Immuno-Oncology Drugs: A Land of Opportunity? Wolfram C. M . Dempke, MD, PhD, MBA Professor of Haematology & Oncology SaWo Oncology Ltd Cambridge, April 2017

Immune Therapy in 2017 Only 10-15% of patients achieve durable clinical responses. However, responses are seen across various histologies. Cell evading immune surveillance is far from being clear, but several IO resistance mechanisms have been identified so far. Many encouraging results with combinations (e.g., > 800 clinical trials for PD-1/PD-L1 combinations ongoing), however, toxicity is critical. Current research focus: conversion of “cold” tumours to “hot” tumours.

Resistance Dempke et al. 2015

IOs: Resistance Mechanisms At least one third of solid tumours (TCGA data) are non-T cell- inflamed (“cold tumours”) Several mechanisms of resistance to IO drugs have been identified: - β-catenin/Wnt overexpression/mutation - downregulation of target (e.g., PD-1/PD-L1) - JAK1,2 mutations - PTEN loss (→ PI3K-γ mutations) - impaired binding to MHCs - bypassing by other checkpoint molecules

Overcoming IO Resistance Based on the concept of “hot” (inflamed) and “cold” (non-inflamed) tumours, three general mechanisms to overcome IO resistance have been identified: Targeting the tumour microenvironment with small molecules to induce CD8+ T cell infiltration (“crossing the PD-L1 wall“): IDOs, A-2A-R inhibitors, PI3K-γ inhibitors Combination of different checkpoint inhibitors and co-stimulators (“bypassing PD-1/PD-L1 expression change“): anti-PD-1/PD-L1 + anti-CTLA-4, CD40, ICOS, OX40 etc. . Tumour Vaccination Concepts

IO Treatment: Quo Vadis? Targeted Therapies (e.g., TKIs, SKIs etc.) Targeted Therapies (Second-Line) Chemotherapy, Others, BSC 10% No Cure (except CML) Immuno-oncology Drug Combinations (Second-Line) Immuno-Oncology Drugs (e.g., Checkpoint modulators) Tumour Vaccination Approaches (?), CTx, BSC 90% Immuno-Oncology Drugs plus Small Molecules Cure (10-15%)

T Cell “Stay on the gas“ “Cutting the brakes“ IL-2R (CD122) CTLA-4 (CD152) PD-1 (CD279) CD137 (4-1BB) PD-L1 (CD274) ICOS (CD278) TIM-3 T Cell CD27 VISTA (B7-H5) LAG-3 (CD223) “Stay on the gas“ “Cutting the brakes“ CD28 KIRi OX40 (CD134) CCR4 (CD194) BTLA (CD272) KIRs IDO-1,2 GITR (CD357) B7-H3 (CD276) CD40 TIGIT A2AR Novel Immune Checkpoint! T cell stimulation

Small Molecules & New Targets IDO1,2 Inhibitors (e.g., Indoximod, Epacadostat, BMS- 986205 etc.) PI3K-γ Inhibitors (e.g., IPI-549) Adenosine-A2A-Receptor Inhibitors (e.g., CPI-444) Others: anti-CD73, TIGIT, oral compounds targeting VISTA and PD-L1 (e.g., CA-170, BMS-202 etc.)

PI3K-γ Inhibitor: IPI-549 PI3K-γ (phosphoinositide-3 kinase) is mainly expressed on myeloid cells. Growing evidence suggests that high levels of PI3K-γ are associated with IO resistance and poor prognosis. Targeting PI3K-γ with IPI-549 can enhance CD8+ T cell infiltration and thereby overcome resistance to checkpoint inhibitors (e.g., anti-PD-1/PD-L1). De Henau et al. 2016

PI3K-γ Inhibitor: IPI-549 PI3K-γ (phosphoinositide-3 kinase) controls a critical switch between immune stimulation and suppression during inflammation and cancer. In addition, selective inactivation of macrophage PI3K-γ stimulates and prolongs NFκB activation and inhibits C/EBPβ activation, thus promoting an immuno-stimulatory transcriptional program that restores CD8+ T cell activation and cytotoxicity. Kaneda et al. 2016

CD122/ 155 TIGIT CD122/155 TIGIT MTIG7192G

PI3K-γ Inhibitor: IPI-549 The small molecule IPI-549 (Infinity) targets PI3K-γ, is active as a single molecule and increases CD8+ T cells in mice. The molecule has demonstrated a large IC50 window (excellent safety profile in the ongoing phase I trial) and can reverse resistance to checkpoint inhibitors. IPI-549 has shown synergistic effects with anti-PD-1 antibodies in animal models.

