Committee

Abbott Laboratories, AstraZeneca Pharmaceuticals LP, Boehringer Ingelheim Pharmaceuticals Inc, Bristol-Myers Squibb Company, Celgene Corporation, EMD Serono Inc, Genentech BioOncology, GlaxoSmithKline, ImClone Systems, a wholly owned subsidiary of Eli Lilly and Company, Lilly, Merck, Novartis Pharmaceuticals Corporation, Pfizer IncConsulting AgreementsAstraZeneca Pharmaceuticals LP, Boehringer

Ingelheim Pharmaceuticals Inc, Bristol-Myers Squibb Company, Celgene Corporation, Genentech BioOncology, GlaxoSmithKline, ImClone Systems, a wholly owned subsidiary of Eli Lilly and Company, Lilly, Merck, Novartis Pharmaceuticals Corporation, Pfizer IncContracted Research

Advantagene

Inc

, Celgene Corporation, GlaxoSmithKline, Merck,

Inovio

Pharmaceuticals

Data and Safety Monitoring Board

Abbott Laboratories, Amgen

Inc

, Lilly, Peregrine Pharmaceuticals

Inc

,

Synta

Pharmaceuticals Corp

Slide5

Disclosures for

Dr RizviAdvisory Committee and Consulting Agreements

AstraZeneca Pharmaceuticals LP, Merck, Novartis Pharmaceuticals Corporation, Roche Laboratories IncOwnership InterestGritstone Oncology

Slide6

Disclosures for

Dr WakeleeConsulting Agreements

ACEA Biosciences Inc, Genentech BioOncology, Helsinn Group, Peregrine Pharmaceuticals Inc, Pfizer IncContracted ResearchAstraZeneca Pharmaceuticals LP, Bristol-Myers Squibb Company, Celgene Corporation, Clovis Oncology, Exelixis Inc, Genentech BioOncology

, Gilead Sciences Inc, Lilly, Novartis Pharmaceuticals Corporation, Pfizer Inc, Pharmacyclics LLC, an AbbVie Company, Roche Laboratories Inc, XcoveryGrants

Clovis Oncology,

Exelixis

Inc

, Gilead Sciences

Inc

,

Pharmacyclics

LLC, an AbbVie Company,

Xcovery

Slide7

Disclosures for Moderator Neil Love, MD

Dr Love is president and CEO of Research To Practice, which receives funds in the form of educational grants to develop CME activities from the following commercial interests: AbbVie Inc, Acerta Pharma, Agendia Inc, Amgen Inc, Ariad Pharmaceuticals Inc, Array BioPharma

Inc, Astellas Pharma Global Development Inc, AstraZeneca Pharmaceuticals LP, Baxalta Inc, Bayer HealthCare Pharmaceuticals, Biodesix Inc, bioTheranostics Inc, Boehringer Ingelheim Pharmaceuticals Inc, Boston Biomedical Pharma Inc, Bristol-Myers Squibb Company, Celgene Corporation, Clovis Oncology, CTI BioPharma Corp, Daiichi Sankyo Inc, Dendreon Pharmaceuticals Inc, Eisai Inc, Exelixis Inc, Foundation Medicine, Genentech BioOncology, Genomic Health Inc, Gilead Sciences Inc, Halozyme Inc, ImmunoGen Inc, Incyte Corporation, Infinity Pharmaceuticals Inc, Janssen Biotech Inc, Jazz Pharmaceuticals Inc, Lexicon Pharmaceuticals Inc, Lilly, Medivation

Inc, a Pfizer Company, Merck, Merrimack Pharmaceuticals Inc, Myriad Genetic Laboratories Inc, NanoString Technologies, Natera Inc, Novartis Pharmaceuticals Corporation, Novocure, Onyx Pharmaceuticals, an Amgen subsidiary, Pharmacyclics LLC, an AbbVie Company, Prometheus Laboratories Inc, Puma Biotechnology Inc, Regeneron Pharmaceuticals Inc, Sanofi Genzyme, Seattle Genetics, Sigma-Tau Pharmaceuticals Inc, Sirtex Medical Ltd, Spectrum Pharmaceuticals Inc, Taiho Oncology Inc, Takeda Oncology, Tesaro Inc, Teva Oncology, Tokai Pharmaceuticals Inc and VisionGate Inc.

Slide8

Agenda

Module 1:

Front-Line TreatmentModule 2: Second- and Later-Line Therapy Module 3: Toxicities Associated with and Relative Contraindications to Immune Checkpoint Inhibition 

Module 4: Ongoing Investigation, Future Directions with Immune Checkpoint Inhibitors 

Slide9

Module 1: Front-Line

Treatment

Slide10

In general, which first-line treatment regimen would you most likely recommend for a younger patient with metastatic

nonsquamous cell lung cancer and no identified targetable mutations with a PD-L1 TPS of 60%?

A patient with squamous lung cancer?PembrolizumabPembrolizumabPembrolizumabPembrolizumab

PembrolizumabNONSQUAMOUSSQUAMOUSPembrolizumab

Pembrolizumab

Pembrolizumab

Pembrolizumab

Pembrolizumab

Pembrolizumab

Pembrolizumab

Slide11

Would you generally order a PD-L1 assay for an otherwise healthy patient who presents with metastatic NSCLC?

Yes, PD-L1 IHC 22C3 pharmDx

Yes, PD-L1 IHC 22C3 pharmDx Yes, PD-L1 IHC 22C3 pharmDx Yes, PD-L1 IHC 22C3 pharmDx Yes, PD-L1 IHC 22C3 pharmDx, PD-L1 IHC 28-8 pharmDx

Yes, PD-L1 IHC 22C3 pharmDx 

Slide12

A 65-year-old patient presents with significant respiratory distress and highly symptomatic metastatic

nonsquamous lung cancer and a PD-L1 TPS of 60%. What would be your most likely treatment recommendation?

PembrolizumabCarbo/pem/pembrolizumabPembrolizumabPembrolizumab +/- carbo/pemetrexed

PembrolizumabPembrolizumab

Slide13

A 65-year-old patient presents with significant respiratory distress and highly symptomatic metastatic

squamous cell cancer of the lung and a PD-L1 TPS of 60%. What would be your most likely treatment recommendation?

