Immunotherapy – the good news and the bad - PowerPoint Presentation

Slide1

Immunotherapy – the good news and the bad

Associate Professor Philip Beale

Chair ANZGOG Clinical Trials Group

Medical Oncologist Sydney

Concord Hospital

Chris O’Brien Lifehouse

Royal Prince Alfred Hospital

Slide2

Outline

Background to immunotherapy

Immunotherapy in

gynaecological

cancer

Ongoing trials

Future directions

Slide3

What is Immune therapy

3 types

1. Immune boosting therapy

2. Immunotherapy – drugs that have been designed to unlock the immune system to allow targeted destruction of cancer cells

3. Vaccine type therapy – preventative and treatment

Slide4

Slide5

1

2

3

5

6

4

tumour cells

dendritic cells

(APCs)

CD8

+

T cell

priming

CD8

+

T cells

proliferate

memory T cells

tumour antigens

‘6 steps’ of the anti-tumour immune response

Chemotherapy

Targeted therapy

Radiotherapy

Slide6

Slide7

Tumour

vaccines

Presented By Lukas Rob at 2018 ASCO Annual Meeting

Slide8

Slide9

Overall Survival

Months

Patients at risk:

73%

74%

67%

64%

59%

45%

Percentage of PFS

0

10

20

30

40

50

60

70

80

90

100

0

3

6

9

12

15

18

39

30

24

33

27

21

Overall Survival (%)

36

0

IPI3410412913614916418220522825428531540NIVO5515717518119120121323024426529231630NIVO+IPI491701921982002092212262472652923147*P<0.0001NIVO+IPI (N=314)NIVO (N=316)IPI (N=315)Median OS, mo (95% CI)NRNR (29.1–NR)20.0 (17.1–24.6)HR (98% CI) vs. IPI0.55 (0.42–0.72)*0.63 (0.48–0.81)*--HR (95% CI) vs. NIVO0.88 (0.69–1.12)----NIVO+IPINIVOIPI9Database lock: Sept 13, 2016, minimum f/u of 28 monthsLarkin (2017). Overall Survival Results From a Phase III Trial of Nivolumab Combined With Ipilimumab in Treatment-naïve Patients With Advanced Melanoma (CheckMate 067)

Slide10

Immunotherapy 2011-2018 –

FDA

approved indications

2011

2012

2013

2014

2015

2016

2017

2018

Melanoma

(

ipilimumb

)

Melanoma (

nivo

)

NSCLC 2L PDL1+

(

pembro

)

HNSCC 2L

(

pembro

)

Pembro

:

-

cHL

- NSCLC 1L

- Urothelial

-

Any

MSI-H

- Gastric PDL1+

Nivo

:- NSCLC 2L- RCCcHL (Nivo)HNSCC (Nivo)Melanoma (pembro)Nivo:- HCCMerkel cell(avelumab)Urothelial(durvalumab)Atezolizumab:- NSCLCNSCLC - adjuvant(durvalumab)- Melanoma (adjuvant)- MSI-H CRC- Urothelial- UrothelialMelanoma (ipi/nivo)Melanoma (ipilimumb)Melanoma (nivo)Nivo:- NSCLC 2L- RCCMelanoma (pembro)cHL (Nivo)- UrothelialNSCLC 2L PDL1+ (pembro)HNSCC 2L(pembro)Pembro: - cHL- Urothelial HNSCC (Nivo)Atezolizumab:- NSCLCMerkel cell(avelumab)PBS listedTGA approved (non-PBS)- Any MSI-H Gynae FDA approved indication

Slide11

Immunotherapy in

Cervical Cancer

Slide12

Immunotherapy in recurrent cervical cancer

- reported trials

Trial

Phase

N

Population

Treatment

Results

NCT01585428

1

II

9

Recurrent/metastatic

ACT

ORR 33%

GOG 265

2II

50Recurrent/metastaticAXAL (Lm-LLO)1yr OS 38%

KEYNOTE-0283

1b24

Recurrent/metastaticPembrolizumabORR 17%

KEYNOTE-1584

II47

PD-L1+ recurrent/metastaticPembrolizumabORR 17%

CheckMate

3585I/II24

Recurrent/metastatic cervical, vaginal, vulval

Nivolumab

ORR 20.8%

1: Stevanović et al. (2015) JCO, 33

(14), 1543–1550; 2

: Leath et al., presented at SGO 2017; 3: Frenel

et al. (2017) JCO, 35(36), 4035–4041. 4: Schellens et al., presented at ASCO 2017;

5:

Hollebecque et al., presented at ASCO 2017;

Slide13

Immunotherapy in cervical cancer

- current trials

Trial

Phase

N

Population

Treatment

AIM2CERV

III

450

1

st

line locally adv. cervical ca

ChemoRT

+/- adjuvant AXAL (Lm-LLO)

