The targeted kinase inhibitor cabozantinib plus a two-drug immunotherapy combination of nivolumab and ipilimumab may be capable of slowing cancer progression in patients with advanced renal cell carcinoma who received no prior lines of therapy, according to a study published by Choueiri et al in The New England Journal of Medicine.
“Patients who received … cabozantinib in addition to…nivolumab and ipilimumab experienced significantly improved progression-free survival compared [with] those who received only nivolumab and ipilimumab,” explained lead study author Toni Choueiri, MD, the Jerome and Nancy Kohlberg Professor of Medicine at Harvard Medical School as well as Medical Director of International Strategic Initiatives and Director of the Lank Center for Genitourinary Cancer at the Dana-Farber Cancer Institute.
Background
Nivolumab and ipilimumab both work by blocking immune checkpoints, the molecular brakes that prevent the immune system from attacking the cancer. Releasing the brakes can allow the immune system’s T cells to invade the tumors and kill the cancer cells.
Nivolumab plus cabozantinib and nivolumab plus ipilimumab are both standard-of-care first-line treatments in patients with advanced renal cell carcinoma. Cabozantinib is capable of inhibiting several cancer-promoting pathways—including MET, VEGFR, and TAM—and may enhance responses to checkpoint inhibitors to provide an additive or synergistic benefit when combined with nivolumab and ipilimumab.
Study Methods and Results
In the new COSMIC-313 phase III trial, researchers assigned 855 previously untreated patients with advanced or metastatic renal cell carcinoma at intermediate or poor risk of survival to receive either the combination of cabozantinib with nivolumab and ipilimumab or only nivolumab and ipilimumab.
The researchers discovered that the patients who received all three agents had a 27% decreased risk of progression or mortality compared with those who received the immunotherapy drugs. Further, patients receiving all three agents in COSMIC-313 have not yet reached their median progression-free survival, whereas patients receiving nivolumab plus ipilimumab have a median progression-free survival of 11.3 months. The researchers reported that the progression-free survival advantage met the primary endpoint. Overall survival is a secondary endpoint of the COSMIC-313 trial.
Currently, the patients have been followed for between 17.7 and 20 months. At this point, the trial has shown no significant overall survival benefit for patients receiving all three agents.
Conclusions
“This is the first study to evaluate a triplet therapy against a contemporary immune-oncology doublet control, and it was designed to answer an important question of whether adding cabozantinib to dual checkpoint inhibition can improve outcomes for this patient population,” underscored Dr. Choueiri. “The initial findings provide a clear look at the efficacy and safety profile of this triplet therapy and demonstrate a significant progression-free survival benefit,” he concluded.
Disclosure: The research in this study was funded by Exelixis and supported in part by the Dana-Farber/Harvard Cancer Center Kidney SPORE and Program 5P30CA006516-56, the Kohlberg Chair at Harvard Medical School and the Trust Family, Michael Brigham, Pan Mass Challenge, Hinda and Arthur Marcus, and Loker Pinard Funds for Kidney Cancer Research at Dana-Farber. For full disclosures of the study authors, visit nejm.org.