PembrolizumabCarbo/nab paclitaxel/pembrolizumabPembrolizumabPembrolizumab +/- carbo/nab paclitaxel

PembrolizumabPembrolizumab

Slide14

Anti-PD-1/PD-L1

Antibodies: Mechanism of ActionPD-1 expression on tumor-infiltrating lymphocytes is associated with decreased cytokine production and effector function3 Approved Drugs:

Nivolumab/pembrolizumab binds PD-1 receptors on T cells and disrupts negative signaling triggered by PD-L1/PD-L2 to restore T-cell antitumor functionAtezolizumab binds PD-L1 receptors

MHC

PD-L1

PD-1

PD-1

PD-1

PD-1

T-cell

receptor

T-cell

receptor

PD-L1

PD-L2

PD-L2

MHC

CD28

B7

T cell

NF

κ

B

Other

PI3K

Dendritic

cell

Tumor cell

IFN

γ

IFN

γ

R

Shp-2

Shp-2

Nivolumab/

Pembrolizumab

: PD-1 Receptor Blocking

Ab

Atezolizumab

: PD-L1 Receptor Blocking Ab

Slide15

PD-1/PD-L1 Inhibitors in NSCLC

Checkpoint

inhibitor

Antibody typeStage

PD-L1

test

Anti-PD-1

Nivolumab

(BMS-936558)

IgG4

Approved 2

nd

line

CheckMate

057/017

28-8

“complementary”

Pembrolizumab

(MK-3475)

IgG4 (humanized)

1

st

line – PD-L1 ≥50%

2

nd

line – PD-L1 ≥1%

Keynote

010/024

22C3

“companion”

Anti-PD-L1

Atezolizumab

(MPDL3280A)

IgG1

(engineered)

Approved 2

nd

line

OAK, BIRCH,

IMpower

SP142

“complementary”

Durvalumab

(MEDI-4736)

IgG1

Phase III

(ATLANTIC, PACIFIC,

BR31, ARCTIC, MYSTIC, LUNG-MAP)

SP263

Avelumab

(MSB0010718C)

IgG1

Phase III

(JAVELIN)

National Institutes of Health. Available at: http://

clinicaltrials.gov

Slide16

Biomarkers: PD-L1 (IHC) as a Biomarker in Lung Cancer for Anti-PD-(L)1 Therapy

Drug

Nivolumab

1,2

Pembrolizumab

3

Atezolizumab

4

Durvalumab

5

Assay

Rabbit

mAb

28-8

automated IHC

Murine

mAb

22C3

IHC

Rabbit

mAb

SP142

automated IHC

Rabbit

mAb

SP263

automated IHC

Cells scored

Tumor cell membrane

Tumor cell

(and stroma)

Infiltrating immune cells

Tumor cell membrane

Tissue

FFPE

FFPE

FFPE

FFPE

Cut-point

1%-50%

1%-50%

1%-50%

1%-50%

TC1 or IC1

NR

1.

Gettinger

SN

et al.

J

Clin

Oncol

2015;33(

suppl

);Abstract

8025. 2.

Gettinger

SN

et al.

J

Clin

Oncol

2015.

3

.

Garon

EB

et al.

N

Engl

J

Med

2015;372(21):

2018-28

. 4. Horn

L

et al.

J

Clin

Oncol

2015;33(

suppl

);Abstract

8029.

5

.

Rebelatto

MC

et al.

J

Clin

Oncol

2015;33(

suppl

);Abstract

8033.

Slide17

Key endpoints

Primary: PFS (RECIST v1.1 per blinded, independent central review)Secondary: OS, ORR, safetyKEYNOTE-024 Study

DesignPembrolizumab 200 mg IV q3wk(2 years)PDaPembrolizumab 200 mg

q3wk for 2 yearsPlatinum doublet chemotherapy

(4-6 cycles)

NCT02142738

Reck

M et al.

N

Engl

J Med

2016;375(19):1823-33.

R

Key Eligibility

Criteria

Untreated Stage IV NSCLC

PD-L1

TPS ≥50%

ECOG PS 0-1

No activating EGFR mutation or ALK translocation

No untreated brain metastases

No active autoimmune disease requiring systemic therapy

N = 305

1:1

Slide18

KEYNOTE-024: Response and Progression-Free Survival

ORR

is improved, with a control arm that performs as expected (from other Phase III trials)45% ORR is the best RR ever reported in 1st line setting (and with a monotherapy!)Time to response is identical between pembrolizumab and chemotherapyPFS is improved by 4.3 months (HR of 0.50

)Improvement of PFS in all subgroups (except female/never smokers)Strongest signal of PFS benefit observed in SCC (HR of 0.35)imaging was every

9

weeks

Reck

M et al.

N

Engl

J Med

2016;375(19):1823-33

,

Proc ESMO

2016;Abstract

LBA8_PR

.

Events, n

Median,

mo

HR (95% Cl)

P

Pembro

73

10.3

0.50

<0.001

Chemo

116

6.0

(0.37-0.68)

CR

PR

Slide19

KEYNOTE-024: Overall Survival

Clear survival benefitEstimated rate of OS at 12 months: 70% (pembro

) vs 54% (chemo)HR for death: 0.60Crossover was limited to 50% of the patientsReck M et al. N Engl J Med 2016;375(19):1823-33.

Events, n

Median,

mo

HR (95% Cl)

P

Pembro

44

NR

0.60

0.005

Chemo

64

NR

(0.41-0.89)

Slide20

KEYNOTE-024: Select Adverse Events

Reck M et al.

N Engl J Med 2016;375(19):1823-33.

