Current experience in immunotherapy for metastatic renal cell carcinoma

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1 Current experience in immunotherapy for metastatic renal cell carcinoma Axel Bex, MD, PhD The Netherlands Cancer Institute FOIU, Tel Aviv, 3 July 2018

2 Financial and Other Disclosures Off-label use of drugs, devices, or other agents: None or FILL IN HERE; including your local regulatory agency, such as FDA, EMA, etc. Data from IRB-approved human research is presented [or state: is not ] I have the following financial interests or relationships to disclose: Pfizer Roche Genentech Ipsen Novartis BMS Disclosure code C, S C C C C C 2

3 OS probability Immune checkpoint inhibitors have changed the RCC treatment landscape CheckMate-025: Nivolumab vs everolimus in second-line mrcc Real-world setting in n=264 Dutch patients from a 2 nd -line nivolumab registry Overall survival Median OS, months (95% CI) Nivolumab (n=410): 25.0 (21.8 NE) Everolimus (n=411): 19.6 ( ) HR 0.73 (98.5% Cl ) P= Time, months CI, confidence interval; HR, hazard ratio; NE, not estimable; OS, overall survival; PFS, progression-free survival. Motzer RJ et al. N Engl J Med. 2015;373: , Verhaart et a., ASCO 1-5 June, 2018

4 Checkpoint inhibitor combination trials in first-line an embarassment of riches Study Sponsor N Therapy Endpoint Subtype MK Merck Sharp & Dohme 840 Pembrolizumab 200 mg IV Q3W PLUS axitinib PFS central 5 mg PO BID review 426/KEYNOTE-426 vs OS NCT ¹ sunitinib 50 mg PO QD 4/2 weeks JAVELIN Renal 101 NCT ¹ Pfizer 583 Avelumab administered at 10 mg/kg IV Q2W in combination with axitinib, 5 mg PO BID vs sunitinib given at 50 mg PO QD 4/2 weeks PFS, OS clear cell component with or without sarcomatoid features clear cell component NCT ¹ Hoffmann-La Roche 900 Atezolizumab as a fixed dose of 1200 mg via IV infusion on days 1 and 22 of each 42-day plus bevacizumab 15 mg/kg via IV infusion on days 1 and 22 of each 42-day cycle vs sunitinib given at 50 mg PO QD 4/2 weeks Checkmate 214 NCT ¹ Bristol-Myers Squibb 1070 Nivolumab 3 mg/kg combined with ipilimumab 1 mg/kg solutions IV Q3W for 4 doses then nivolumab 3 mg/kg solutions IV Q2W vs sunitinib given at 50 mg PO QD 4/2 weeks NCT ¹ Eisai Inc. 735 Lenvatinib 18 mg PO QD, plus everolimus 5 mg PO, QD or lenvatinib 20 mg PO QD, plus pembrolizumab 200 mg IV, Q3W vs sunitinib 50 mg PO QD 4/2 weeks PFS investigator reviewed OS in participants with detectable PD- L1 PFS OS PFS, OS clear cell histology and/or a component of sarcomatoid carcinoma clear-cell component clear-cell component Checkmate 9ER NCT Bristol-Myers Squibb 1014 Nivolumab 3 mg/kg combined with ipilimumab 1 mg/kg solutions IV and cabozantinib (triplet) vs nivolumab 3 mg/kg solutions IV and cabozantinib vs sunitinib given at 50 mg PO QD 4/2 weeks PFS, OS clear-cell component

5 UPDATED EAU GUIDELINES RECOMMENDATIONS FOR THE TREATMENT OF FIRST-LINE METASTATIC CLEAR-CELL RENAL CANCER.

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9 Immune combination leads to a high complete response rate

10 OS in the ITT (including favorable IMDC risk) and ORR and PFS in favorable risk

11 OS data of CheckMate 214 per PD-L1 status Slide 26 Presented by Motzer et al., SITC 2017

12 Immotion 151 trial of atezolizumab plus bevacizumab versus sunitinib in patients with clear-cell or sarcomatoid mrcc Study Design

13 Baseline Characteristics CheckMate 214 included by IMDC risk factors of which 23 % favorable, 61% intermediate and 17% poor risk Presented By Robert Motzer at 2018 Genitourinary Cancers Symposium: Translating Evidence to Multidisciplinary Care

14 Progression-Free Survival in PD-L1+ Presented By Robert Motzer at 2018 Genitourinary Cancers Symposium

15 PFS and ORR by IRC Presented By Robert Motzer at 2018 Genitourinary Cancers Symposium: Translating Evidence to Multidisciplinary Care

16 Overall Survival in ITT Presented By Robert Motzer at 2018 Genitourinary Cancers Symposium

17 Treatment-related AEs<br /> 20% frequency in either arm and > 5% difference between arms Presented By Robert Motzer at 2018 Genitourinary Cancers Symposium: Translating Evidence to Multidisciplinary Care

18 PD-1 Blockade Based Combinations in mrcc:<br />Are they Additive or Synergistic? Presented By David McDermott at 2018 Genitourinary Cancers Symposium: Translating Evidence to Multidisciplinary Care

19 Results in context CheckMate 214 and IMmotion 151 used different PD- L1 IHC staining OS benefit in CheckMate 214 independent of PD-L1 tumour expression IMmotion 151 lacks mature OS data and no significant PFS difference across all PD-L1 groups in IRC

20 CABOSUN trial of cabozantinib versus sunitinib in IMDC intermediate and poor risk patients Slide 23

21 Genomic correlates of response to immune checkpoint therapies in clear cell renal cell carcinoma Miao D et al., Science 2018

22 Immotion 150 biomarker analysis Transscriptome map of angiogenesis and immuneassociated genes in RCC McDermott et al., AACR 2017

23 Sunitinib Demonstrated Improved PFS in AngiogenesisHigh Subset vs AngiogenesisLow Subset

24 Molecular subtypes of clear cell RCC are associated with sunitinib response in the metastatic setting ccrcc1/ccrcc4 tumors: lower RR, shorter PFS and OS than ccrcc2/ccrcc3 tumors (P = 0.005, and , respectively) when treated with sunitinib. ccrcc4: strong inflammatory, Th1-oriented but suppressive immune microenvironment, with high expression of PDCD1 (PD-1) and its ligands Beuselinck et al., Clin Cancer Res 2015; Escudier et al, 2018 Genitourinary Cancers Symposium

25 Conclusion If no drug-related contraindications present the IMDC prognostic model is currently the only tool for patient selection based on higher level of evidence Tumor or immune-cell PD-L1 expression reveal trends but checkpoint inhibition is effective irrespective of expression Angiogenic or immune-inflammatory genotypes are emerging but have not been tested in phase 3 Clinical subgroup analysis is interesting but cross-trial comparisons should not be done