NCT02635360

II

881st

line locally adv. cervical caChemoRT

vs. pembro-chemoRT

PRIMMOII

43

Recurrent/persistent cervical ca

Immune ‘cocktail’ (Vit D, aspirin, PPI, cyclophosphamide)+ Curcumin +

3x8Gy RT +

pembrolizumab

NCT02725489II33Advanced women’s cancersDurvalumab + Vigil autologous tumour cell immunotherapy

NCT03340376

II48Recurrent cervical cancer

Atezolizumab +/- doxorubicinNCT02598960I/II30

Recurrent/refractory cervical ca

Nivolumab + BMS-986156 (anti-GITR)

Slide14

Immunotherapy in

Uterine Cancer

Slide15

Immunotherapy in recurrent endometrial cancer

- reported trials

Trial

Phase

N

Population

Treatment

Results

NCT01876511

1,2

II

86

MMR-deficient cancers

Pembrolizumab

ORR 53%

KEYNOTE-028

3

1b24PD-L1+ endometrial caPembrolizumabORR 13%

NCT01375842

4Ia15

Advanced endometrial caAtezolizumabORR 13%

1. Le et al. (2015) NEJM

, 372(26), 2509–25202. Le et al. (2017) Science,

357(6349), 409–413 3. Ott et al. (2017). JCO, 35(22), 2535–2541

4.

Fleming et a. (2017) Presented at ASCO 2017, abstract #5585

Slide16

Immunotherapy in endometrial cancer

- current trials

Trial

Phase

N

Population

Treatment

PHAEDRA

II

70

Advanced endometrial ca

Durvalumab

(anti-PD-1)

AtTEnd

III

450

Advanced endometrial ca

Carbo-paclitaxel +/-

Atezolizumab

NCT03015129

II80Advanced endometrial caDurvalumab +/- tremelimumab

NCT02912572

II70

Advanced endometrial caAvelumab

TOPIC

II

51Advanced endometrial ca

Pembrolizumab

+ doxorubicinNCT03241745

II40Advanced uterine cancerNivolumab

Slide17

What about Tumour biology?

Markers on the cancer cells can predict for response to treatment

Mismatch repair deficiency

PD-L1 expression on tumour cells

Tumour mutational burden

Slide18

Mismatch repair deficiency predicts response of solid

tumors

to PD-1 blockade

Le et al. (2017)

Science

,

357

(6349), 409–413

Slide19

Piulats

, J. M., & Matias-

Guiu

, X. (2016). Immunotherapy in endometrial cancer: In the nick of time.

Clinical Cancer Research

,

22

(23), 5623–5625

May 23, 2017:

FDA grants accelerated approval to

pembrolizumab

for first tissue/site agnostic indication

Slide20

Immunotherapy in

Ovarian Cancer

Slide21

Zhang, L (2003).

The New England Journal of Medicine

,

348

(3), 203–13

Slide22

Immunotherapy in ovarian cancer

- reported trials

Trial

Phase

N

Population

Treatment

Results

Fujita

1

II

24

Post 1st line EOC

ACT

3yr DFS 82 vs. 54.5%

Hamanishi

2II

20Platinum-resistant OCNivolumabORR 15%

Matulonis

3II11Recurrent EOC

IpilimumabORR 9%KEYNOTE-028

4

1b26PD-L1+ recurrent EOCPembrolizumabORR 11.5%

JAVELIN 1b51b

124

Recurrent OCAvelumabORR 9.7%

NCT013758426I12

Recurrent OCAtezolizumab

ORR 22%

1: Fujita et al. (1995) CCR, 1(5), 501–507; 2: Hamanishi

et al. (2015) JCO

, 33(34), 4015–4022; 3: Matulonis et a. (2016)

CCR;22(2 Suppl):Abstract nr B72; 4: Varga et al. (2017)

JCO 35, no. 15_suppl 5513-5513.

5: Disis et al. (2016) JCO.2016.34.15_suppl.5533; 6:

Infante et al. (2016) Annals of Oncology, Volume 27, Issue suppl_6, 1 October 2016, 871P,

Slide23

Nivolumab

(anti-PD-1) in Patients with Platinum-Resistant Ovarian Cancer

Hamanishi

, J (2015.

Journal of Clinical Oncology

,

33

(34), 4015–4022.

