Indication for- and timing of cytoreductive nephrectomy Kidney- and bladder cancer: Immunotherapy

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1 Indication for- and timing of cytoreductive nephrectomy Kidney- and bladder cancer: Immunotherapy Axel Bex, MD, PhD The Netherlands Cancer Institute Oslo, September 4, 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 CARMENA investigated the role of CN SURTIME the sequence of CN

4 SURTIME and CARMENA included patients who require sunitinib Time to targeted therapy in patients with low-volume but non-resectable metastatic disease after CN N=28 from an institutional database of 202 primary mrcc patients Median timo to TT 14 months Bex et al., GU ASCO, J Clin Oncol 34, 2016 (suppl 2S; abstr 604)

5 Study design R Immediate Nephrectomy Deferred Nephrectomy N E P H R E C T O M Y Cycle 1 (6 wk) Cycle 2 Cycle 3 Cycle 4 Progression status at week 16 Cycle 1 (6 wk) Cycle 2 N E P H R E C T Cycle 3 (4 wk) O M Y Progression status at week 28 Cycle 4 Cycle 5 Progression status every 12 weeks = Sunitinib = Progression status 4 weeks after CN 5

6 Baseline characteristics Immediate nephrectomy (N=50) Deferred nephrectomy (N=49) Median age (years) Performance status (WHO) - WHO 0 36 (72.0%) 31 (63.3%) - WHO 1 14 (28.0%) 18 (36.7%) Male 41 (82.0%) 39 (79.6%) MSKCC intermediate risk 43 (86.0%) 44 (89.8%) 2 measurable metastatic sites 43 (86.0%) 46 (93.9%) Mean (SD) primary tumor size (mm) 93.1 (37.8) 96.8 (31.3) 6

7 Week 16 evaluation (+/-15 days window) Week 28 evaluation (+/-15 days window) Progression-free survival (ITT) HR (95%CI)=0.88 (0.56, 1.37), p=0.569 Stratified by WHO performance status (0 versus 1) Progression-free status at w28 (±15 days) Immediate nephrectomy (N=50) Deferred nephrectomy (N=49) Progression-free at week (42.0%) 21 (42.9%) Deferred [95% CI] [28.2% 56.8%] [28.8% 57.8%] p-value (one-sided Fisher exact test) 0.61 Immediate Progression week 28 or treatment failure 25 (50.0%) 24 (49.0%) Not assessable 4 (8.0%) 4 (8.2%) 7

8 Overall Survival (ITT) Immediate Deferred HR (95%CI)=0.57 (0.34, 0.95), p=0.032 Stratified by WHO performance status (0 versus 1) Immediate nephrectomy (N=50) Deferred nephrectomy (N=49) Survival status Dead 35 (70.0) 28 (57.1) Reason of death Progression Surgery related toxicity 1 0 Progression and surgery related toxicity 1 0 Cardiovascular disease (not due to toxicity or progression) 1 0 Other (not due to toxicity or progression) 1 0 Unknown 1 3 8

9 Overall survival after week 16 (%) Overall Survival Landmark analysis at week PD before w16 No PD before w Months Patients-at-Risk Excluded- Immediate Deferred Immediate Deferred Assessment of progression status at week 16 prior to planned CN in the deferred arm 9

10 Patient disposition Presented By Arnaud Mejean at 2018 ASCO Annual Meeting

11 Patient characteristics (1) Presented By Arnaud Mejean at 2018 ASCO Annual Meeting

12 Overall <br />survival (ITT) Presented By Arnaud Mejean at 2018 ASCO Annual Meeting

13 Overall survival (ITT) Presented By Arnaud Mejean at 2018 ASCO Annual Meeting

14 Overall survival by patient population Presented By Arnaud Mejean at 2018 ASCO Annual Meeting

15 Secondary nephrectomy in Arm B (sunitinib alone) Presented By Arnaud Mejean at 2018 ASCO Annual Meeting

16 Conclusions from both SURTIME and CARMENA Despite its limitations, CARMENA is a practice changing trial and SURTIME complements the results Patients with poor risk MSKCC should not undergo CN Patients with intermediate MSKCC risk who require systemic therapy should not undergo immediate CN but receive sunitinib first

17 Finally, open questions remain Should CN be performed at a later stage in all patients except those who progress (SURTIME) or only when necessary (CARMENA)? First-line therapy with nivolumab plus ipilimumab will replace sunitinib for intermediate and poor risk patients. Will we need new studies or treat patients with primary metastatic RCC with the tumour in place followed by resection when necessary?

