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)

Key Inclusion Criteria

• Non-metastatic

kidney cancer

• Resectable

disease by scan

• >T1bN any

(resectable) M0 disease

Primary endpoint: DFS Secondary endpoints: OS, DFS (ccRCC only), biomarker analysis, LVEF changes, incidence of CHF, QoL, safety

n = 1943

Sunitinib QD (4/2 schedule) Sorafenib BID for 6 weeks Placebo Treat for up to 9 courses or until disease progression

• r

unacceptabl e toxicity

R A N D O M I S E Stratify

Risk

• Intermediate-high
• Very high

Histology

• Clear cell
• Non–clear cell

PS

• 0 vs 1

Surgery

• Open
• Laparoscopic

Surgery

Hass NB et al., 2015 ASCO Annual Meeting

Haas NB, et al. Lancet 2016; 387:2008-16

ASSURE – no difference in disease-free survival was seen between treatment arms

Primary end point: DFS Secondary end points: OS, PRO, safety

R A N D O M I S E

Target: n = 720

Sunitinib 50 mg (4/2 schedule) Placebo

Key inclusion criteria

• Age ≥18 years
• Predominant clear cell

histology

• High-risk RCC (as per UISS

criteria)

• No evidence of macroscopic

disease after nephrectomy

• ECOG PS 0, 1 or 2
• No prior anti-cancer therapy

Phase III S-TRAC trial – adjuvant sunitinib vs. placebo

Ravaud et al. N Engl J Med. 2016 Dec 8;375(23):2246-2254

Ravaud A et al. ESMO 2016 Ravaud A et al. N Engl J Med 2016 Oct 9

S-TRAC - superior disease-free survival for sunitinib-treated patients

ASSURE & S-TRAC – subtle differences

S-TRAC N = 615 ASSURE (sunitinib arm) N = 647 T-stages(n)

• T1-2
• T3-4

none 615 (100%) 469 (36.3%) 824 (63.7%) Histology

• Clear cell
• Non clear-cell

99.0% 1% 79% (=1021 patients) 21% Completion of 1 year sunitinib (%) 55,6% 59% Starting sunitinib at 50 mg/d 306 (100%) 438/647 (67.7%)

S-TRAC N = 615 ASSURE (sunitinib arm) N = 647 T-stages(n)

• T1-2
• T3-4

none 615 (100%) 469 (36.3%) 824 (63.7%) Histology

• Clear cell
• Non clear-cell

99.0% 1% 79% (=1021 patients) 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

ASSURE subgroup analysis pT3/pT4 or N1 clear cell RCC

Haas NB et al., JAMA Oncol. 2017 Sep 1;3(9):1249-1252.

S-TRAC N = 615 ASSURE (sunitinib arm) N = 647 T-stages(n)

• T1-2
• T3-4

none 615 (100%) 469 (36.3%) 824 (63.7%) Histology

• Clear cell
• Non clear-cell

99.0% 1% 79% (=1021 patients) 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

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.

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

R A N D O M I S E Pazopanib daily X 52 weeks Placebo daily X 52 weeks

Key inclusion criteria

• Resected non-metastastic

clear-cell RCC

• pT2, G3 or G4, N0
• pT3, any grade, N0
• pT4, any grade, N0
• pT1-4, any grade, N1
• Adequate PD and organ

function

Phase III PROTECT trial – adjuvant pazopanib vs. placebo

Ravaud et al. NEJM

PROTECT Study: Adjuvant Pazopanib/Placebo

Motzer RJ et al., J Clin Oncol. 2017 Sep 13

DFS in ITT 600mg

DFS in ITT All DFS in ITT 800mg

Motzer RJ et al., J Clin Oncol. 2017 Sep 13

PROTECT Study: Adjuvant Pazopanib/Placebo

November 2017: First adjuvant therapy approved for M0 RCC

2016 EAU Consensus Recommendations—same data

Bex A et al. Eur Urol. 2017 May;71(5):719-722. S-TRAC DFS HR 0.76 ASSURE DFS HR 1.02 EAU Meta: HR 0.89

EAU Panelists IKCC Patient Advocates

2016 EAU Consensus Recommendations—same data

Bex A et al. Eur Urol. 2017 May;71(5):719-722. S-TRAC DFS HR 0.76 ASSURE DFS HR 1.02 EAU Meta: HR 0.89

EAU Panelists IKCC Patient Advocates

2016 EAU Consensus Recommendations—same data

Bex A et al. Eur Urol. 2017 May;71(5):719-722. S-TRAC DFS HR 0.76 ASSURE DFS HR 1.02 EAU Meta: HR 0.89

EAU Panelists IKCC Patient Advocates 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

Ongoing Phase 3 Randomized Adjuvant Studies

Hoffmann-La Roche, PIs: S Pal, R Uzzo, NCT03024996 Merck, PI: T Choueiri, NCT03142334

1:1 N=664

KEYNOTE 564 IMmotion 010

• High risk or

limited M1 NED

• Post

nephrectomy ≤12 wks

• Clear cell or

sarcomatoid

• Stratification

Factors:

• T2/T3a vs. >T3b
• PD-L1 (IC0 vs

IC1/2/3

• Region (US/Can vs

ROW)

R a n d

• m

i z e

Atezolizumab 1200mg IV Q3 wks x 16 cycles Placebo IV Q3 wks x 16 cycles

• 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

Senbabaoglu et al., Genome Biol.2016 Nov 17;17(1):231. Harshman LC et al., Kidney Cancer 1 (2017) 31–40

CPI therapy

nephrectomy

Neoadjuvant:

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

CPI therapy

nephrectomy

CPI therapy

nephrectomy

Neoadjuvant: Adjuvant:

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

EA8143 Phase III Perioperative PD-1 Blockade Non-metastatic RCC: PROSPER RCC

• 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

ClinicalTrials.gov Identifier: NCT03055013

nephrectomy

N N N N

screening

Bx: Tumor biopsy N: nivolumab S: serum sample MRI MRI Bx S S S S Day 0 Day -14 Day -28 Day -42 Day -56

High risk ccRCC – Neoadj Nivo Trial

• Preop Biopsy - Mutations (neoantig),

ImSig

• Post-treatment analysis, cell sorting,

ImSig

Acknowledgements

GU onc

• Bob Motzer
• Martin Voss
• Marie Carlo
• Joe Lee
• Darren Feldman
• Devyn Coskey

Urology

• Jonathan Coleman
• Paul Russo
• Karim Touijer
• Alvin Goh

Pathology

• Victor Reuter
• Yingbei Chen
• Satish Tickoo

IR/Radiology

• Jeremy Durack
• Oguz Akin

SKI / IPOP

• Ming Liu
• Breanna Nixon
• David Kuo
• Alejandro Sanchez
• Kyle Blum
• Renzo DiNatale
• Tim Chan
• Ming Li

Epidemiology

• Sujata Patil

Our patients and their families