Adverse event, n (%)

Pembrolizumab

(N = 154)

Chemotherapy

(N = 150)

All grades

Grade ≥3

All grades

Grade

≥

3

Diarrhea

22 (14.3)

6 (3.9)

20 (13.3)

2 (1.3)

Fatigue

16 (10.4)

2 (1.3)

43 (28.7)

5

(3.3)

Pyrexia

16 (10.4)

0

8 (5.3)

0

Immune-mediated adverse event

Any

45 (

29.2)

15 (9.7)

7 (4.7)

1 (0.7)

Pneumonitis

9 (5.8)

4 (2.6)

1 (0.7)

1 (0.7)

Severe skin reaction

6 (3.9)

6 (3.9)

0

0

Colitis

3 (1.9)

2 (1.3)

0

0

Slide21

FDA Approval of Pembrolizumab as First-Line Therapy for Patients with PD-L1-Positive NSCLC

“On October 24, 2016, the US Food and Drug Administration approved pembrolizumab for the treatment of patients with metastatic non-small cell lung cancer (NSCLC) whose tumors express PD-L1 [Tumor Proportion Score ≥50%] as determined by an FDA-approved test. This is the first FDA approval of a checkpoint inhibitor for first-line treatment of lung cancer. This approval also expands the indication in second-line treatment of lung cancer to include all patients with PD-L1-expressing NSCLC.”

http://www.fda.gov/Drugs/InformationOnDrugs/ApprovedDrugs/ucm526430.htm

Slide22

CheckMate

026:

A Phase III

Trial of Nivolumab vs Chemotherapy in First-Line NSCLC

Nivolumab

3 mg/kg IV q2wk

n

= 271

Crossover

nivolumab

(optional)

Chemotherapy

(histology dependent

)

Maximum of 6 cycles

n = 270

R

Key Eligibility Criteria

Stage IV or recurrent NSCLC

No prior systemic therapy for advanced disease

No

EGFR/ALK

mutations sensitive to available targeted inhibitor therapy

≥1% PD-L1

expression

CNS metastases permitted if adequately treated at least 2 weeks prior to randomization

1:1

Socinski

M et al.

Proc ESMO

2016;Abstract LBA7_PR.

Tumor scans

q6wk

until

wk

48 then

q12wk

Disease progression

Disease progression or unacceptable toxicity

Primary Endpoint:

PFS (≥5% PD-L1+)

Secondary Endpoints:

PFS

(

≥1%

PD-L1

+)

OS

ORR

Stratification factors at randomization:

PD-L1 expression (<5% vs ≥5%)

Histology (squamous vs

nonsquamous

)

Slide23

Nivolumab

Chemotherapy

Months

PFS (%)

24

21

18

15

12

9

6

3

27

100

80

60

40

0

20

0

Nivolumab

n = 211

Chemotherapy

n = 212

Median PFS, months

4.2

5.9

1-year PFS rate, %

23.6

23.2

All randomized patients (≥1% PD-L1+): HR =

1.17

HR =

1.15

,

P

= 0.2511

Socinski

M et al.

Proc ESMO

2016;Abstract LBA7_PR.

CheckMate

026: Primary Endpoint (PFS per IRRC in ≥5% PD-L1

+)

Slide24

CheckMate

026: Overall Survival (≥5% PD-L1+)

Nivolumab n = 211Chemotherapyn = 212

Median OS, months 14.413.2

1-year OS rate, %

56.3

53.6

All randomized patients (≥1% PD-L1+): HR =

1.07

HR =

1.02

Months

OS (%)

24

21

18

15

12

9

6

3

30

100

80

60

40

0

20

0

27

Nivolumab

Chemotherapy

60.4% in the

chemotherapy

arm had subsequent

nivolumab

therapy

43.6% in the

nivolumab

arm had subsequent systemic therapy

Socinski

M et al.

Proc ESMO

2016;Abstract LBA7_PR.

Slide25

Have you or would you use an anti-PD-1/PD-L1 antibody in combination with chemotherapy for a patient with metastatic NSCLC?

I haveI haven't but would for the right patient

I haveI haven’t but would for the right patient I haven’t and would not I haven’t and would not 

Slide26

Carboplatin AUC

5

mg/mL/min + pemetrexed 500 mg/m2 q3wk for 4 cyclesPDEndpointsPrimary: ORR (RECIST v1.1 per blinded, independent central review)Key secondary: PFS

Langer C et al. Lancet Oncol 2016;17(11):1497-1508, Proc ESMO 2016;Abstract LBA46_PR.

KEYNOTE-021

Cohort G

R

Key Eligibility

Criteria

Untreated

Stage

IIIB

or

IV

nonsquamous

NSCLC

No activating EGFR mutation or ALK translocation

Provision of a sample

for PD-L1 assessment

ECOG PS 0-1

No untreated brain metastases

No ILD or pneumonitis requiring systemic steroids

Pembrolizumab

200 mg

q3wk

for 2 years

+

carboplatin

AUC 5 mg/mL/min +

pemetrexed

500 mg/m

2

q3wk for 4

cycles

Pembrolizumab

200 mg q3wk

for 2 years

N = 123

1:1

Slide27

KEYNOTE-021: Survival

dataMedian PFS improved by 4.1 months No difference in OS Estimated rate of OS @ 12 months: 75% (combo) vs 72% (CT)In chemotherapy arm, crossover is 51% to

anti-PD-1/PD-L1 therapies (pembrolizumab and others)Langer C et al.  Lancet Oncol 2016;17(11):1497-1508, Proc ESMO 2016;Abstract LBA46_PR.

Events, n

Median

HR (95% Cl)

Pembro

+ chemo

 (

n

= 60)

23

13.0

mo

0.53

(0.31-0.91)

Chemo alone

 (n = 63)

33

8.9

mo

p

= 0.0102

Events, n

HR (95% Cl)

Pembro

+ chemo

13

0.90

(0.42-0.91)

Chemo alone

14

Slide28

KEYNOTE-021: Select Adverse Events

Pembrolizumab

+ Carbo/Pemetrexed(n = 59)

Carbo/Pemetrexed(n = 62)

AEs

Grade 1-2

Grade

≥3

Grade 1-2

Grade

≥3

Fatigue

61%

3%

40%

0

Anemia

20%

12%

39%

15%

Decreased neutrophil count

12%

5%

10%

3%

Decreased lymphocyte

count

5%

3%

3%

2%

Thrombocytopenia

2%

4%

3%

3%

Hypothyroidism

15%

0

5%

0

Hyperthyroidism

8%

0

2%

0

Pneumonitis

3%

2%

0

0

Langer CJ et al. Lancet

Oncol

2016;17(11):1497-1508.