PI3K-γ Inhibitor: IPI-549 IPI-549 (20 mg twice daily) is currently evaluated in a phase I clinical trial alone and in combination with nivolumab (NCT02637531).

IDO-1 Inhibitor: BMS-986205 Indoleamine pyrrole 2,3-dioxygenase (IDO) converts L-tryptophane to kynurenine. This results in a decreased tryptophan level which then suppresses T cell proliferation, a mechanism being involved to terminate the immune reaction. High IDO expression is associated with resistance to chemo-, radio- and immunotherapy and a marker of poor prognosis. Dempke et al. 2017

CD122/ 155 TIGIT CD122/155 TIGIT MTIG7192G

IDO-1 Inhibitor: BMS-986205 Overexpression of IDOs (IDO-1 and IDO-2) (e.g., by IFN-γ, IL-6, TNF-α) leads to Treg activation and stimulates PD-1 and PD-L1 expression. Moreover, treatment with anti-CTLA-4 antibodies stimulates also IDO overexpression. Several IDO inhibitors are currently undergoing phase II/III clinical development: indoximod (NewLink Genetics, inhibits IDO-2); epacadostat (Incyte, inhibits IDO-1). Dempke et al. 2017

IDO-1 Inhibitor: BMS-986205 BMS-986205 is a new small molecule targeting IDO-1 and is currently undergoing phase I/II clinical evaluation (NCT02658890) either alone or in combination with nivolumab (25-100 mg). Clinical data demonstrated a >60% reduction of plasma kynurenine in this trial (epacadostat: < 50%). In addition, reduction of intratumoural kynurenine was found to be up to 90%. MTD is not reached so far; and no grade 4-5 toxicities were seen for the combination. BMS-986205 is thought to be the best-in-class of all IDOs tested.

IDO-1 Inhibitor: BMS-986205

IDO-1 Inhibitor: BMS-986205 Treatment with nivolumab and BMS-986205: Patient with a metastatic head-and-neck tumour (previously pre-treated with two lines of platinum-based chemotherapy).

IDO-1 Inhibitor: BMS-986205 Treatment with nivolumab and BMS-986205: Patient with a metastatic renal cell carcinoma (previously treated with pazopanib).

IDO-1 Inhibitor: Indoximod Indoximod is a small molecule targeting IDO-2. The drug is currently undergoing phase II clinical evaluation. Preclinical data demonstrated a synergistic effect of indoximod and nivolumab and pembrolizumab. Thus, the combination of indoximod and pembrolizumab in a phase II trial for metastatic malignant melanoma is ongoing (NCT02073123) (N = 60).

IDO-1 Inhibitor: Indoximod

IDO-1 Inhibitor: Indoximod Patients

IDO-1 Inhibitor: Indoximod

IDO-1 Inhibitor: Indoximod Parameter All Patients (N = 60) Cutaneous/Non-ocular (N = 51) ORR 31(52) 30(59) CR 6(10) 6(12) PR 25(42) 24(47) SD 13(22) 11(22) DCR 44(73) 41(80) PD 16(27) 10(20)

IDO-1 Inhibitor: Indoximod The ORR for the entire study cohort was 52% (CR rate: 12%). The combination of indoximod and pembrolizumab has shown an ORR of 59% and a DCR of 80% in patients with cutaneous and non-ocular advanced melanoma. The combination was well tolerated. Historic controls: - Pembrolizumab alone: ORR 33% - Ipilimumab + Nivolumab: ORR 57.6%

Adenosine-A2A-Receptor Inhibitor: CPI-444 The adenosine-A2A receptor is generally accepted to be a checkpoint inhibitor. Several studies have demonstrated that blockage of this receptor can enhance the anti-tumour activity of other checkpoint inhibitors (e.g., anti-CTLA-4; anti-PD-1/PD-L1). Receptor antagonists have been developed for cancer treatment, although some antagonists are been tested in phase III trials for Parkinson’s disease. Leone et al. 2015

Leone et al. 2015

Adenosine-A2A-Receptor Inhibitor: CPI-444 Tumours secret nucleotides into the tumour environment; this creates an immunosuppressive niche that promotes tumour growth and metastasis. Adenosine signaling via the adenosine-A2A-receptor on immune cells suppresses anti-tumour immunity and has been shown to limit the effıcacy of immunotherapies such as anti- PD-L1 or anti-PD-1 monoclonal antibodies. Blockade of this receptor (e.g., with CPI-444) was found to restore tumour infiltration with CD8+ T cells in vivo.