Slide24

<br />KEYNOTE-100 (NCT02674061): Phase 2, Two-Cohort Study of Pembrolizumab for Recurrent Advanced Ovarian Cancer<br />

Presented By Ursula Matulonis at 2018 ASCO Annual Meeting

Slide25

<br />

Presented By Ursula Matulonis at 2018 ASCO Annual Meeting

Slide26

Best Change From Baseline in Tumor Size in Cohorts A + B: Based on RECIST v1.1 per BICR

Presented By Ursula Matulonis at 2018 ASCO Annual Meeting

Slide27

Immunotherapy in

recurrent

ovarian cancer

- current/planned trials

Trial

Phase

N

Population

Treatment

NCT02498600

II

96

Recurrent EOC

Nivolumab +/- Ipilimumab

ATLANTE

III

405

Platinum sensitive EOC

Carbo-combo + Bevacizumab +/-

Atezolizumab

JAVELIN 200III

550

Platinum resistant EOC

Lip Dox vs. Avelumab vs. both

NRG GY009

III

488Platinum resistant EOC

Lip Dox +

Atezolizumab and/or Bev

ANITAIII414Platinum sensitive EOC

Platinum-combo

 niraparib +/- Atezolizumab

AVANOVA-Immune1II338Platinum sensitive EOC

Niraparib/Bev +/- anti-PD-1 (part 1)

Slide28

Immunotherapy in

newly diagnosed

ovarian cancer

- current/planned trials

Trial

Phase

N

Population

Treatment

iPRIME

II

75

Fronline

EOC

NACT +/-

Durvalumab

+ Tremelimumab

JAVELIN 100III951Frontline EOC

CP +/- Avelumab

IMaGYN050

III1300Frontline EOCCP + Bev +/- Atezolizumab

ATHENA

III1000Frontline EOC

CP  Rucaparib and/or NivolumabFIRSTIII

700

Frontline EOCCP +/- TSR-042  TSR-042 +

niraparibENGOT ov43III1500

Frontline EOC

CP +/- pembrolizumab + olaparib

Slide29

Dendritic Cell Vaccine <br />With Chemotherapy In Patients With Epithelial Ovarian Carcinoma After Primary Debulking Surgery

Presented By Lukas Rob at 2018 ASCO Annual Meeting

Slide30

DCVAC/OvCa

Presented By Lukas Rob at 2018 ASCO Annual Meeting

Slide31

DCVAC/OvCa

Presented By Lukas Rob at 2018 ASCO Annual Meeting

Slide32

Study Design in First-Line Setting

Presented By Lukas Rob at 2018 ASCO Annual Meeting

Slide33

PFS<br />~ 6-month Benefit in mPFS and 57% Decrease<br />in The Hazard of Progression in Arm B

Presented By Lukas Rob at 2018 ASCO Annual Meeting

Slide34

OS<br />A Trend Towards Improved OS in Arm B

Presented By Lukas Rob at 2018 ASCO Annual Meeting

Slide35

Future directions:

‘closing’ the immune cycle

Slide36

Sullivan, R. J., & Flaherty, K. T. (2015). New Strategies in Melanoma: Entering the Era of Combinatorial Therapy.

Clinical Cancer Research

,

21

(11), 2424–2435.

Novel immunotherapy combinations

Slide37

New ideas

Combination therapy

1. Adding to chemotherapy (already being trialled successfully in lung cancer

2. Combination immunotherapy – successful in melanoma treatment

3. Adding immunotherapy to other targeted agents (

PARPi

in ovarian cancer)

4. Better understanding of which treatment works for which patient

Slide38

Willis, J. C. D (2015).

Nature Reviews Immunology

,

15

(March), 1–7

Slide39

April 2016 cover (reproduced without permission)

Can we afford to wait for all these trials of promising drugs?

Can we

afford not to?

Slide40

Immunotherapy in

gynaeoclogical

cancers….both good and bad news

Slide41

Good news :

we have identified a group of patients with endometrial cancer who definitely respond to immunotherapy

Many new trials are underway or reporting

New ideas are being generated every month

Not so good news:

Response rates - so far - are generally modest, 10-20%, but can last for some time

Need to be smarter in picking the right patients and the right time in treatment to get the best results

Bad news

Immunotherapy doesn’t work for many patient with ovarian cancer

Costs are high

Approval is difficult

Conclusion

Slide42

Pembro

:

Melanoma (

nivo

)

NSCLC 2L PDL1+

(

pembro

)

HNSCC 2L

(

pembro

)

Pembro

:

-

cHL

- NSCLC 1L

- Urothelial

-

Any

MSI-H

Nivo

:

- NSCLC 2L

- RCC

cHL

(

Nivo

)

HNSCC (

Nivo

)

Melanoma

(

pembro

)Nivo:- HCCMerkel cell(avelumab)Urothelial(durvalumab)Atezolizumab:- NSCLC- Melanoma (adjuvant)- MSI-H CRC- Urothelial- UrothelialMelanoma (ipi/nivo)- Any MSI-H ‘Future’ approved indications?20142015201620172018201920202021?Cervical cancer(pembro)?ovarian?endometrial(e.g. MMR+POLE)