Developping the next generation of studies in RCC

Developping the next generation of studies in RCC Bernard Escudier Institut Gustave Roussy Villejuif, France

Disclosure Information Advisory/Consultancy Role Pfizer, Exelixis, Novartis, BMS, Bayer, Roche, Nektar, Acceleron, Cerulean, Eisai Excuses for all sponsors/investigators who will be criticized along my talk I will focus on mrcc

Where are we in clinical trials for mrcc? In clinical trial.gov: Around 150 studies in «RCC» No «strategic» studies except: NCT02560012 (Personalized Targeted Inhibitors Treatment in Renal Cell Cancer) Efficacy of PD 1 inhibitors (pembrolizumab monotherapy!) Several studies on immune therapy combined with radiotherapy Some phase I combination studies with PD1-PDL1 inhibitors: CB-839, Varlilumab (anti CD27 ), HBI 8000, CXCR4 antagonist (X4P-001), Vorinostat Some phase I combination with VEGF inhibitors: axitinib and TRC105, axitinib and dalantercept, anti CD27 and sunitinib

Where are we in clinical trials for mrcc? In clinical trial.gov: Around 100 studies in «RCC» No «strategic» studies except: NCT02560012 (Personalized Targeted Inhibitors Treatment in Renal Cell Cancer) Efficacy of PD 1 inhibitors (pembrolizumab monotherapy!) Several studies on immune therapy combined with radiotherapy Some phase I combination studies with PD1-PDL1 inhibitors: CB-839, Varlilumab (anti CD27 ), HBI 8000 Some phase I combination with VEGF inhibitors: axitinib and TRC105, axitinib and dalantercept, anti CD27 and sunitinib Some phase 3

Some important phase 3 on pure immunotherapy Vaccine+ VEGFR inhibition PD1 + CTLA4 inhibition ADAPT 3 Phase III CheckMate-214 1 Phase III Sunitinib Sunitinib 50 mg/day 4/2 R N = 450 AGS-003 + sunitinib 8 injections in first year followed by quarterly boosters + sunitinib R N = 1071 Nivolumab + ipilimumab 3 mg/kg IV + 1 mg/kg IV every 3 weeks 4 then nivolumab 3 mg/kg IV every 2 weeks Primary endpoint: OS Co-primary endpoint: PFS, OS

Some important phase 3 on VEGF + PD1/PDL1 inhibition PD-L1 + VEGF inhibition PD1 + VEGFR TK inhibition Javelin renal 101 2 Phase III Immotion-151 2 Phase III Lenvatinib + everolimus or pembrolizumab 3 Phase III KEYNOTE-426 3 Phase III Sunitinib 50 mg/day 4/2 Sunitinib 50 mg/day 4/2 Sunitinib 50 mg/day 4/2 Sunitinib 50 mg/day 4/2 R N = 583 R N = 830 R N = 735 R N = 840 Avelumab + axitinib 10 mg/kg IV every 2 weeks + 5 mg PO BD Atezolizumab + bevacizumab 1,200 mg IV + 15 mg/kg IV every 3 weeks Lenvatinib + pembro 20 mg/day + 200 mg (IV) every 3 weeks Axitinib + pembro 5 mg BID + 200 mg (IV) every 3 weeks Lenvatinib + everolimus 18 mg/day + 5 mg/day Primary endpoint: PFS Co-primary endpoint: PFS, OS Primary endpoint: PFS Co-primary endpoint: PFS, OS

But all of them without the good control arm 1. Nobody still uses sunitinib 4/2 schedule without dose adaptation

RAINBOW Study: Efficacy Data 1 Patients, n Group 4/2 2/1 Group 2/1 Control 208 106 with 50 mg on 2/1 102 with <50 mg on 2/1 41 211 Median treatment duration, mo (interquartile range) 28.2 (14.2 70.8) 7.8 (5.8 22.4) 9.7 (5.3 16.7) mpfs, mo (interquartile range) 30.2 (23.2 47.1) 10.4 (7.7 23.0) 9.7 (8.9 11.7) mos, mo NR (36-mo probability: 72.7%) 23.2 (10.6 NE) 27.8 (23.1 35.8) Patients in the 2/1 group had less favorable characteristics in terms of ECOG PS and the presence of brain metastases. 1. Bracarda S, et al. Ann Oncol, 2015.