Slide29

Issues in First-Line Treatment of Patients with

TPS < 50%Nonsquamous NSCLCChoice of platinum doubletUse of bevacizumab

Use of maintenance therapySquamous NSCLC Choice of platinum doubletRole, if any, of necitumumab

Slide30

In general, which first-line treatment regimen would you most likely recommend for a younger patient with metastatic

nonsquamous lung cancer and no identified targetable mutations with a PD-L1 TPS of 10%?Carbo/pem/

bevCarbo/pemCarbo/pem/bevCarbo/pemCarbo/

pem/bevCarbo/pem/bev

Slide31

In general, which first-line treatment regimen would you most likely recommend for a younger patient with metastatic

squamous lung cancer and no identified targetable mutations with a PD-L1 TPS of 10%?Carbo/gem or

carbo/nab paclitaxelCarbo/nab paclitaxelCarbo/paclitaxel or carbo/nab paclitaxelCarbo/paclitaxel Cis/gem

Cis/gem

Slide32

A 55-year-old patient in otherwise excellent health is about to be treated

up front for metastatic squamous cell lung cancer with a TPS of 10% and is interested in any option that will help extend his survival. Would you offer this patient necitumumab as part of up-front treatment?

NoNoYesYesYesYes

Slide33

Primary

endpoint: Overall survival

SQUIRE: Necitumumab with Cisplatin/Gemcitabine in Stage IV Squamous Carcinoma of the Lung

Thatcher N et al.

Lancet

Oncol

2015;16(7):763-74.

PD

PRCRSD

PD

PD

Maximum of 6 cycles

R

Screening

Entry criteria:

Stage IV

squamous

NSCLC

ECOG PS 0-2

Neci

q3wk

(

800 mg D1, D8)

Gem-cis

q3wk

(N = 548)

Gemcitabine

(1,250

mg/m², D1, D8)

Cisplatin

(

75 mg/m², D1)

Gem

-cis

+

neci

q3wk

(

N

= 545)

Necitumumab

(800 mg D1,

D8)

Gemcitabine

(1,250

mg/m², D1,

D8)

Cisplatin

(

75 mg/m², D1)

Slide34

Median

OS:Gem-cis

+ neci: 11.5 mosGem-cis: 9.9 mos HR: 0.84; p = 0.012

Toxicities (Gr ≥ 3) – Skin rash 7.0% vs <1%, hypomagnesemia 9.0% vs <1%, HSR 0.4% vs 0.0Patients/events:Gem-cis + neci: 545/418Gem-cis: 548/442

Thatcher N et al.

Lancet

Oncol

2015;16(7):763-74.

SQUIRE: Primary Outcome Overall Survival (ITT

)

1-yr OS

2-yr OS

48%

20%

43%

17%

Months

Overall survival (%)

Slide35

Overall Survival in Patients With EGFR-Positive NSCLC

1. Hirsch FR et al. WCLC 2015;Abstract ORAL32.05;

2. Herbst R et al. WCLC 2015;Abstract PLEN04.01

SQUIRE (EGFR FISH+)1S0819 (SqCLC-EGFR FISH+)2 GC+N GC N = 111 N = 97Unstratified HR (95% CI) 0.70 (0.52, 0.96)

Median, months (95% CI) 12.6 (11.5, 15.9) 9.2 (7.2, 12.1)

Median 95%

N Events in Months Conf.

Int

Cetuximab

Arm

55 50 11.8 (8.6

–

13.5)

Control Arm

56 52 6.4 (4.2

–

8.7)

P = 0.006

HR=0.56 (0.37-0.84)

Slide36

Module

2:

Second- and Later-Line Therapy

Slide37

A

60-year-old current smoker with asymptomatic squamous cell cancer of the lung with limited pulmonary metastases and a TPS of 70% receives pembrolizumab but on first evaluation is found to have disease progression on imaging with new lesions and is still asymptomatic. What would be your most likely treatment recommendation? What if the patient were moderately symptomatic?

Continue pembrolizumabCarbo/nab paclitaxel +/- ramucirumabContinue pembrolizumabCarbo/paclitaxel

Cis/gemCarbo/nab paclitaxelContinue pembrolizumab and add

carbo/

nab

paclitaxel

Carbo/

nab

paclitaxel

+/-

ramucirumab

Carbo/paclitaxel

Cis/gem

ASYMPTOMATIC

SYMPTOMATIC

Carbo/gem

+/-

ramucirumab

Carbo/gem

+/-

ramucirumab

Slide38

A patient with metastatic

squamous cell lung cancer and a PD-L1 TPS of <1% receives first-line chemotherapy and experiences asymptomatic disease progression. What would you most likely recommend for this patient? What if the patient were symptomatic?

NivolumabAtezolizumabAtezolizumabAtezolizumabNivolumabAtezolizumab

AtezolizumabAtezolizumabASYMPTOMATIC

SYMPTOMATIC

Atezolizumab

Atezolizumab

Atezolizumab

Atezolizumab

Slide39

A patient with metastatic

nonsquamous lung cancer and a PD-L1 TPS of <1% receives first-line chemotherapy and experiences asymptomatic disease progression. What would you most likely recommend for this patient? What if the patient were symptomatic?

NivolumabAtezolizumabAtezolizumabAtezolizumabNivolumabAtezolizumab

AtezolizumabAtezolizumabASYMPTOMATIC

SYMPTOMATIC

Atezolizumab

Atezolizumab

Atezolizumab

Atezolizumab

Slide40

CheckMate

017: Nivolumab versus Docetaxel in Squamous NSCLCBrahmer J et al.

N Engl J Med 2015;373(2):123-35.

Slide41

CheckMate

057: Nivolumab vs Docetaxel in Nonsquamous

NSCLCPhase III, 582 patients randomized Nivolumab 3 mg/kg q2wk vs docetaxel 75 mg/m2 Q3Primary endpoint OSTrial stopped early by DSMC, met its primary endpoints at interim analysis

Nivolumab (n = 292)Docetaxel (

n = 290

)

ORR

19%

12%

P-value

0.02

Median DOR,

mos

17.2

5.6

71 (24%) patients on nivolumab

were treated beyond RECIST v1.1-defined progression

Non-conventional benefit was observed in 16 patients (not included in best overall response)

Borghaei

H et al.

N

Engl

J Med

2015;373(17):1627-39.

