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.

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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342 A phase 3 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 for ImmunoTherapy of Cancer ◽

10.1136/jitc-2020-sitc2020.0342 ◽

2020 ◽

Vol 8 (Suppl 3) ◽

pp. A367-A367

Author(s):

Toni Choueiri ◽

Laurence Albiges ◽

Thomas Powles ◽

Nehal Mohamed ◽

Fong Wang ◽

...

Keyword(s):

Renal Cell Carcinoma ◽

Informed Consent ◽

Cell Carcinoma ◽

Renal Cell ◽

Advanced Renal Cell Carcinoma ◽

Phase 3 ◽

Link Type ◽

Poor Risk ◽

Recist 1.1 ◽

Written Informed Consent

BackgroundCabozantinib (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).MethodsThis 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.ResultsN/AConclusionsN/ATrial RegistrationClinicalTrials.gov: NCT03937219Ethics ApprovalThis study is being conducted in compliance with Good Clinical Practice (GCP), including International Conference on Harmonisation (ICH) Guidelines, the most recent accepted version of the Declaration of Helsinki, and all applicable local laws and regulatory requirements. The appropriate Institutional Review Boards (IRBs) or Ethics Committees (ECs) of participating centers have approved approve the study protocol. All patients have provided written informed consent.ConsentAll patients have provided written informed consent.

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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

ESMO Open ◽

10.1136/esmoopen-2020-000798 ◽

2020 ◽

Vol 5 (6) ◽

pp. e000798

Author(s):

Sahra Ali ◽

Jorge Camarero ◽

Paula van Hennik ◽

Bjorg Bolstad ◽

Maja Sommerfelt Grønvold ◽

...

Keyword(s):

Renal Cell Carcinoma ◽

Cell Carcinoma ◽

Renal Cell ◽

Phase Iii ◽

Advanced Renal Cell Carcinoma ◽

Cancer Drug ◽

European Medicines Agency ◽

Poor Risk ◽

Significant Difference ◽

Risk Patients

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 (C) in combination with nivolumab (N) and ipilimumab (I) in patients (pts) with previously untreated advanced renal cell carcinoma (aRCC) of intermediate or poor risk.

Journal of Clinical Oncology ◽

10.1200/jco.2020.38.6_suppl.tps767 ◽

2020 ◽

Vol 38 (6_suppl) ◽

pp. TPS767-TPS767 ◽

Cited By ~ 3

Author(s):

Toni K. Choueiri ◽

Laurence Albiges ◽

Thomas Powles ◽

Christian Scheffold ◽

Fong Wang ◽

...

Keyword(s):

Checkpoint Inhibitors ◽

Prognostic Score ◽

Geographic Region ◽

Phase Iii ◽

Clinical Activity ◽

Phase 3 ◽

Double Blind ◽

Poor Risk ◽

Recist 1.1 ◽

Flat Dose

TPS767 Background: 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 N and as part of a triplet combination with N and the CTLA-4 inhibitor I in pts with 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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