COSMIC-313: Triplet Therapy Is Active in Renal Cell Carcinoma, but Toxicities Pose a Challenge

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The addition of cabozantinib to nivolumab plus ipilimumab prolonged progression-free survival in untreated intermediate-risk patients with advanced renal cell carcinoma (RCC), according to the first results of the phase III COSMIC-313 trial. These findings were presented as a Presidential Symposium during the European Society for Medical Oncology (ESMO) Congress 2022.1

Cabozantinib plus nivolumab/ipilimumab achieved a 27% reduction in the risk of disease progression compared with nivolumab/ipilimumab (P = .013). Median progression-free survival was not reached with the triplet combination compared with 11.3 months with nivolumab/ipilimumab alone. Objective response rates were 43% and 36% with the triplet and doublet combinations, respectively, and the median duration of response was not reached in either treatment arm.

COSMIC-313 is the first trial to show that adding a tyrosine kinase inhibitor to dual checkpoint inhibition may improve progression-free survival in this setting. However, the three-drug regimen had higher toxicity rates, which may temper enthusiasm for this approach.

“COSMIC-313 is the first phase III study to use immunology standard of care as the control group. In intermediate- and poor-risk patients, the three-drug combination improved progression-free survival. Response rates and disease control rates were generally higher with the triplet than the doublet. The side effects were generally manageable but were more frequent with the three-drug combination. Follow-up for overall survival is very important and ongoing,” said lead author Toni K. Choueiri, MD, Director of the Lank Center for Genitourinary Oncology, Dana-Farber Cancer Institute and the Jerome and Nancy Kohlberg Professor of Medicine at Harvard Medical School.

Toni K. Choueiri, MD

Toni K. Choueiri, MD

Sumanta K. Pal, MD, FASCO

Sumanta K. Pal, MD, FASCO

“Although COSMIC-313 met its primary endpoint, we still need to see overall survival. The toxicity of the triplet therapy may potentially get in the way of [the effect of] individual agents,” said formal study discussant Sumanta K. Pal, MD, FASCO, Co-Director of the Kidney Cancer Program, City of Hope, Duarte, California.

Study Details

The global, double-blind, COSMIC-313 trial randomly assigned 855 patients with untreated clear cell advanced renal cell carcinoma and measurable disease in a 1:1 ratio to receive cabozantinib plus nivolumab/ipilimumab every 3 weeks for four cycles or nivolumab/ipilimumab. Both arms received maintenance nivolumab every 4 weeks for up to 2 years. Stratification factors were region and risk category.

The primary endpoint was progression-free survival, according to blinded independent review, in the first 550 patients enrolled in the trial. Progression-free survival was also evaluated in an intention-to-treat analysis. The secondary endpoint was overall survival. At the first interim assessment, the independent review board allowed the trial to continue.

Baseline factors were well balanced between the two arms. According to International Metastatic RCC Database Consortium staging, 75% were intermediate risk and 25% were poor risk. A total of 65% had been treated with prior nephrectomy. The most common sites of metastasis, in descending order, were the lungs, lymph nodes, liver, and bone.

Key Results and Toxicity

“The triplet yielded statistically significant and clinically meaningful improvement in progression-free survival, with an early separation of curves,” Dr. Choueiri told the audience. “We need further follow-up to confirm an overall survival benefit.”

“Progression-free survival improved across all prespecified subgroups favoring the triplet combination, including those with prior nephrectomy and larger tumor burden. The subgroup analysis suggested a benefit in the intermediate-risk group,” he continued. A further analysis according to risk group revealed that no benefit was observed in poor-risk patients.

The objective response rate was 43% with the triplet vs 56% with the doublet. The rate of complete response was 3% in both arms of the study. The rate of disease control was 86% with the triplet vs 72% with the doublet, and the median duration of response was not reached in either group.

The incidence of adverse events was much higher with the triplet than the doublet: 54% vs 20%. Treatment-related adverse events were consistent with the known safety profiles of the three drugs. Treatment-related adverse events occurring in more than 20% of patients included elevated liver function tests, diarrhea, and skin toxicity—and the rates were higher with the triplet regimen. Treatment-related deaths were reported in five patients who received the triplet therapy and four given nivolumab/ipilimumab alone. Corticosteroids were required in 58% of the experimental arm vs 35% of the nivolumab/ipilimumab group. 