Nivolumab

(n = 292

)

Docetaxel

(n = 290

)

mOS

,

mo

12.2

9.4

HR = 0.73;

p

= 0.0015

1-yr OS rate = 51

%

1-yr OS rate = 39%

Slide42

KEYNOTE-010:

Pembrolizumab versus DocetaxelTPS ≥50%

All patientsPembro

2 mg/kg vs docetaxel HR 0.54 (14.9 mo vs 8.2 mo; p = 0.0002)Pembro 10 mg/kg vs docetaxel HR 0.50 (17.3 mo vs 8.2 mo; p < 0.0001).

Pembro

2 mg/kg

vs

docetaxel HR 0.71

(10.4

mo

vs

8.5

mo

;

p

= 0.0008

)

Pembro

10 mg/kg

vs

docetaxel

HR 0.61

(12.7

mo

vs 8.5

mo

;

p

< 0.0001

)

Herbst

RS et

al.

Lancet

2016;387(10027):1540-50.

Slide43

OAK:

Atezolizumab versus Docetaxel in NSCLCRittmeyer A et al. Lancet 2017;389(10066):255-65.

Slide44

OAK: Overall Survival According to PD-L1 Levels

Population

Atezolizumab

DocetaxelHazardratiop

-value

ITT

(N = 850)

13.8

mo

9.6

mo

0.73

0.0003

TC3 or IC3

(N = 137)

20.5

mo

8.9

mo

0.41

<0.0001

TC2/3 or IC2/3

(N = 265

)

16.3

mo

10.8

mo

0.67

0.0080

TC1/2/3 or IC1/2/3

(N = 463)

15.7

mo

10.3

mo

0.74

0.0102

TC0 and IC0

(N = 379)

12.6

mo

8.9

mo

0.75

0.0215

Rittmeyer

A et al.

Lancet

2017;389(10066):

255-65

;

Barlesi

F et al.

Proc ESMO

2016;Abstract

LBA44_PR

Slide45

Issues in Second-Line or Later Treatment of Patients with TPS < 50%

Role of ramucirumabEGFR TKIs in patients with non-EGFR mutated diseaseLung-MAP trial

Slide46

A 60-year-old patient with metastatic

squamous cell lung cancer and no targetable mutations with a TPS of 10% receives carboplatin/paclitaxel, followed by

nivolumab, which results in disease progression. What would be your most likely treatment recommendation?Docetaxel + ramucirumabDocetaxel + ramucirumabGemcitabineGemcitabine

GemcitabineGemcitabine

Slide47

A 60-year-old patient with metastatic

nonsquamous lung cancer and no targetable mutations with a TPS of 10% receives carboplatin/pemetrexed

followed by pemetrexed maintenance, experiences progressive disease, is started on pembrolizumab and experiences progression again. What would be your most likely treatment recommendation? Docetaxel + ramucirumabDocetaxel + ramucirumabResume carbo, add taxane and consider bev

GemcitabineDocetaxel + ramucirumab Docetaxel + ramucirumab 

Slide48

REVEL: Docetaxel ±

Ramucirumab in the Second-Line Setting

Median (95% CI)

Censoring

rate

RAM + DOC

RAM + DOC

vs

PL + DOC

:

10.5

31.8%

PL + DOC

9.1

27.0%

Stratified

HR

= 0.857

Stratified log-rank

p

=

0

.0235

0

20

40

60

80

100

Overall

survival

(%)

0

3

6

9

12

15

18

21

24

27

30

33

36

Survival

time

(months)

RAM + DOC

PL + DOC

Censored

Toxicities

(Gr

≥3): Fatigue/nausea 14

vs

10%,

stomatitis

4

vs

2%

No increase in Gr

3-4 hemorrhage

but Gr

1-2 hemorrhage =

26.5

vs 12.9

% (largely epistaxis

)

Garon

EB et al.

Lancet

2014;384(9944):665-73.

328

of

1,240

(26%) patients had squamous histology

OS HR

squamous

subset

=

0.88 (

p

= NS

)

Slide49

REVEL: Select Treatment-Emergent Adverse Events

Ramucirumab

+ docetaxel(n = 627)Placebo + docetaxel

(n = 618)AEsAny GradeGrade ≥3Any Grade

Grade

≥3

Fatigue

55%

14%

49%

10%

Hypertension

11%

6%

5%

2%

Neutropenia

55%

49%

45%

39%

Febrile neutropenia

16%

16%

10%

10%

Leucopenia

21%

14%

19%

12%

Garon

EB et al.

Lancet 2014; 384(9944):665-73.

Slide50

Do you generally use EGFR TKIs in patients with metastatic NSCLC without targetable mutations who have exhausted

other options?No

NoNoNoNoNo

Slide51

FDA Modifies the Indication for Erlotinib in NSCLC

“On October 18, 2016, the US Food and Drug Administration modified the indication for erlotinib in the treatment of non–small cell lung cancer (NSCLC) to limit its use to patients whose tumors have specific epidermal growth factor receptor (EGFR) mutations.The labeling change applies to patients with NSCLC receiving maintenance, second-line, or later treatment. These indications will be limited to patients whose tumors have EGFR exon 19 deletions or exon 21 L858R substitution mutations as detected by an FDA-approved test. The first-line indication previously was limited to patients with EGFR exon 19 deletions or exon 21 substitution mutations

.” http://www.ascopost.com/News/44048

Slide52

LUX-Lung 8:

Progression-Free Survival with Second-Line Afatinib versus Erlotinib in Squamous Cell Carcinoma of the LungMedian follow-up time: 18.4 months

 Afatinib (n = 398)

Erlotinib (n = 397)

Median PFS, months

2.6

1.9

HR

0.81

Log

-

rank

p

-

value 0.0103

Soria JC et al.

Lancet

Oncol

2015;16(8):897-907.

Slide53

LUX-Lung 8 Primary Analysis: Overall Survival

Median follow-up time: 18.4 monthsSoria JC et al. Lancet Oncol 2015;16(8):897-907.

