European Medicines Agency extension of indication to include the combination immunotherapy cancer drug treatment with nivolumab (Opdivo) and ipilimumab (Yervoy) for adults with intermediate/poor-risk advanced renal cell carcinoma

On the 15 November 2018, the Committee for Medicinal Products for Human Use adopted an extension to an existing indication for the use of nivolumab (Opdivo) in combination with ipilimumab (Yervoy) for the first-line treatment of adult patients with intermediate/poor-risk advanced renal cell carcinoma (RCC). The approval was based on results from the Pivotal CA209214 study, a randomised, open-label, phase III study, comparing nivolumab +ipilimumab with sunitinib in subjects≥18 years of age with previously untreated advanced RCC (not amenable for surgery or radiotherapy) or metastatic RCC, with a clear-cell component. A total of 1096 patients were randomised in the trial, of which 847 patients had intermediate/poor-risk RCC and received either nivolumab (n=425) in combination with ipilimumab administered every 3 weeks for 4 doses followed by nivolumab monotherapy 3 mg/kg every 2 weeks or sunitinib (n=422) administered orally for 4 weeks followed by 2 weeks off, every cycle. A statistically significant difference in overall survival (OS) was observed in the nivolumab + ipilimumab group compared with the sunitinib group in intermediate/poor-risk subjects (HR 0.63 (99.8% CI 0.44 to 0.89); stratified log-rank 2-sided p-value<0.0001). The median OS was not reached for the nivolumab + ipilimumab group and was 25.95 months for the sunitinib group. The OS rates were 89.5% and 86.2% at 6 months, and 80.1% and 72.1% at 12 months in the nivolumab +ipilimumab and the sunitinib groups, respectively. K-M curves separated after approximately 3 months, favouring nivolumab + ipilimumab. This was not mirrored in the favourable-risk patients where no statistically significant difference was observed between nivolumab + ipilimumab and sunitinib in favourable-risk patients (HR 1.45 (descriptive 99.8% CI 0.51 to 4.12), p =0.2715).

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A phase III study (COSMIC-313) of cabozantinib in combination with nivolumab and ipilimumab in patients with previously untreated advanced renal cell carcinoma of intermediate or poor-risk.

Journal of Clinical Oncology ◽

10.1200/jco.2020.38.15_suppl.tps5102 ◽

2020 ◽

Vol 38 (15_suppl) ◽

pp. TPS5102-TPS5102

Author(s):

Toni K. Choueiri ◽

Laurence Albiges ◽

Thomas Powles ◽

Christian Scheffold ◽

Fong Wang ◽

...

Keyword(s):

Renal Cell Carcinoma ◽

Cell Carcinoma ◽

Renal Cell ◽

Prognostic Score ◽

Phase Iii ◽

Advanced Renal Cell Carcinoma ◽

Phase 3 ◽

Poor Risk ◽

Recist 1.1 ◽

Flat Dose

TPS5102 Background: Cabozantinib (C) inhibits tyrosine kinases involved in tumor growth, angiogenesis, and immune regulation, including MET, VEGFR, and TAM kinases (Tyro3, AXL, MER), and may promote an immune-permissive tumor environment, resulting in enhanced response to immune checkpoint inhibitors. C has shown preliminary clinical activity and tolerability in combination with the PD-1 inhibitor nivolumab (N) and as part of a triplet combination with N and the CTLA-4 inhibitor ipilimumab (I) in patients (pts) with advanced renal cell carcinoma (aRCC) (Nadal et al. ASCO 2018). C is approved for pts with aRCC, and N+I is approved as a combination therapy in pts with previously untreated aRCC of intermediate or poor risk. We present the study design of a phase 3 trial of C+N+I vs N+I in previously untreated pts with aRCC of IMDC intermediate or poor risk (NCT03937219). Methods: This randomized, double-blind, controlled phase 3 study evaluates the efficacy and safety of C+N+I vs N+I in previously untreated pts with IMDC intermediate or poor risk aRCC. Eligible pts are randomized 1:1 to receive C+N+I or N+I in combination with placebo, stratified by IMDC prognostic score and geographic region. Pts receive C (40 mg oral QD) + N (3 mg/kg IV Q3W) x 4 doses + I (1 mg/kg IV Q3W) x 4 doses, followed by C (40 mg oral QD) + N (480 mg IV flat dose Q4W). Control pts receive C-matched placebo and the same treatment regimen for N+I as the experimental arm. N will be administered for a maximum of 2 years. Eligibility criteria include histologically confirmed metastatic or aRCC with a clear cell component, intermediate or poor risk RCC per IMDC criteria, measurable disease per RECIST 1.1, KPS ≥70%, adequate organ and marrow function and age ≥18 years. Exclusion criteria include prior systemic therapy for aRCC and uncontrolled significant illnesses. The primary endpoint is PFS per RECIST 1.1 by BICR; the secondary endpoint is OS. Additional endpoints include ORR, safety, correlation of biomarkers with outcomes, and pharmacokinetics of C in combination with N+I. The first patient was enrolled in June 2019 and enrollment is ongoing. Clinical trial information: NCT03937219 .

