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 Ipi adj. Nivo 1st Nivo 2nd Pem-bro 1st Pembro 2nd Ipi mono Nivo +Ipi Melanoma 2011 2012 2013 2014 2015 2016 Nivo 2nd RCC Nivo 2nd NSCLC (sq) Pembro 2nd NSCLC Nivo 2nd NSCLC (n-sq) Non-Melanoma 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%) Bladder Cancer (15-30%) Ovarian Cancer (6-23%) Head-and-Neck Cancer (20-25%) Hodgkin’s Lymphoma (65-87%) GI Tumours, TNBC, Mesothelioma, HCC, …. Some patients DO respond to IO drug treatment – biomarkers to identify them?

NSCLC: KEYNOTE-001 Many patients do NOT respond to IO drug treatment – resistance mechanisms? Cure!

“Cold” and “Hot” Tumours

T cell immune surveillance of cancer T cell response, Elimination, Immunoediting, Escape Resistance to Immune Therapy T cell response, Host/Tumour Immune Suppression, Peripheral Tolerance Overcome with CTLA-4 or PD-1 mAB, or both Escape HOT Host/Tumour Immune Suppression, no T cell response, Immune Privilege Overcome by vaccination AND block immune suppression No Escape COLD

“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 Vemurafenib plus Ipilimumab I ALAT & ASAT Grade 3 in 6/16 patients: study stopped! Ribas et al. 2013 Dabrafenib plus Ipilimumab (ongoing) No grade 3/4 liver toxicity reported so far. 1 patient with severe colitis Puzanov et al. 2014 Dabrafenib plus Trametinib plus Ipilimumab No grade 3/4 liver toxicity reported, two cases with severe colitis/GI perforation): study stopped! Minar et al. 2015 Nivolumab plus Erlotinib Grade 3/4 ALAT & ASAT in 4/21 patients Rizvi et al. 2014 Durvalumab plus Gefitinib or Osimertinib Grade 3/4 ALAT & ASAT and > 50% ILD reported: study stopped! Creelan et al. 2015

IOs and IOs: Toxicities Study Phase Main Toxicity Reference Ipilimumab plus IDO inhibitor 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 Ongoing (no results yet) BMS, personal communication Pembrolizumab plus Utomilumab (4-1BB agonist)

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“!