Background: The phase III CheckMate 9ER trial originally included a nivolumab plus ipilimumab plus cabozantinib triplet arm, which was discontinued early due to the evolving treatment landscape for first-line advanced renal cell carcinoma (aRCC). We report an exploratory analysis of patients randomised to the triplet regimen before enrolment discontinuation. Methods: Patients with clear-cell aRCC received nivolumab (3 mg/kg) plus ipilimumab (1 mg/kg) Q3W for four cycles with once-daily cabozantinib (40 mg), then nivolumab (240 mg) Q2W plus once-daily cabozantinib (40 mg). CheckMate 9ER primary (progression-free survival [PFS] by blinded independent central review [BICR]) and key secondary (overall survival [OS], objective response rate [ORR] by BICR, and safety) endpoints were applied, along with investigator-assessed PFS and ORR. Results: Fifty patients were randomised to the triplet regimen. After a median follow-up of 39.1 months (range, 33.4–44.5), median PFS (95% CI) was 9.9 (5.7–16.8) months by BICR and 13.9 (7.3–24.7) months by investigator; median OS (95% CI) was 37.0 (31.8-not estimable) months. ORR (95% CI) was 44.0% (30.0–58.7; complete response, 8.0%) by BICR and 48.0% (33.7–62.6; all partial responses) by investigator. Grade 3–4 treatment-related adverse events (TRAEs) occurred in 84.0%, most commonly alanine aminotransferase increased (20.0%), aspartate aminotransferase increased (16.0%), and hepatotoxicity (16.0%). Grade 3–4 hepatic immune-mediated AEs occurred in 40.0%. There were no grade 5 TRAEs. Conclusions: These results suggest that the nivolumab plus ipilimumab plus cabozantinib triplet combination has clinical activity in patients with previously untreated aRCC, although monitoring of overlapping toxicities will be important in future studies of this regimen. ClinicalTrials.gov registration: NCT03141177.
Bibliographical noteFunding Information:
TKC reports research grants, consulting fees, honoraria, and advisory board fees from AstraZeneca, Aravive, AVEO Pharmaceuticals Bayer, BMS, Calithera, Circle Pharma, Eisai, EMD Serono, Exelixis, GlaxoSmithKline, IQVIA, Infinity, Ipsen, Janssen, Kanaph, Lilly, Merck, NiKang, Novartis, Pfizer, Precede Bio, Roche, Sanofi-Aventis, Surface Oncology, Takeda, Tempest, UpToDate, and CME events (Peerview, OncLive, MJH, and others), outside the submitted work; institutional patents filed on molecular biomarkers and immunotherapy, and ctDNA; past fees from NCCN, GU Steering Committee, ASCO, and ESMO; stock ownership in Pionyr, Tempest, Osel, and Precede Bio, outside the submitted work; other financial or non-financial interests include medical writing and editorial assistance support that may have been funded by communications companies in part; potential funding (in part) from non-US sources/foreign components for mentor of several non-US citizens on research projects; independent funding by drug companies and/or royalties potentially involved in research around the subject matter (institutional); support in part by the Dana-Farber/Harvard Cancer Center Kidney SPORE (2P50CA101942-16) and Program 5P30CA006516-56, the Kohlberg Chair at Harvard Medical School and the Trust Family, Michael Brigham, and Loker Pinard Funds for Kidney Cancer Research at DFCI.
We thank the patients and their families for making this trial possible; the CheckMate 9ER global trial manager; and the staff of Dako, an Agilent Technologies company, for collaborative development of the PD-L1 IHC 28-8 pharmDx assay. Patients treated at Memorial Sloan Kettering Cancer Center were supported in part by Memorial Sloan Kettering Cancer Center Support Grant/Core Grant (P30 CA008748). Professional medical writing and editorial assistance was provided by Richard Daniel, PhD, of Parexel, funded by Bristol Myers Squibb .
- Clinical trial
- Renal cell carcinoma