Immunotherapy:Where next?

- evolving agents and combinations

Dr Heather Shaw

University College London Hospital and

Mount Vernon Cancer Centre

December 2018 - ACP

Where are we now?• Immunotherapy increasingly becoming standard of care for a variety of

tumour types (first, second or occasionally third line therapy)– single agent (antiPD1/PDL1) and combination (antiCTLA4/PD1)– combination with chemotherapy (lung)

• Melanoma• Renal• Lung • HNSCC• Urothelial carcinoma• Classical Hodgkin Disease• Merkel cell carcinoma

December 2018 - ACP

AND……

What is out there?

December 2018 - ACP

• Anti – CTLA4– Ipilimumab– Tremelimumab

• Anti – PD1– Nivolumab– Pembrolizumab– Spartalizumab– Cemiplimab

• Anti – PDL1– Atezolizumab– Avelumab– Durvalumab

Adapted from Mellman, et al. Nature, 2011:480;481-9 Pardoll DM. Nat Rev Cancer 2012;12:252-64

What are we looking for?

• Durable disease control

• Tolerability

• Acceptable toxicity profile

• Speed of onset of response

• Deliverability of proposed regimen

December 2018 - ACP

Is what we have not enough?

Months

Patients at risk:

73%

74%

67%

64%

59%

45%

Pe

rce

nta

ge o

f P

FS

0

10

20

30

40

50

60

70

80

90

100

0 3 6 9 12 15 18 393024 332721

Ove

rall

Surv

ival

(%

)

36

0IPI 34104129136149164182205228254285315 4

0NIVO 55157175181191201213230244265292316 3

0NIVO+IPI 49170192198200209221226247265292314 7

*P<0.0001

NIVO+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+IPI

NIVO

IPI

Database lock: Sept 13, 2016, minimum f/u of 28 monthsLarkin, Checkmate 067, oral presentation AACR 2017

CHECKMATE 067

?

Is what we have too toxic?

• Most select AEs were managed and resolved within 3-4 weeks (85–100% across organ categories)

• ORR was 70.7% for pts who discontinued NIVO+IPI due to AEs, with median OS not reached

NIVO+IPI(N=313)

NIVO

(N=313)IPI

(N=311)

Patients reporting event, %Any

GradeGrade 3-

4Any

GradeGrade 3-

4Any

GradeGrade 3-

4

Treatment-related adverse event (AE)

95.8 58.5 86.3 20.8 86.2 27.7

Treatment-related AE leading to discontinuation

39.6 31.0 11.5 7.7 16.1 14.1

Treatment-related death, n (%)

2 (0.6)a 1 (0.3)b 1 (0.3)b

aCardiomyopathy (NIVO+IPI, n=1); Liver necrosis (NIVO+IPI, n=1). Both deaths occurred >100 days after the last treatment.bNeutropenia (NIVO, n=1); colon perforation (IPI, n=1).1

Larkin J, et al. NEJM 2015;373:23‒34.

CHECKMATE 067 – Safety Summary

New agent and combination development (1)

• Agent/combination must have an efficacy signal• Is anti-PD1 the benchmark?

• May be different dependent on setting for use

• Little point in new agents/combinations which:• Treat the same population who already derive benefit from current therapy

• Do not add benefit over current therapy

• Do not reduce toxicity from current therapy

• What to combine??

December 2018 - ACP

New agent and combination development (2)

• Pre-clinical evidence of rationale for agent/combination

• Early phase testing (PK/PD/tumour bx) must show evidence that the pre-clinical mechanism of action is demonstrated in vivo (human!)

• Toxicity profile must be “acceptable” at potentially therapeutic doses• Greater toxicity may be acceptable if the possible gain is judged sufficient

• To investigator

• To patient

• Are we looking in a first line or subsequent setting?• primary resistance to currently available therapy

• secondary resistance to therapy

December 2018 - ACP

Gin and tonic plus a garnish of your favouriteanti-PD1/PDL1?

• Current active clinical trial combinations include:

• IO – IO• IO – metabolic therapy• IO – targeted therapy • IO – chemotherapy• IO – radiotherapy• IO – endocrine therapy• IO – epigenetic therapy• IO – viral therapy• IO – vaccine therapy• IO – surgery• IO – cellular therapy• IO – and every therapeutic modality not mentioned above!

December 2018 - ACP

Including one: IO – FMT!!