But all of them without the good control arm 1. Nobody still uses sunitinib 4/2 schedule without dose adaptation 2. Axitinib first line is likely superior to sunitinib, so how to interprete Javelin 101 and Keynote 426, if axitinib + PD1/PDL-1 is superior to sunitinib

Objective response rate (%) Study 1046: Axitinib Objective Response Rate 100 80 60 40 48% (95% CI: 42 55) 54% (95% CI: 40 67) P=0.019* 34% (95% CI: 22 48) 59% (95% CI: 49 70) 20 0 Total (N=213 ) Axitinib titration (N=56) Placebo titration (N=56) Non-randomized (N=91) Rini BI, et al. Lancet Oncol 2013;14:1233 42

Progression-Free Survival (probability) Cabosun PFS (Choueiri et al, ESMO LBA 2016) 1.0 0.8 Cabozantinib Sunitinib 0.6 0.4 0.2 0.0 0 6 12 18 24 30 Time since randomization (months) Arm PFS Events Median PFS (95% CI), mo HR (95% CI)* Cabozantinib Sunitinib 64 61 8.2 (6.2, 9.0) 5.6 (3.4, 8.1) 0.69 (0.48-0.99) p-value (one-sided) = 0.012

Where are we in clinical trials for mrcc? In clinical trial.gov: Around 100 studies in «RCC» No «strategic» studies except: NCT02560012 (Personalized Targeted Inhibitors Treatment in Renal Cell Cancer) None of the studies, I would like to see!!!!! Except the SURF study (Study to Assess Various Sunitinib Schedules in Renal Cell Carcinoma: NCT02689167)

SURF study ENROLLING FRANCE PI: Prof. A Thierry Vuillemin Inclusion: -mrcc -clear cell -Sunitinib 50mg/d 4 / 2 n = 248 patients # when dose adaptation required R A N D O M I S A T I O N 1:1 Arm A Sunitinib 37,5 mg 4 /2 Arm B Sunitinib 50 mg 2 /3

Where are we in clinical trials for mrcc? In clinical trial.gov: Around 100 studies in «RCC» No «strategic» studies except: NCT02560012 (Personalized Targeted Inhibitors Treatment in Renal Cell Cancer) None of the studies, I would like to see!!!!! Except the SURF study (Study to Assess Various Sunitinib Schedules in Renal Cell Carcinoma: NCT02689167) The TITAN study (NCT02917772): Tailored ImmunoTherapy Approach With Nivolumab in Subjects With Metastatic or Advanced Renal Cell Carcinoma (TITAN-RCC)

Tailored ImmunoTherapy Approach with Nivolumab in RCC n=200 Key Inclusion Criteria Metastatic/locally advanced RCC Clear cell component Untreated or pretreated with 1 prior TKI (1 st or 2 nd line) Measurable disease as per RECIST v1.1 ECOG PS 0-1 Intermediate/high risk by IDMC Nivo Induction Nivolumab 3 mg/kg IV Q2W x 8 Strata: -1 st vs. 2 nd Line -IMDC risk group (RCC TITAN; phase II) CR/PR SD/PD CR/PR Ipi Boost 1 Nivolumab 3 mg/kg IV Ipilimumab 1 mg/kg IV Q3W x 2 Nivo Maintenance Nivolumab 3 mg/kg IV Q2W SD/PD CR/PR/SD Ipi Boost 2 Nivolumab 3 mg/kg IV Ipilimumab 1 mg/kg IV Q3W x 2 Planned start Date: 12/2016 No. of sites: multi-national (GE, UK, F, I, E, P, Cz, Hungary, PL tbd) Study Director: Prof. Dr. Marc-Oliver Grimm Primary Endpoint: Objective response rate Secondary Endpoints: OS, ORR, PFS after boost, Safety, QoL Exploratory Endpoints: Biomarker analysis PD* *At time of PD after initial response: Boost/Re-boost with additional Ipilimumab (2/4 cycles according to the schedule above) possible for patients with CR, PR or SD for 3 months, no irae requiring treatment discontinuation

What is the next generation of clinical trials? The one which answers key questions Not the one which develops a new PD1 or PDL1 inhibitor. Not the one which adds to the current standard of care a drug which is supposed to improve PFS by 30%...