Afatinib n = 398

Erlotinib n = 397

Median,

months

7.9

6.8

HR

0.81

p

-value

0.0077

3

6

9

12

15

30

18

21

24

27

Time of overall survival (months)

0.2

0.4

0.6

0.8

1.0

0

Estimated OS probability

0

36.4%

28.2%

22.0%

14.4%

Slide54

GDC-0032

vs

SoC

Palbociclibvs Soc

AZD4547

vs

SoC

GDC-0032

Palbociclib

AZD4547

FGFR

CDK4/6

PI3K

Nonmatch

substudies

Stage 1

Stage 2

BMN 673

vs

SoC*

BMN 673*

HRD

Nivo

/

ipi

vs

nivolumab

Checkpoint

naive

Durvalumab

+

tremelimumab

*

vs

SOC

Checkpoint

r

efractory

Matched

s

ubstudies

Lung-MAP amended to 2

nd

line therapy & beyond to accommodate

nivolumab

approval

Prescreening

added back

Eligibility criteria

broadened

http

://www.lung-map.org/healthcare-providers.

Accessed March 2017

Second-

Line

Squamous

NSCLC: Updated

Lung-MAP Trial

Schema

*

Substudies

in development

Slide55

In

general, when do you believe checkpoint inhibitors should be introduced into the treatment of patients with EGFR-mutant NSCLC? Have you observed any meaningful clinical responses to anti-PD-1/PD-L1 antibodies in a patient with an EGFR or other tumor driver mutation?

After appropriate targeted treatment and 2 lines of chemotherapyAfter appropriate targeted treatment and 1 line of chemotherapy After EGFR TKIs and platinum doublet with bevacizumabNoYesYes

CHECKPOINT INHIBITORS FOR EGFR+, TPS <50%MEANINGFUL CLINICAL RESPONSES?

After appropriate targeted treatment and 1 line of chemotherapy 

Yes

No

After appropriate targeted treatment and 1 line of chemotherapy

Yes

After appropriate targeted treatment and 1 line of chemotherapy 

Slide56

Module

3:

Toxicities Associated with and Relative Contraindications to Immune Checkpoint Inhibition

Slide57

How often do you believe

pseudoprogression occurs with anti-PD-1/anti-PD-L1

therapy?6% of the timeNot much if imaging is at 8 weeks or laterVery rarely- if everRare (<5%)

Very rarely2.8% of the time

Slide58

Have you had any patients in whom anti-PD-1/anti-PD-L1 therapy was stopped because of toxicity, protocol requirements, et cetera, who experienced sustained responses after treatment was discontinued?

YesYes

YesYesYes4 years1.5 years and counting12 months

6 months6 months and countingRESPONSE OFF TREATMENT? DURATION OF RESPONSE

Yes

7 months and counting

Slide59

Are anti-PD-1/PD-L1 antibodies effective in patients with brain metastases? Have you observed any meaningful clinical responses to anti-PD-1/PD-L1 antibodies in a patient with brain metastases?

Yes, about as effective as with systemic metastasesYes, about as effective as with systemic metastases

Yes, about as effective as with systemic metastases Yes, but less effective than with systemic metastasesYes, about as effective as with systemic metastases YesYes

NoNoNoEFFECTIVE IN BRAIN METS?

OBSERVED RESPONSES?

Yes, but less effective than with systemic metastases 

Yes

Slide60

Less common:

hematologic; cardiovascular;

ocular; renalImmune-Related Adverse Events (IRAEs) Associated with Immune Checkpoint Inhibitors

HypophysitisThyroiditisAdrenal insufficiency

Colitis

Dermatitis

Pneumonitis

Hepatitis

Pancreatitis

Motor

and

sensory neuropathies

Arthritis

Courtesy of Julie R

Brahmer

, MD.

Occasional (5%-20%)

irAEs

Grade 3/4 uncommon

Slide61

Rash and pruritus

Patients should immediately report symptomsTreatmentMild: Supportive care, increase monitoringAntihistamines, topical non-Rx strength steroidsModerate: Hold treatment, consider steroids (oral)Severe: Permanently discontinue, start steroidsCourtesy of Corey J Langer, MD

Slide62

Diarrhea and colitis

Symptoms occur after an average of 6-7 weeksDiarrhea, abdominal pain, mucus/blood in stoolPeritoneal signs, bowel perforation, ileusPatients should immediately report bowel changes; rule out infectious/alternative causes TreatmentMild: Supportive care, increase monitoringModerate: Hold treatment, consider steroids

Severe: Permanently discontinue, start steroidsConsider infliximab, GI consultationTaper steroids slowly over at least several weeks and consider opportunistic infectious prophylaxisCourtesy of Corey J Langer, MD

Slide63

Hypophysitis

and endocrinopathiesCan present with severe HADifferential includes CNS metsMRI with pituitary cutsPituitary dysfunction may be reversible or permanentAdrenal insufficiencyHypothyroid

Weber JS et al. J Clin Oncol 2012;30(21):2691-7.

Slide64

Adrenal insufficiency

Nonspecific complaints Fatigue, fevers, nauseaConsider endocrinopathies early, especially with fatigueRisk of adrenal crisisCheck TSH, cortisol, ACTH, consider othersInitiate replacement therapy, referrals Patient education

Stress dosing, communication to providersCourtesy of Corey J Langer, MD

Slide65

Liver toxicity

Monitor liver function tests before each doseRule out viral hepatitis, disease progressionTreatment of mild elevationIncrease frequency of monitoringAST/ALT > 2.5-5x ULN or bilirubin > 1.5-3x ULNHold treatment, increase monitoringAST/ALT > 5x ULN or bilirubin > 3x ULNPermanently discontinue, start steroidsCourtesy of Corey J Langer, MD

Slide66

Pneumonitis

Image courtesy of Mike Postow, MD

Slide67

Pneumonitis Management

Radiographic changes: monitorMild to moderate symptoms: high-dose prednisone, consider hospitalization/pulmonary evaluationSevere symptoms or hypoxia: high-dose steroid, hospitalize, pulmonary evaluation, bronchoscopy**Taper steroids slowly over at least several weeks and consider opportunistic infectious prophylaxis**

Courtesy of Corey J Langer, MD

Slide68

Yes

For a patient who has received all standard treatments and with a life expectancy of 6 to 12 months because of metastatic disease, would you discuss the option of an anti-PD-1/anti-PD-L1 antibody if the patient had the following condition and currently did not require active treatment for it…

CROHN’S DISEASE NoYesYesYesYesYes

MSNoYesYes

Yes

No

No

LUPUS

No

Yes

Yes

Yes

No

Yes

RA

Maybe

Yes

Yes

Yes

Yes

Yes

PSORIASIS

Maybe

Yes

Yes

Yes

Yes

Slide69

Menzies AM et al.