Expert Point of View

“Hats off to the investigators for the first comparison of triplet to doublet in advanced renal cell carcinoma. This is also the first results using a contemporary control group. The study met its primary endpoint,” said Dr. Pal during his discussion of the COSMIC-313 trial.

“Then the elephant in the room is that we haven’t seen the overall survival results. If the study meets the prespecified overall survival endpoint, we will see the triplet regimen utilized in a broader array of patients. However, we will need to attend to toxicity and quality of life,” Dr. Pal stated. In addition, he added, “if the study doesn’t meet the primary endpoint, I am optimistic we can identify a subset that benefits from this triplet therapy.”

Dr. Pal continued: “The improved progression-free survival in the intermediate-risk group runs counter to what I expected. This might be explained by the type of patients who enrolled in the trial. When I solicited opinions from Twitter, most said, ‘those with more aggressive disease,’” Dr. Pal noted.

“Does toxicity stand in the way of treatment? The takeaway is that grades 3 and 4 toxicities were substantially higher with the triplet, especially elevations in liver transaminases. Other studies will assess triplet therapy in this setting. An open-label trial design may allow us to discern the source of toxicity,” he suggested.

“As we add more therapies, we add more toxicity. We need to determine how to select patients for a more aggressive regimen and use a risk-adapted approach. Biomarker studies are needed. Another way forward is to use therapies without overlapping toxicities,” Dr. Pal stated.


DISCLOSURE: Dr. Choueiri reported financial and/or nonfinancial relationships (including potential reimbursements for travel and meals) with Alexion Pharmaceuticals, Alligent, Analysis Group, ASCO, AstraZeneca, Bayer, Bristol Myers Squibb, Cerulean Pharma, Clinical Care Options, Corvus Pharmaceuticals, Eisai, EMD Serono, Exelixis, Foundation Medicine, Genentech/Roche, GlaxoSmithKline, Harborside Press, Heron, Ipsen, Kidney Cancer Journal, The Lancet Oncology, Lilly, Lpath, Merck, Jansen, Michael J. Hennessy Associates, Navinata Healthcare, NCCN, The New England Journal of Medicine, Novartis, Peloton Therapeutics, Pfizer, PlatformQ Health, Prometheus, Sanofi/Aventis, and UpToDate. He has received institutional research funding from Agensys, Analysis Group, AstraZeneca, Bayer, Bristol Myers Squibb, Calithera Biosciences, Celldex, Cerulean Pharma, Congressionally Directed Medical Research Programs, Corvus Pharmaceuticals, Eisai, Exelixis, Foundation Medicine, Gateway for Cancer Research, GlaxoSmithKline, Ipsen, Merck, National Cancer Institute, Novartis, Peloton Therapeutics, Pfizer, Prometheus, Roche/Genentech, Seattle Genetics/Astellas, Takeda, and Tracon Pharma; holds international patents for biomarkers and has other relationships with ClinicalThinking, Envision Pharma Group, Fishawack Group of Companies, Health Interactions, and Parexel (medical writing assistance). He holds stock or other ownership interests in Pionyr Immunotherapeutics and Tempest Therapeutics. Dr. Pal has received travel accomodations from Ipsen and CRISPR Therapeutics.


1. Choueiri T, Powles TB, Albiges L, et al: Phase III study of cabozantinib in combination with nivolumab and ipilimumab in previously untreated advanced renal cell carcinoma of IMDC intermediate or poor risk (COSMIC-313). ESMO Congress 2022. Abstract LBA8. Presented September 12, 2022.

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Expert Point of View: Sumanta K. Pal, MD, FASCO

“Hats off to the investigators for the first comparison of triplet to doublet in advanced renal cell carcinoma. This is also the first results using a contemporary control group. The study met its primary endpoint,” said Sumanta K. Pal, MD, FASCO, Co-Director of the Kidney Cancer Program, City of...