What are the key questions? 1. How to get CR and cure patients? 2. How to use «immunoscores» to select patients? 3. How long should we treat with PD1/PDL-1 inhibitors? 4. Should we treat beyond progression? 5. How to treat PD1 failure? 6. In second line, should we use cabozantinib or nivolumab? 7. How to treat rare RCC tumors? 8. Cytoreductive nephrectomy

What are the key questions? 1. How to get CR and cure patients? Just do small combination trials with the primary endpoint being CR rate Will be small studies With rapid readout

Phase 1/2 Combination of MBG453 (anti-tim-3) and PDR001 (Anti-PD-1) Phase 1/1b: Dose finding MBG453 Phase II: Advanced solid tumours, based on anti-tumour activity during phase 1 dose escalation Patients with advanced solid tumours RCC (n = 30) Group 1: Naïve to anti-pd-1/pd-l1 Group 2: Pre-treated with anti-pd-1/pd-l1 MBG453 + PDR001 Primary endpoints: Safety and tolerability ORR DLTs Melanoma (n = 30) NSCLC (n = 30) Group 3: Naïve to anti-pd-1/pd-l1 Group 4: Pre-treated with anti-pd-1/pd-l1 Group 5: Naïve to anti-pd-1/pd-l1 Group 6: Pre-treated with anti-pd-1/pd-l1 Completion: November 2018 Clinicaltrials.gov Identifier: NCT02608268

What are the key questions? 1. How to get CR and cure patients? 2. How to use «immunoscores» to select patients?

Genomic classification of RCC ccrcc1 ccrcc2 ccrcc3+nl ccrcc4 Beuselinck et al. Clin Cancer Res. 2015 Mar 15;21(6):1329-39.

How to use such genomic classification? 12M 24M 24.5M 8M 22M 35M 50M 14M Beuselinck et al. Clin Cancer Res. 2015 Mar 15;21(6):1329-39.

What are the key questions? 1. How to get CR and cure patients? 2. How to use «immunoscores» to select patients? 3. How long should we treat with PD1/PDL-1 inhibitors?

Get back to randomisation discontinuation trial! Response assessment Tumour shrinkage 25% Sorafenib 400mg b.i.d. open-label Sorafenib 400mg b.i.d. 12-week run-in Tumour growth/ shrinkage <25% Sorafenib 400mg b.i.d. 12 weeks Placebo * 12 weeks Progression free at 24 weeks (%) Tumour growth 25% Off study * Patients who progressed on placebo could cross over to sorafenib Ratain MJ, et al. J Clin Oncol 2006;24:2505 12

New trial Response assessment SD or PR NIVOLUMAB Until PD or CR Placebo Until PD or CR NIVOLUMAB 3 months PD good PS NIVOLUMAB beyond progression Placebo 12 weeks TTF endpoint Rapid PD ADD ANOTHER CHECKPOINT

Who will run this trial? Second-line mrcc TKI failures R A N D O M I Z E CABOZANTINIB NIVOLUMAB

No more nccrcc trials such as this one! Everolimus n=35 Sunitinib n=33 Age (median, range) 58 (23-73) 60 (28-76) 0.72 Gender (M:F) 24:11 19:14 0.45 Nephrectomy 27 25 1.0 Histology Papillary Sarcomatoid w/ clear-cell Chromophobe Unclassified Translocation 13 6 6 6 4 14 6 6 4 3 P-value 0.97 Tannir N, et al. Eur Urol. 2016;69(5):866-874.

But trials such as CREATE trial Screened pts PRCC1 per local pathology N=41 PRCC1 analysis set Centrally confirmed PRCC1 and enrolled N=23 (all started crizotinib) MET+ N=4 MET+ analysis set Eligible and evaluable, N=4 Incl. 1 MET amplified MET- N=16 Eligible and evaluable, N=16 Incl. 1 MET amplified MET? N=3 Eligible and evaluable, N=3

Number of patients But with challenges Studies should be very multicentric Logistic should be simplified Registry should be favored Cost should be decreased Screened Eligible and treated Time

We should not replicate Carmena trial for each new drug or regimen But focus on patients which raise the real question Not poor risk patients Not good risk patients with small metastatic burden But the one with good PS and metastatic tumor burden > 20-30% of the tumor burden..

Conclusions It is obviously time for new generation of clinical trials in RCC It is our responsibility to run GOOD trials which will answer important questions We should find a way to avoid «me too» trials

This is the role of all of us