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EX3 Investigating Time to Next Treatment As a Surrogate Endpoint for Overall Survival in Previously Untreated Intermediate- to Poor-Risk Advanced Renal Cell Carcinoma Patients: An Insight from the Phase III CheckMate-214

Value in Health ◽

10.1016/j.jval.2020.08.028 ◽

2020 ◽

Vol 23 ◽

pp. S402

Author(s):

S. Branchoux ◽

C.L. Sofeu ◽

M. Kurt ◽

A.F. Gaudin ◽

A. Italiano ◽

...

Keyword(s):

Renal Cell Carcinoma ◽

Overall Survival ◽

Cell Carcinoma ◽

Renal Cell ◽

Surrogate Endpoint ◽

Phase Iii ◽

Advanced Renal Cell Carcinoma ◽

Poor Risk

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Nivolumab plus ipilimumab versus sunitinib in previously untreated advanced renal-cell carcinoma: analysis of Japanese patients in CheckMate 214 with extended follow-up

Japanese Journal of Clinical Oncology ◽

10.1093/jjco/hyz132 ◽

2019 ◽

Vol 50 (1) ◽

pp. 12-19 ◽

Cited By ~ 5

Author(s):

Yoshihiko Tomita ◽

Tsunenori Kondo ◽

Go Kimura ◽

Takamitsu Inoue ◽

Yoshiaki Wakumoto ◽

...

Keyword(s):

Renal Cell Carcinoma ◽

Cell Carcinoma ◽

Safety Profile ◽

Renal Cell ◽

Objective Response ◽

Japanese Patients ◽

Advanced Renal Cell Carcinoma ◽

Poor Risk ◽

Risk Patients

Abstract Background Nivolumab plus ipilimumab (NIVO+IPI) demonstrated superior efficacy over sunitinib (SUN) for previously untreated advanced renal cell carcinoma (aRCC) in CheckMate 214, with a manageable safety profile. We report efficacy and safety with extended follow-up amongst Japanese patients. Methods CheckMate 214 patients received NIVO (3 mg/kg) plus IPI (1 mg/kg) every 3 weeks for four doses, then NIVO (3 mg/kg) every 2 weeks; or SUN (50 mg) once daily for 4 weeks (6-week cycle). This subgroup analysis assessed overall survival (OS), objective response rate (ORR) and progression-free survival (PFS) per investigator in International Metastatic Renal Cell Carcinoma Database Consortium (IMDC) intermediate/poor-risk and intent-to-treat (ITT) patients and safety (ITT patients). Results Of 550 and 546 patients randomized to NIVO+IPI and SUN, 38 and 34, respectively, were Japanese. Of these, 31 (NIVO+IPI) and 29 (SUN) patients were IMDC intermediate/poor-risk. In IMDC intermediate/poor-risk patients with 30 months’ minimum follow-up, there was a delayed trend in OS benefit with NIVO+IPI (hazard ratio [HR] 0.56; 95% confidence interval [CI]: 0.19–1.59; P = 0.2670), and 24-month OS probability favoured NIVO+IPI (84%) versus SUN (76%). The ORR was 39% with NIVO+IPI and 31% with SUN (P = 0.6968). PFS was similar in both treatment arms (HR 1.17; 95% CI: 0.62–2.20; P = 0.6220). Efficacy in ITT patients was similar to IMDC intermediate/poor-risk patients. Grade 3–4 treatment-related adverse event incidence was lower with NIVO+IPI versus SUN (58 versus 91%). Conclusions Japanese patients with untreated aRCC in the NIVO+IPI arm had a numerically higher ORR and improved safety profile versus patients in the SUN arm. A delayed OS benefit appears to be emerging with NIVO+IPI. Longer follow-up is needed. https://clinicaltrials.gov/ct2/show/NCT02231749?term=NCT02231749&rank=1 identifier: NCT02231749.

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