Update on Adjuvant and Salvage Options for Patients with Kidney - PowerPoint PPT Presentation

Update on Adjuvant and Salvage Options for Patients with Kidney Cancer A Ari Hakimi, MD Assistant Attending, Dept of Surgery, Urology Sidney Kimmel Center for Prostate and Urologic Cancer Memorial Sloan Kettering Cancer Center, New York

Adjuvant therapy for patients undergoing nephrectomy

History of Adjuvant Therapy in RCC • 1985-2016: 13 Randomized trials resulted • Encompassed 6473 patients • Heterogeneous array of systemic therapies • Before 2004 - Observation was typical control • Modern-day trials employ placebo • ~30 years: only 1 positive trial (S-TRAC) Harshman, Xie et al CANCER (in press)

Recent Phase III perioperative studies – all in the adjuvant setting

Adjuvant Sorafenib vs Sunitinib vs Placebo The Phase III ASSURE Trial (ECOG E2805) Sunitinib QD Stratify R (4/2 schedule) Key Inclusion Risk Treat for A • Intermediate-high Criteria up to • Very high N • Non-metastatic 9 courses or n = Histology D kidney cancer 1943 • Clear cell until Sorafenib O • Non – clear cell • Resectable disease BID for Surgery PS M disease by scan progression 6 weeks • 0 vs 1 • >T1bN any I or Surgery (resectable) unacceptabl S • Open M0 disease e toxicity • Laparoscopic E Placebo Primary endpoint: DFS Secondary endpoints: OS, DFS (ccRCC only), biomarker analysis, LVEF changes, incidence of CHF, QoL, safety Hass NB et al., 2015 ASCO Annual Meeting

ASSURE – no difference in disease-free survival was seen between treatment arms Haas NB, et al . Lancet 2016; 387:2008-16

Phase III S-TRAC trial – adjuvant sunitinib vs. placebo Key inclusion criteria Sunitinib 50 mg • Age ≥ 18 years R (4/2 schedule) • Predominant clear cell A histology N Target: • High-risk RCC (as per UISS n = 720 criteria) D • No evidence of macroscopic O disease after nephrectomy M • ECOG PS 0, 1 or 2 I Placebo • No prior anti-cancer therapy S E Primary end point: DFS Secondary end points: OS, PRO, safety Ravaud et al. N Engl J Med. 2016 Dec 8;375(23):2246-2254

S-TRAC - superior disease-free survival for sunitinib-treated patients Ravaud A et al. ESMO 2016 Ravaud A et al. N Engl J Med 2016 Oct 9

ASSURE & S-TRAC – subtle differences S-TRAC ASSURE (sunitinib arm) N = 615 N = 647 T-stages(n) - T1-2 none 469 (36.3%) - T3-4 615 (100%) 824 (63.7%) Histology - Clear cell 99.0% 79% (=1021 patients) - Non clear-cell 1% 21% Completion of 1 year sunitinib (%) 55,6% 59% Starting sunitinib at 50 mg/d 306 (100%) 438/647 (67.7%)

ASSURE & S-TRAC – subtle differences S-TRAC ASSURE (sunitinib arm) N = 615 N = 647 T-stages(n) - T1-2 none 469 (36.3%) - T3-4 615 (100%) 824 (63.7%) Histology - Clear cell 99.0% 79% (=1021 patients) - Non clear-cell 1% 21% Completion of 1 year sunitinib (%) 55,6% 59% Starting sunitinib at 50 mg/d 306 (100%) 438/647 (67.7%)

ASSURE subgroup analysis pT3/pT4 or N1 clear cell RCC Haas NB et al., JAMA Oncol. 2017 Sep 1;3(9):1249-1252.

ASSURE & S-TRAC – subtle differences S-TRAC ASSURE (sunitinib arm) N = 615 N = 647 T-stages(n) - T1-2 none 469 (36.3%) - T3-4 615 (100%) 824 (63.7%) Histology - Clear cell 99.0% 79% (=1021 patients) - Non clear-cell 1% 21% Completion of 1 year sunitinib (%) 55,6% 59% Starting sunitinib at 50 mg/d 306 (100%) 438/647 (67.7%)

ASSURE subgroup analysis – dose intensity for sunitinib did not significantly affect DFS Haas NB et al., JAMA Oncol. 2017 Sep 1;3(9):1249-1252.