Ann

Oncol

2017;28(2):368-76.Toxicity of Anti-PD-1 Antibodies in Patients with Preexisting Autoimmune DisordersRetrospective study of 52 patients with melanoma and preexisting autoimmune disease (AD)

Immune toxicity characteristic

(N = 52)

Number (%)

Flare of AD on

anti-PD-1

Yes

No

20 (38%)

32 (62%)

Median time to flare

38 days

Grade of flare

Grade 1-2

Grade 3

Grade 4

17 (33%)

3 (6%)

0 (0%)

Anti-PD-1 antibodies induced relatively frequent immune toxicities that were often mild and easily managed without the need for treatment discontinuation.

Slide70

Module

4:

Ongoing Investigation, Future Directions with Immune Checkpoint Inhibitors

Slide71

T-Cell Immune Checkpoints

as Targets for ImmunotherapyAdapted from Mellman I et al. Nature 2011;480:481-9.

CTLA-4

PD-1

TIM-3

BTLA

VISTA

LAG-3

HVEM

CD27

CD137

GITR

OX40

CD28

T cell

stimulation

Blocking

antibodies

Agonistic

antibodies

Inhibitory

receptors

Activating

receptors

T cell

B7-1

T cell

Targeted Therapy

Vaccines

Chemotherapy

Slide72

Anti-PD/PD-L1

as Backbone to Combination Tx?Nivolumab

PembrolizumabAtezolizumabDurvalumabChemotherapyRadiation/ablationEGFR/ALK TKIAnti-VEGF/VEGFR inhibitorVasc disrupt agentHypomethylating agentHDAC inhibitorSPK inhibitorC-Met inhibitorGlutaminase inhibitorDasatinib

VaccineGene therapyIL15 agonistPEG IL10TGFᵦR1 inhibitorAnti-CD27Anti-CXCR4Anti-CSF-1RIDO-1 inhibitorAnti-CTLA4Anti-LAGAnti-TIM-3Anti-KIR

Chemotherapy

Radiation

EGFR/ALK

TKI

Anti-VEGF/VEGFR inhibitor

Hypomethylating

agent

HDAC inhibitor

CDK

inhibitor

BTK inhibitor

PI3K

inhibitor

KIT/CSF1R/FLT3

inh

FGFR inhibitor

JAK1

inhibitor

CRM1

inhibitor

FAK

inhibitor

Anti-EGFR

Anti-CEACAM1

PEG hyaluronidase

Vaccine

Oncolytic

PEG IL10

Anti-CSF-1

IDO1

inhibitor

Anti-CTLA4

Anti-B7-H3

Chemotherapy

Radiation

EGFR/ALK

TKI

Anti-VEGF/Ang-2

MEK

inhibitor

Vaccine

Adoptive

cell therapy

Anti-CEA/CD3

Anti-CEA/IL-2

Anti-OX40

Anti-CD40

Anti-CD27

Anti-CSF-1

Adenosine A2A

inhibitor

IDO-1

inhibitor

Anti-CTLA4

Anti-TIGIT

Chemotherapy

Radiation

EGFR/ALK TKI

VEGFR

inhibitor

BTK

inhibitor

MEK

inhibitor

HAD

inhibitorPARP inhibitorWEE1 inhibitorATR inhibitor

Anti-OX40CXCR4 inhibitorCSF

Anti-CD73Anti-CCR4Anti-CSF1RAnti-NKG2AAdenosine A2a inhibitorIDO1 inhibitorAnti-CTLA4Anti-PD-1Avelumab: ALK inhibitor (crizotinib and lorlatinib), anti-41BB, anti-OX40

Slide73

Are there any situations in which you would use the combination of an anti-PD-1/PD-L1 antibody and an anti-CTLA-4 antibody outside of a trial setting?

Yes, small cell lung cancer, second lineNo

Yes, small cell lung cancerYes, very functional patient with small cell lung cancerYes, small cell lung cancerYes, second- or third-line therapy

Slide74

CheckMate

012: A 3-Arm Phase I Trial of

Nivolumab Alone or with Ipilimumab in NSCLCGettinger S et al. Proc WCLC 2016;Abstract OA03.01Primary endpoint: safety and tolerabilitySecondary endpoints:

ORR (RECIST v1.1) and PFS rate at 24 weeks assessed by investigatorsExploratory endpoints: OS, efficacy by PD-L1 expression

Stage IIIB/IV NSCLC (any histology

),

no prior chemotherapy for advanced

disease,

ECOG

PS

0 or

1

Nivolumab 3 mg/kg IV

q2wk

Nivolumab 3 mg/kg IV q2wk

+

Ipilimumab 1 mg/kg IV

q12wk

Nivolumab 3 mg/kg IV

q2wk

+

Ipilimumab 1 mg/kg IV

q6wk

Until disease

progression

or unacceptable

toxicity

Slide75

CheckMate

012: Response by PD-L1 expressionGettinger S et al. Proc WCLC 2016;Abstract OA03.01

Nivo 3 q2wk + ipi 1 q6/12wkNivo 3 q2wkOverall

ORR (%)<1%≥1%PD-L1 expression≥50%5 CRs (10% were achieved in the nivolumab monotherapy cohort (1 in a patient with tumor PD-L1 expression <1%)6 CRs (8%) were achieved in the nivolumab + ipilimumab

cohorts (3 in patients with tumor PD-L1 expression <1%)

43

23

21

13

57

28

92

50

n

77

52

19

16

46

32

13

12

Slide76

CheckMate

012: PFS by PD-L1 expressionGettinger S et al. Proc WCLC 2016;Abstract OA03.01

100

80

60

40

20

0

0

6

12

18

24

30

36

42

48

Median 12.7 months

(95% CI 7.8,

23.0)

Nivo

3

q2wk

+

i

pi

1

q6/12wk

PFS (%)

Median

8

.

0

months

(95% CI

4

.

1, 13

.