Adenosine-A2A-Receptor Inhibitor: CPI-444 CPI-444 (Corvus) is a small molecule that targets the adenosine-A2A-receptor and is currently undergoing phase I clinical evaluation either alone or in combination with atezolizumab (N = 113; NCT02655822). Heavily pre-treated patients (up to 5 prior treatment lines) were enrolled. 80% of the patients enrolled had prior chemotherapy; 50% were resistant or refractory to anti-PD-1/PD-L1 treatment.

Adenosine-A2A-Receptor Inhibitor: CPI-444 CPI-444 was found to be well tolerated as single agent and in combination with atezolizumab (common grade 1-2 toxicities: nausea, fatigue, pruritus). In patients resistant or refractory to anti-PD-1 or anti-PD-L1 treatment 23/37 patients with PR or SD still remain on study. Amongst all patients treated those with RCC, TNBC, and NSCLC appeared to be “good responders”. CPI-444 treatment was found to significantly increase CD8+ T cells in a NSCLC patients (14% → 70%).

Adenosine-A2A-Receptor Inhibitor: CPI-444 Treatment of a NSCLC patient with CPI-444. Left: pre-treatement; right: tumour shrinkage after 2 months of treatment.

Adenosine-A2A-Receptor Inhibitor: CPI-444 Patient with metastatic renal cell carcinoma who received pre-treatment with TKIs, nivolumab, bevacizumab, and mTOR inhibitors before enrollment. Left: IHC stain revealed only marginal tumour infiltration of CD8+ T cells (14%, before treatment with CPI-444). Right: massive infiltration with CD8+ TILs (70%) following CPI-444 treatment (2 months).

Others: TIGIT TIGIT (T cell immuno-receptor with Ig and ITIM domains) is a novel immune checkpoint molecule. TIGIT binds CD122 and CD155 (dendritic cells, macrophages); intracellular signaling is then propagated via CD 226. TIGIT stimulation inactivates NK cells and CD8+ TILs whereas Tregs (high expression!) are activated.

CD122/ 155 TIGIT CD122/155 TIGIT MTIG7192G

Others: TIGIT Blake et al. 2016

Others: TIGIT TIGIT antagonistic monoclonal antibodies have shown excellent tumour regression in vivo in combination with other checkpoint inhibitors (e.g., PD-1 and PD-L1). Several TIGIT monoclonal antibodies are currently in phase I/Ib development (alone or in combination): - MTIG-7192G (Genentech; NCT02794571) - BMS-986207 (BMS; NCT02913313

Others: anti-CD73 Ecto-5’-nucleotidase (CD73) is mainly expressed on the surface of many tumour cells (GPI-anchored) and catalyses the conversion of AMP to adenosine and phosphate. CD73 expression is associated with a poor prognosis. Activation of CD73 results in a “adenosine cloud” which suppresses immune response of T cells. Blockade of CD73, however, can enhance the efficacy of anti- PD-1/PD-L1 and anti-CTLA-4 antibodies in animal models.

Others: anti-CD73 Allard et al. 2013

Others: anti-CD73 Anti-CD73 monoclonal antibodies are currently evaluated in early phase I trials (either alone or in combination with checkpoint inhibitors): - MEDI9447 (AstraZeneca; NCT02503774) - CPX-006 (Corvus; phase I in preparation)

Executive Summary Field is incredibly competitive Many “breakthrough” immune therapies Field is incredibly competitive New targets are already tested in phase I trials Resistance is gradually emerging Combinations may improve efficacy Most critical issue: Toxicity! Current focus: How to convert “cold” tumours to “hot” tumours (→ small molecules)?

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