18 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

19 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

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

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23 Immune combination leads to a high complete response rate

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

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

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

27 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

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

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

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

31 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

32 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

33 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

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

35 Sunitinib Demonstrated Improved PFS in AngiogenesisHigh Subset vs AngiogenesisLow Subset

36 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

37 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

38 Metastatic Urothelial cancer (UCC) chemotherapy Gemcitabine/Cisplatin vs MVAC (MTX/Vinblastine/Doxorubicine/Ci splatin) standard MVAC vs accelerated MVAC J Clin Oncol; 23 (2005) Eur J Can 42:50 (2006)

39 Platinum-refractory UCC Vinflunine vs Best Supportive Care Bellmunt J et al. JCO 2009;27:

40 EAU MMIBC Update

41 Feb 2016 After platinum-treatment: Response rate 15%

42 Key Eligibility Criteria a muc with progression during or following platinum-based chemotherapy 2 prior lines of therapy Measurable disease per RECIST v1.1 ECOG PS 0-1 Evaluable sample for PD-L1 testing TCC histology as primary component (N = 931) Stratification Factors No. of risk factors b (0 vs. 1/2/3) Liver metastases (yes vs. no) PD-L1 status (0/1 vs. 2/3) Chemotherapy (vinflunine vs. taxanes) R 1:1 Atezolizumab 1200 mg q3w Chemotherapy (investigator s choice) Vinflunine q3w Docetaxel q3w Paclitaxel q3w Loss of clinical benefit No crossover permitted per protocol RECIST v1.1 progression Survival followup

43 Overall Survival Powles T, et al. EAS 2017, Lancet IMvigor211. OS Analysis: PDL1 IC2/3 (Prim endpoint) 100 Atezolizuma b Events / Patient s Median OS (95% CI) 72/ mo (8.6, 15.5) 12-mo OS Rate (95% CI) 46% (37, 56) 80 Chemothera py 88/ mo (8.4, 12.2) 41% (32, 50) No. at Risk Atezolizum ab Chemother apy HR = 0.87 (95% CI: 0.63, 1.21) P = Months

44 Overall Survival OS Analysis: ITT Population 100 Events / Patient s Median OS (95% CI) 12-mo OS Rate (95% CI) Atezolizuma b Chemothera py 324/ / mo (7.8, 9.6) 8.0 mo (7.2, 8.6) 39% (35, 44) 32% (28, 37) HR = 0.85 (95% CI: 0.73, 0.99) P = Months No. at Risk Atezolizumab Chemotherapy Median follow-up duration in ITT population: 17.3 mo (range, 0 to 24.5 mo) Powles T, et al. EAS 2017, Lancet IMvigor211.

45 KEYNOTE-045: Pembrolizumab vs Investigator s choice chemo Bellmunt J, et al, NEJM 2017; ASCO-GU 2018

46 Metastatic UCC - cisplatin-ineligible ORR 41 vs 30% PFS 5.8 vs 4.2 months OS 9.3 vs 8.1 months

47 Jan 2017 Cisplatinineligible: Response rate 24%

48 Biomarker Findings and Mature Clinical Results From KEYNOTE-052: First-Line Pembrolizumab in Cisplatin-ineligible Advanced Urothelial Cancer Presented By Peter O''Donnell at 2017 ASCO Annual Meeting

49 Confirmed Objective Response Rate

50 ± anti-ctla4 ± chemotherapy Trial Ongoing studies first line Design Number of patients Primary endpoint(s) IMvigor130 (NCT ) R Atezolizumab Atezolizumab + platinum/gemcitabine Platinum/gemcitabine + placebo 1200 PFS, OS KEYNOTE-361 Pembrolizumab (NCT ) 990 PFS, OS Pembrolizumab + R platinum/gemcitabine Platinum/gemcitabine + placebo DANUBE (NCT ) R Durvalumab Durvalumab + tremelimumab Platinum/gemcitabine 1000 PFS, OS CheckMate 901 (NCT ) R Nivolumab + ipilimumab Platinum/gemcitabine + placebo 735 PFS, OS

51 Conclusion EMA and FDA approved pembrolizumab and atezolizumab based on phase 2 data for cisplatin ineligble patients. However, in ongoing studies these patients had poorer outcome in unselected populations than on chemotherapy. This resulted in changing the EMA and FDA label for PD-L1 positives. PD-L1 selection is controversial: no association with pembro in 2 nd line whereas it was the reverse for atezolizumab Based on phase I/II and phase Ib trials, durvalumab and avelumab (PD-1/PD-L1 inhibitors) are currently only approved for this indication in the United States