2

)

100

80

60

40

20

0

0

6

12

18

24

30

36

42

48

100

80

60

40

20

0

0

6

12

18

24

30

36

42

48

Median NR

(95% CI 7.8, NR)

All treated patients (

n = 77

)

≥1%

PD-L1 (n = 46

)

≥50%

PD-L1 (n = 13

)

Nivo

3 q2wk

Median 3.6 months

(95% CI 2.3, 6.6)

100

80

60

40

20

0

Months

0

6

12

18

24

30

36

42

48

Median 8.3 months

(95% CI 2.2, NR

)

100

80

60

40

20

0

Months

0

6

12

18

24

30

36

42

48

PFS (%)

100

80

60

40

20

0

Months

0

6

12

18

24

30

36

42

48

Median 3.5 months

(95% CI 2.2, 6.6)

All treated patients (

n = 52)

≥1%

PD-L1 (n = 32)

≥50%

PD-L1 (n = 12)

Data are based on median follow-up durations of 16 months (combination cohorts) and 22 months (monotherapy)

Slide77

CheckMate

012: Treatment-Related AEsGettinger S et al. Proc WCLC 2016;Abstract OA03.01

Patients with an event, %Nivo 3 q2wk(n = 52)Nivo 3 q2wk + ipi 1 q12wk(n = 38)Nivo 3 q2wk + ipi 1 q6wk(n = 39)

15

Grade 1-2

Grade 3-4

Pulmonary

Pulmonary

Pulmonary

Hypersensitivity/

infusion

rxn

Hypersensitivity/

infusion

rxn

Hypersensitivity/

infusion

rxn

Slide78

CheckMate

227: A Phase III Trial of Nivolumab Alone or in Combination with Ipilimumab or ChemotherapyJanuary 19, 2017: Company stated that it would NOT ask for accelerated approval of this combination based on (unknown to us) data available at the time.

http://investor.bms.com/investors/news-and-events/press-releases/press-release-details/2017; www.clinicaltrials.gov. Accessed March 2017Key eligibility criteria:Stage IV or recurrent NSCLCNo prior systemic therapy for advanced diseaseNo EGFR/ALK mutations sensitive to available targeted inhibitor therapyCNS metastases permitted if adequately treated

≥2 weeks prior to randomizationStratification factor at randomization:Histology (squamous vs nonsquamous)

Randomize 1:1:1

Disease

progression or unacceptable toxicity

PD-L1+

(≥

1

%)

PD-L1

‒

(<

1

%)

Tumor

scans

q6wk

until

week 48 then

q12wk

Nivolumab

monotherapy

240 mg

q2wk

Nivolumab

3 mg/kg q2wk

+

i

pilimumab

1 mg/kg q6wk

Chemotherapy

Nivolumab

360 mg q3wk + chemotherapy

Nivolumab

3 mg/kg

q2wk +

ipilimumab

1 mg/kg q6wk

Chemotherapy

Slide79

KEYNOTE 021 – Cohorts D and H

N = 44 patientsPembrolizumab 2 mg/kg q3wk + ipilimumab 1 mg/kg q3wkORR only 25%, not related to PD-L1 expressionSignificant toxicity

Gubens MA et al. Proc ASCO 2016;Abstract 9027.

Slide80

Lancet

Oncol

2016;17(3):299-308.

Slide81

Durvalumab

10-20 mg/kg q2 or 4wk + tremelimumab 1 mg/kg

Durvalumab 10-20 mg/kg q2 or 4wk + tremelimumab 3 mg/kg Durvalumab

15 mg/kg q4wk +

tremelimumab

10 mg/kg

All evaluable

6/26

(23%)

5/25 (20%)

0/9 (0%)

PD-L1

≥ 25%

2/9 (22%)

2/5 (40%)

0/4 (0%)

PD-L1

<

25%

4/14 (29%)

2/17 (12%)

0/4 (0%)

PD-L1 negative

4/10 (40%)

1/10

(10%)

0/3 (0%)

Antonia S et al.

Lancet

Oncol

2016;17(3):299-308

.

Objective Response Rate with

Durvalumab

Combined with

Tremelimumab

Slide82

MYSTIC: A Phase III Trial of

Durvalumab

with or without Tremelimumab versus Standard of Care in NSCLCFirst-line Stage IV NSCLCAll histologiesEGFR and ALK wild type

DurvalumabTremelimumab(Anti-CTLA-4)Durvalumab(anti-PD-L1)

Platinum doublet chemotherapy SOC

OS

PFS & OS

NCT02453282

(Closed)

www.clinicaltrials.gov

. Accessed March 2017

Slide83

VEGF-A through binding to VEGF-R2 induces

immunosuppression Adapted from: T. Voron, et al., Frontiers in Oncology, April 2014 Volume 4 Article 70Andrea Facciabene

et al. Cancer Res 2012;72:2162-71.Treg: limit antitumor immunity and promote angiogenesisRamucirumab: Immunological Pathways (MDSC and Treg)

Slide84

*

Patients

may continue treatment for up to 35 cycles, until confirmed progressive disease or discontinuation for any other reason. NCT02443324

Multicohort

Phase I Study of

Ramucirumab

with

Pembrolizumab

Herbst

RS et al.

Proc ESMO

2016;Abstract LBA38.

Phase 1a: DLT assessment

(n = 6 to 12)

Primary:

Safety and tolerability

Secondary:

PK

Phase 1b: cohort expansion

(n = 155)*

Primary:

Safety and tolerability

Secondary:

PK and preliminary efficacy

Exploratory:

Biomarkers and immunogenicity

Schedule 1: Gastric/GEJ, BTC

3+3 design (n = 3 to 6 patients)

Ram 8 mg/kg, Day 1 and 8

Pembro

200 mg fixed. Day 1

Both IV every 3 weeks

Schedule 2: Gastric/GEJ, NSCLC, UC

3+3 design (n = 3 to 6 patients)

Ram 10 mg/kg, Day 1

Pembro

200 mg fixed, Day 1

Both IV every 3 weeks

Cohort A: 15 Gastric/GEJ (2

nd

-3

rd

line)

Cohort A1: 25 BTC (2

nd

-3

rd

line)

Cohort A2: 25 Gastric/GEJ (1

st

line)

Cohort B: 15 Gastric/GEJ (2

nd

-3

rd

line)

Cohort C: 25 NSCLC (2

nd

-4

th

line)

Cohort D: 25 UC (2

nd

-4

th

line)

Cohort E: NSCLC (1st

line)

Interim analysis

Final analysis