Download Immune Therapy in 2016

Immune Oncology Drugs:
A Wolf in Sheep’s Clothing?
Immune Therapy in 2016
• Glass half-full:
- A subset of patients clinically respond (increasing range of histologies)
- Variety of effective approaches (CTLA-4, PD-1, PD-L1, CAR T cells)
- For patients in whom a response occurs, response can be quite durable
- Notable toxicities are immune-related, but these are usually manageable and
reversible
- Encouraging early reports with combinations
• Glass half-empty:
- Vast majority of patients do not response to single checkpoint mABs
- Is the survival “tail” really as high and as flat as we thought?
- Lack of clear predictive biomarker of response (including tumour PD-L1)
- Move to dual checkpoint therapy met with increased toxicity
SCCHN patient: Durvalumab
Ninety-six year-old female, progressed on previous cetuximab, PD-L1+, and no
treatment-related toxicities reported to date. Treatment ongoing at 16 weeks; confirmed
PR ongoing.
Dempke et al. 2015
Dempke et al. 2015
NK Cell Receptors
Handgretinger et al. 2016
Approval of Checkpoint mABs
Pembro
2nd
Ipi
mono
Nivo
2nd
Ipi
adj.
Nivo 2nd
NSCLC (sq)
Pembro 1st
Nivo
+Ipi
Melanoma
Non-Melanoma
2011
Nivo
1st
2012
2013
Pembro
2nd
NSCLC
2014
Nivo 2nd
NSCLC (nsq)
2015
2016
Nivo 2nd
RCC
Atezo 2nd
Bladder
Nivo 4th
Hodgkin
Activity of PD-1/PD-L1 mAB
• Melanoma (17-50% of patients responding)
• Lung Cancer (10-30%)
• Renal Cancer (12-29%)
Some patients DO respond to IO
• Bladder Cancer (15-30%)
drug treatment – biomarkers to
• Ovarian Cancer (6-23%)
identify them?
• Head-and-Neck Cancer (20-25%)
• Hodgkin’s Lymphoma (65-87%)
• GI Tumours, TNBC, Mesothelioma, HCC, ….
NSCLC: KEYNOTE-001
Many patients do NOT respond to
IO drug treatment – resistance
Cure!
mechanisms?
“Cold” and “Hot” Tumours
T cell immune surveillance of cancer
T cell response, Elimination,
Immunoediting,
T cell response, Host/Tumour
Immune Suppression,
Peripheral Tolerance
Escape
Escape
Resistance to
Immune Therapy
Overcome with
CTLA-4 or PD-1 mAB,
or both
HOT
Host/Tumour Immune
Suppression, no T cell response,
Immune Privilege
COLD
No
Escape
Overcome by
vaccination AND
block immune
suppression
“Cold” and “Hot” Tumours
Spranger et al., 2015
Responsive to
immune therapy!
Resistant to
immune therapy!
Role of β-Catenin for IO Resistance
β-Catenin and IO Resistance
• Approximately one third of solid tumours (TCGA data) are non-
T cell-inflamed.
• Activation of WNT/β-catenin signalling likely contributes to the
non-T cell-inflamed phenotype that occurs in many cancers.
• β-Catenin as a mediator of immune-exhaustion may represent
a rationale therapeutic target to overcome IO resistance (“cold“
versus “hot“ tumour).
Therapeutic Intervention: Opportunities
• Non-Immunogenic tumours (epigenetically silenced)
- epigenetic immunotherapy (e.g., in combination with HADCs, HMAs)
• Tumours with immune checkpoint related immune evasion
- co-inhibitory checkpoint inhibitors (e.g., TIM-3, LAG-3)
• Non-Immunogenetic tumours
- common cytokine-receptor γ family (IL-2, IL-7, IL-15, IL-21)
- co-stimulatory checkpoint pathways (OX-40, CD137, GITR, CD40)
- cancer vaccines
- chemotherapy/radiation
- T cell therapies (e.g., CARTs)
TKIs plus IOs: ongoing studies
IO plus IO Combinations: Rationale
Makouk & Weiner 2015
TKIs and IOs: Toxicities
Study
Phase
Main Toxicity
Reference
I
ALAT & ASAT Grade 3 in 6/16 patients:
study stopped!
Ribas et al. 2013
Dabrafenib plus
Ipilimumab
I
(ongoing)
No grade 3/4 liver toxicity reported so far.
1 patient with severe colitis
Puzanov et al. 2014
Dabrafenib plus
Trametinib plus
Ipilimumab
I
No grade 3/4 liver toxicity reported, two
cases with severe colitis/GI perforation):
study stopped!
Minar et al. 2015
Nivolumab plus
Erlotinib
I
Grade 3/4 ALAT & ASAT
in 4/21 patients
Rizvi et al. 2014
Durvalumab plus
Gefitinib or
Osimertinib
I
Grade 3/4 ALAT & ASAT and > 50% ILD
reported: study stopped!
Creelan et al. 2015
Vemurafenib plus
Ipilimumab
IOs and IOs: Toxicities
Study
Phase
Main Toxicity
Reference
I/II
Grade 3/4 liver toxicity: study stopped
AACR Abstract 2016
Atezolizumab plus
MOXR0916
I
MTD not reached, no significant AEs
reported
ASCO Abstract 2016
Ipilimumab plus
Nivolumab versus
Ipilimumab
III
55% grade 3/4 AEs for the combination;
27.3% grade 3/4 AEs for Ipi mono
Larkin et al. 2015
Nivolumab plus LAG-3
inhibitor
I
Ongoing (no results yet)
BMS, personal
communication
Pembrolizumab plus
Utomilumab (4-1BB
agonist)
I
Ongoing (no results yet)
ASCO Abstract 2016
Ipilimumab plus IDO
inhibitor
Executive Summary
• Many “breakthrough” immune therapies
• Field is incredibly competitive
• New targets – new modalities
• Resistance mechanisms far from being clear
• Combinations may improve efficacy
• Most critical issue: Toxicity!
• Are combinations financially toxic as well?
IOs: A Wolf in Sheep’s Clothing….
Some beautiful
successes, even
with cure in 10-20%
of patients!
Significant and
increased
toxicities for
combinations
(-> some studies
stopped!)
The “Glass-is-Full“ perspective“!