Renal Cell Carcinoma: Systemic Therapy Progress and Promise

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1 Renal Cell Carcinoma: Systemic Therapy Progress and Promise Michael B. Atkins, M.D. Deputy Director, Lombardi Comprehensive Cancer Ctr Georgetown University Medical Center

2 Everolimus Rini, Campbell, Escudier. Lancet

3 RCC Therapy: 215 Setting Good or 1st-Line intermediate risk* Therapy 2nd-Line Therapy Phase III Alternative Sunitinib Pazopanib HD IL-2 Poor risk* Temsirolimus Sunitinib Prior cytokine Sorafenib Pazopanib Sunitinib or Bevacizumab Prior VEGFR inhibitor Everolimus Axitinib Clinical Trials Prior mtor inhibitor Clinical Trials *MSKCC risk status. Atkins. ASCO 26 Plenary session; Figlin. Clin Adv Hematol Oncol. 27;5:35; Escudier. Drugs. 27;67:1257; Cho. Clin Cancer Res. 27;13:761s; Atkins. Clin Cancer Res. 25;11:3714.

4 New FDA Approved Treatments Agent FDA Approval Date Nivolumab 11/23/15 Cabozantinib 4/26/16 Lenvatinib + Everolimus 5/13/16

5 Blocking Immunologic Checkpoints Effector Phase: Peripheral Tissues Priming: T-Cell Activation in the Lymph Node Dendritic cell Tumor CD28 Cytotoxic T cell B7 Interferons B7 CTLA-4 Ipilimumab Tremelimumab PD1 Nivolumab Pembrolizumab PD-L1 Atezolizumab Durvalumab Avelumab Ribas A. N Engl J Med. 212;366: Spranger S, et al. J Immunother Cancer. 213;1:16.

6 Cancer Immunotherapy Principles Treating the immune system so that it can treat the cancer Jedd Wolchok Because the activated immune system can target many tumor antigens simultaneously, and deepen and broaden over time, IT can cure patients with metastatic cancer The hallmark of effective immunotherapy is the tail on the curve

7 Nivo Overall survival in phase I and II studies Overall Survival (Probability) 1..9 Study.8 Phase I Phase II.7 Median OS, months (95% CI) 22.4 (12.5 NE) 23.4 ( ) year OS 38% year OS 34% 4-year OS 29%.2.1. Number at risk Phase I 34 Phase II Months In phase I and II studies, min follow-up was 5.5 mos and 49.2 mos, respectively NE, not estimable. McDermott et al ASCO Abst 216 5

8 Checkpoint Inhibitor-based Immunotherapy Treatment-free Survival

9 Checkpoint Inhibitor-based Immunotherapy How do we move this anti-pd1 based therapy into early stages of disease?

10 Single Agent Anti-PD1/PDL1 Blockade: Current and Future Directions Combinations With other Immunotherapy With VEGF Inhibitors Biomarker refinement Non-clear cell activity Adjuvant protocols

11 CM 214 Study: Nivo/ipi vs Sunitinib in RCC OS: IMDC intermediate/poor risk Median OS, months (95% CI) 1. NIVO + IPI NR (28.2 NE) SUN 26. (22.1 NE) Overall Survival (Probability).9 Hazard ratio (99.8% CI),.63 (.44.89) P = Months No. at Risk NIVO + IPI SUN Escudier et al ESMO 217

12 Single Agent Anti-PD1/PDL1 Blockade: Current and Future Directions Combinations With other Immunotherapy With VEGF Inhibitors Biomarker refinement Non-clear cell activity Adjuvant protocols

13 Axitinib in Combination With Pembrolizumab in Patients With Advanced Renal Cell Carcinoma: Atkins et al. % Change in Tumor Burden, by Best Response Best Overall Response Axitinib + PEM Pts with baseline assessment 52 (1) Pts with measurable disease at BL 52 (1) Best overall response, n (%) Complete response (CR) 3 (5.8) Partial response (PR) 34 (65.4) Stable disease 1 (19.2) Progressive disease 2 (3.8) Indeterminate* 3 (5.8) Objective response rate (CR+PR) 95% Exact CI 37 (71.2) Complete response Partial response Stable disease 6 Progressive disease Indeterminate* 1 Best % Change in Tumor Size from Baseline N= ORR=71.2% 2 y= * 2 patients indeterminate and 1 patient with no follow-up assessment. 94% of patients with tumor shrinkage * Stable disease or partial response not confirmed. SLD for all target lesions was used for tumor size calculation at BL and all visits. Determination of patient best observed response is indicated. PFS data are immature; only 14 (26.9%) events for the overall analysis. In the overall population, median PFS was > 15.1 months (range 11.4 NE). BL=baseline; CI-confidence interval; ORR=objective response rate; PEM=pembrolizumab; PFS=progression-free survival; pts=patients; SLD=sum of the lesion diameter

