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