Phase III PROTECT trial – adjuvant pazopanib vs. placebo Pazopanib daily Key inclusion criteria R X 52 weeks • Resected non-metastastic A clear-cell RCC N • pT2, G3 or G4, N0 D • pT3, any grade, N0 O • pT4, any grade, N0 M • pT1-4, any grade, N1 Placebo daily I • Adequate PD and organ X 52 weeks function S E Primary end point: DFS: In 08/2011 the primary objective was amended based on high discontinuation due to Aes -> DFS for 600mg starting dose Secondary end points: OS, PRO, safety Ravaud et al. NEJM

PROTECT Study: Adjuvant Pazopanib/Placebo DFS in ITT 600mg Motzer RJ et al., J Clin Oncol. 2017 Sep 13

PROTECT Study: Adjuvant Pazopanib/Placebo DFS in ITT 800mg DFS in ITT All Motzer RJ et al., J Clin Oncol. 2017 Sep 13

November 2017: First adjuvant therapy approved for M0 RCC

2016 EAU Consensus Recommendations — same data IKCC Patient Advocates EAU Panelists S-TRAC DFS HR 0.76 ASSURE DFS HR 1.02 EAU Meta: HR 0.89 Bex A et al. Eur Urol. 2017 May;71(5):719-722.

2016 EAU Consensus Recommendations — same data IKCC Patient Advocates EAU Panelists S-TRAC DFS HR 0.76 ASSURE DFS HR 1.02 EAU Meta: HR 0.89 Bex A et al. Eur Urol. 2017 May;71(5):719-722.

2016 EAU Consensus Recommendations — same data IKCC Patient Advocates EAU Panelists S-TRAC DFS HR 0.76 ASSURE DFS HR 1.02 EAU Meta: HR 0.89 S-TRAC Subgroup Analyses and Updated OS Results “A trial designed to demonstrate a 25% improvement in OS (HR 0.8) with a two-sided a value of 0.05 and 80% power would require approximately 1650 patients and 18.5 yr of follow- up.” Motzer RJ et al., Eur Urol. 2017 Sep 26 Bex A et al. Eur Urol. 2017 May;71(5):719-722.

Ongoing Phase 3 Randomized Adjuvant Studies IMmotion 010 KEYNOTE 564 • High risk or Atezolizumab 1200mg IV limited M1 NED • Q3 wks x 16 cycles Post R nephrectomy ≤ 12 wks a • Clear cell or n sarcomatoid d 1:1 • o Stratification N=664 Factors: m -T2/T3a vs. >T3b i -PD-L1 (IC0 vs z IC1/2/3 -Region (US/Can vs e Placebo IV ROW) Q3 wks x 16 cycles Hoffmann-La Roche, PIs: S Pal, R Uzzo, NCT03024996 Merck, PI: T Choueiri, NCT03142334 • Focused on clear cell and sarcomatoid histologies as well as higher risk T2 and greater • Allow limited resectable M1 disease that would be rendered NED • Placebo controlled with a primary endpoint of DFS Courtesy of Lauren Harshman

CheckMate 914: Phase III study of adjuvant nivolumab + ipilimumab vs. placebo ClinicalTrials.gov Identifier: NCT03138512

Neoadjuvant approach – specific considerations for targeted immunotherapy with checkpoint inhibitors (CPI)

ccRCC TCGA – ‘loaded’ immune microenvironment in the primary tumor Harshman LC et al., Kidney Cancer 1 (2017) 31 – 40 Senbabaoglu et al., Genome Biol.2016 Nov 17;17(1):231.

Neoadjuvant CPI therapy – optimizing systemic benefit through reinvigoration of dormant TILs nephrectomy CPI therapy Neoadjuvant:

Neoadjuvant CPI therapy – optimizing systemic benefit through reinvigoration of dormant TILs nephrectomy CPI therapy Neoadjuvant: nephrectomy Adjuvant: CPI therapy

EA8143 Phase III Perioperative PD-1 Blockade Non-metastatic RCC: PROSPER RCC ClinicalTrials.gov Identifier: NCT03055013 • Primary endpoint: 14.4% absolute benefit in RFS 84.2% power to increase from 55.8%  70.2 % at 5 yrs - • Secondary endpoint OS: 5 yr OS: 78.7% to 85.2%; HR 0.67 • Mandatory presurgical biopsy: diagnosis, correlative science

High risk ccRCC – Neoadj Nivo Trial N N N N nephrectomy screening Day -56 Day -42 Day -28 Day -14 Day 0 S S S S Bx MRI MRI Bx: Tumor biopsy N: nivolumab S: serum sample • Preop Biopsy - Mutations (neoantig), ImSig • Post-treatment analysis, cell sorting, ImSig

Acknowledgements IR/Radiology GU onc  Jeremy Durack  Bob Motzer   Oguz Akin Martin Voss  Marie Carlo  Joe Lee SKI / IPOP  Darren Feldman  Ming Liu  Devyn Coskey  Breanna Nixon  David Kuo Urology  Alejandro Sanchez  Jonathan Coleman  Kyle Blum  Paul Russo  Renzo DiNatale  Karim Touijer  Tim Chan  Alvin Goh  Ming Li Pathology Epidemiology  Victor Reuter  Sujata Patil  Yingbei Chen  Satish Tickoo Our patients and their families