14 Single Agent Anti-PD1/PDL1 Blockade: Current and Future Directions Combinations With other Immunotherapy With VEGF Inhibitors Biomarker refinement Non-clear cell activity Adjuvant protocols

15 Addition of Bevacizumab to Atezolizumab in 1L Was Associated With Improved Benefit in T-EffectorHigh Myeloid InflammationHigh Subgroup T-effectorHigh Myeloid InflammationLow Atezo + bev (n = 23) Atezo (n = 23) Sunitinib (n = 19) PFS measured by independent review facility. T-effector gene signature: CD8A, EOMES, PRF1, IFNG, CD274. High, median expression; low, < median expression. McDermott, AACR 217. Presented by: Dr Michael Atkins, Atezolizumab in RCC, IMmotion15 Crossover. 15

16 Addition of Bevacizumab to Atezolizumab in 1L Was Associated With Improved Benefit in T-EffectorHigh Myeloid InflammationHigh Subgroup T-effectorHigh Myeloid InflammationLow T-effectorHigh Myeloid InflammationHigh Atezo + bev (n = 23) Atezo + bev (n = 2) Atezo (n = 23) Atezo (n = 23) Sunitinib (n = 19) Sunitinib (n = 24) PFS measured by independent review facility. T-effector gene signature: CD8A, EOMES, PRF1, IFNG, CD274. High, median expression; low, < median expression. McDermott, AACR 217. Presented by: Dr Michael Atkins, Atezolizumab in RCC, IMmotion15 Crossover. 16

17 Trial Diagram HCRN GU 26 BMS Metastatic Kidney Cancer Treatment Naïve 12 ccrcc 4 nccrcc PR or CR: Continue Nivolumab 36 mg/kg IV Q3wks x up to 84 wks Nivolumab 24 mg/kg IV Q2wks PD or best response 1 year: Re-induce with N3/I1 q3 weeks x 4, up to 4 combination doses Extensive Biomarker studies to be done in collaboration with the DFHCC Kidney Cancer SPORE Investigators PR or CR: Continue Nivolumab 36 mg/kg IV Q3wks x 48 wks Opened 4/17/17 Atkins, Hammers, McDermott

18 A Roadmap of ImmunotherapyTumor Interactions 4 Priming and activation Anti-CTLA4 Anti-CD137 (agonist) Anti-OX4 (agonist) Anti-CD27 (agonist) IL-2 IL-12 Trafficking of T cells to tumors 3 5 Infiltration of T cells into tumors Anti-VEGF Cancer antigen presentation 2 6 Vaccines IFN-α GM-CSF Anti-CD4 (agonist) TLR agonists Release of cancer cell antigens Chemotherapy Radiation therapy Targeted therapy Chen DS, et al. Immunity. 213;39:1-1. Recognition of cancer cells by T cells CAR T cells 1 7 Killing of cancer cells Anti-PD-L1 Anti-PD-1 IDO inhibitors

19 Single Agent Anti-PD1/PDL1 Blockade: Current and Future Directions Combinations With other Immunotherapy With VEGF Inhibitors Biomarker refinement Non-clear cell activity Adjuvant protocols

20 CM-238 Trial- Nivo vs Ipi in Resected Stage III/IV Melanoma: Primary Endpoint: RFS NIVO IPI Events/patients 154/453 26/453 Median (95% CI) NR NR (16.6, NR) 1 9 HR (97.56% CI).65 (.51,.83) Log-rank P value 8 <.1 71% 7 RFS (%) 66% 6 61% 53% NIVO IPI 1 Nu mb er of pati NIV ent 453 O s at IPI 453 risk Months Weber J et al N Engl J Med 217 8

21 Progression-free Survival in the Intention-to-Treat Durvalumab Adjuvant Therapy in Stage III Population. NSCLCa Antonia SJ et al. N Engl J Med 217. DOI: 1.156/NEJMoa179937

22 Implications of Adjuvant Anti-PD1 Data This data suggests that visible tumor is not required in order to have sufficient TIL to kill residual tumor cells This further suggests that PD1 based adjuvant therapy will be active against RCC and other tumors Several studies have been launched Major impact on Cancer Moonshot Goal achieve 1 years of progress in 5 years

23 Our goal should not be simply to turn RCC into a chronic disease We should strive to make RCC a curable disease