Blocking VEGF in addition to checkpoint inhibition in RCC

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1 Blocking VEGF in addition to checkpoint inhibition in RCC Priti S. Hegde, PhD Director, CI Franchise Lead, Biomarkers Genentech/Roche 15 th IKCS Miami, FL

2 The Tumor Immunity Continuum Known factors that contribute to an effective anti-tumor immune response Inflamed INFLAMED IMMUNE EXCLUDED IMMUNE DESERT Noninflamed CD8+ T cells infiltrated, but non-functional CD8+ T cells accumulated but have not efficiently infiltrated CD8+ T cells are absent from tumour and its periphery Mutational Load TILs CD8 T cells/ifng PD-L1 & checkpoints Angiogenesis Reactive stroma MDSCs Ki67 Low MHC I Respond favorably to checkpoint inhibition Convert to inflamed phenotype with combinations Modified from Hegde PS et al., Clin Canc Res 2016 Where does RCC fit in this picture?

3 Mutations/Mb Renal cell carcinomas represent inflamed tumors with low tumor mutation load Mutation Load in RCC ranked 55 th among 91 distinct cancer types * Frampton et al., AACR 2016 Hegde PS, CIMT 2014

4 The Renal cell carcinoma tumor immunity continuum INFLAMED CD8+ T cells infiltrated, but non-functional IMMUNE EXCLUDED CD8+ T cells accumulated but have not efficiently infiltrated IMMUNE DESERT CD8+ T cells are absent from tumor and its periphery Angiogenesis Immune Reactive Stroma Will combination of checkpoint inhibition with an anti-angiogenesis agent convert an excluded infiltrate phenotype or an immune desert to an inflamed tumor?

5 A. C. CD31 CD8 MHC I PD-L1 CD34/aSMA/ Podoplanin Bevacizumab promotes infiltration of T-cells and upregulated MHC-Class I Pre-treatment Post Bev Post Bev+Atezo Pre-treatment Post Bev Post Bev+Atezo B. % CD31 VPOSVE (Fold Change from Pre-Treatment) CD8 IHC (Fold Change from Pre-Treatment) Pre-treatment Post Bev Post Bev+Atezo P = Pre-treatment Post Bev Post Bev+Atezo 300 P = Durable efficacy of Bevacizumab+Atezolizumab ORR: 40% CD8/Ki67 MHC I (H Score) CD68/ CD163 0 Pre-treatment Post Bev Post Bev+Atezo Wallin J et al., Nature Comm. 2016

6 Hypothesis testing in randomized trials IMmotion 150 (Phase II) Randomize 305 pts 1:1:1 Stratify: PDL1 IHC status Motzer criteria Prior nephrectomy Atezo q3wk +bev q3wk Atezo q3wk Sunitinib 50mg (4wk-on & 2wk-off) PD PD Primary endpoint: IRC-assessed PFS (per RECIST1.1) in ITT and IC1/2/3 Atezo + bev q3wk Atezo + bev q3wk Cross-over IMmotion 151 (Phase III) Randomize ~900 patients Stratify: Liver mets (y/n) PD-L1 (IC1/2/3 vs IC0) MSKCC Criteria (Low, intermediate, high risk) 1:1 Arm A Atezo q3w + Bevacizumab q3w Arm B Sunitinib (4w-on & 2w-off) cross-over not permitted Primary endpoint: Investigator-assessed PFS (per RECISTv1.1) in IC1/2/3 and OS in ITT, followed by OS in IC1/2/3 Until loss of clinical benefit Until loss of clinical benefit

7 Summary Renal Cell Carcinomas represent inflamed tumors with low tumor mutation burden Approximately 60% of RCC tumors represent excluded infiltrate or immune desert phenotypes, both of which are encriched for biology related to tumor angiogenesis Bevacizumab treatment results in increased T-cell infiltration and MHC-Class I expression in RCC tumors The combination of bevacizumab with atezolizumab shows improved clinical benefit both with respect to ORR and durability of response Randomized trials of this combination against standard of care are currently in progress to address the biological hypothesis

8 Mahrukh Huseni Gregg Fine Friedrich Graf-Finkenstein Steve Hodi Jeff Wallin Daniel Waterkamp Konstanty Korski Bob Motzer Dorothee Nickels Herschel Wallen Fabien Giere Martin Voss Zach Boyd Y J Choi William Pao Alex Snyder Shruthi Sampath Jing Yi Suchit jhunjhunwala Cathi Ahearn Mitch Denker Richard Bourgon Wei Zou Craig Cummings Lukas Amler Patients and their families Collaborators at Foundation Medicine and Ventana Medical Systems David McDermott Genentech/Roche investigators Ira Mellman Dan Chen Stuart Lutzker Tom Powles Brian Rini