Approx. 1400 active IO clinical trials for adults

> 1100 active IO clinical trials from FIH to phase II

Initial Efficacy of Anti-Lymphocyte Activation Gene-3 (Anti–LAG-3; BMS-986016) in Combination With Nivolumab in Patients With Melanoma Previously Treated With Anti–PD-1/PD-L1 Therapy

Presented by P. Ascierto, ASCO 2017

IO-IO – antiLAG3

Disease Characteristics and Prior Therapies in Patients<br />With Melanoma Who Received Prior Anti–PD-1/PD-L1 Therapy

Promising Response With BMS-986016 + Nivolumab in Patients<br />With Melanoma Who Received Prior Anti–PD-1/PD-L1 Therapy

Durable Clinical Benefit With BMS-986016 + Nivolumab in Patients<br />With Melanoma Who Received Prior Anti–PD-1/PD-L1 Therapy

Summary & Implications

At least 20 phase I/II studies of antiPD1 plus antiLAG3 are now recruiting/about to recruit in a variety of tumour types including lung, urothelial, melanoma, HNSCC and haematologic ca

IO – metabolic therapy IDO1 and epacadostat

December 2018 - ACPPresented by O. Hamid, ESMO 2017

ECHO-202/Keynote 037 – Study Design

December 2018 - ACP

ECHO-202 – Progression Free Survival:Landmark 18 month analysis (data cut Jun 17)

December 2018 - ACP

ECHO-202 Summary

December 2018 - ACP

Study Design: Phase III Randomized Controlled Trial

Presented By Georgina Long at 2018 ASCO Annual Meeting

ECHO-301/Keynote-252 Study Design

Progression-Free Survival (RECIST v1.1, BICR)<br />

Presented By Georgina Long at 2018 ASCO Annual Meeting

ECHO-301 –Progression Free Survival

Now what?....

December 2018 - ACP

IO-targeted therapy combinations

• Rationale - to increase or enhance anti-tumour immune responses produced by exposure to checkpoint inhibitors• Change in tumour microenvironment – tumour lymphocyte infiltration in

response to targeted therapy

• Release of neoantigens by targeted therapy induced tumour cell apoptosis -?increased tumour kill by immune system

• Issues • More drugs = likely more toxicity

• No or fewer options at point of progression

December 2018 - ACP

Rationale for Parp + Checkpoint Inhibitors

Presented By Kevin Kalinsky at 2018 ASCO Annual Meeting

PARP inhibition and immunotherapy

Open-label, multi-tumor, Phase II basket study of olaparib and durvalumab (MEDIOLA): Germline BRCA-mutated HER2- MBC

MEDIOLA – Study Design

MEDIOLA: Olaparib + Durvalumab (n=25)

Presented By Kevin Kalinsky at 2018 ASCO Annual Meeting

MEDIOLA – Responses

TOPACIO: Niraparib + Pembrolizumab (n=46)

Presented By Kevin Kalinsky at 2018 ASCO Annual Meeting

If there is one – there is probably another…..

PARP inhibition and immunotherapy

• 30+ studies recruiting (pick any PARPi and almost any CPI!!!)

• PARP inhibition/immunotherapy is not just for BRCA mutated patients it seems….• Prostate• Breast cancer• Ovarian cancer• Lung cancer• Head and neck cancer• Rectal cancer• Pancreatic cancer• Cholangiocarcinoma• Lymphoma

December 2018 - ACP

IO – something else!! (TLR9)

• Toll-like receptor 9• Part of innate immune system

• Recognise pathogen-associated patterns

• Produce • inflammatory cytokines

• type I interferon (IFN)

• Trigger inflammation

• Prime antigen-specific adaptive immune

responses

• Instruction of antigen-specific adaptive

immune responses

December 2018 - ACP

Slide 26

Presented By Michael Postow at 2018 ASCO Annual Meeting

Patients with melanoma (sorry!) – post progression on antiPD1Ipilimumab plus TLR9 agonist (tilsotolimod)

Slide 28

Presented By Michael Postow at 2018 ASCO Annual Meeting

Illuminate 204 – Responses

Slide 29

Presented By Michael Postow at 2018 ASCO Annual Meeting

Illuminate 301 now recruiting – ipi vs ipi + tilsotolimod(and other TLR9 agonist studies!)

Summary…• Many, many new agents and combinations being tested

• It is unlikely that more than a very few will yield meaningful new therapies routinely adopted

• Biomarker and translational studies should be integral – not add ons

• Some combinations/agents are driven by rationale and academic interest• Niche areas and unmet need

• Some combinations/agents are driven by commercial pressure• SLOW DOWN!!!!

• Is combination really better than sequence?

• Consider the evidence…..

December 2018 - ACP

December 2018 - ACP