ASCO Rapid Recommendation Update Cautions Against Triplet Therapy for Metastatic Clear Cell RCC

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An ASCO Rapid Recommendation Update advises oncologists to avoid the use of triple combination therapy for the management of metastatic clear cell renal cell carcinoma (RCC).1 The new guidance, which updates recommendations from the original 2022 guideline, reflects findings from a phase III, double-blind, randomized clinical trial exploring survival and safety outcomes of an experimental triplet drug.2,3

New Recommendation Rationale

“What we are always hopeful [in clinical trials] is that we are getting synergistic efficacy, while toxicity is only additive at most,” said Eric A. Singer, MD, of The Ohio State University Comprehensive Cancer Center and Co-Chair on the guideline’s Expert Panel. “Unfortunately, with this trial, we saw the survival endpoints for triplet therapy weren’t as strong as we hoped they would be. The ipilimumab/nivolumab/cabozantinib cohort did have higher probability of 12-month progression-free survival and objective response rate, but it also had a lot more grade 3 or 4 adverse events—79% vs 56%.”

Eric A. Singer, MD

Eric A. Singer, MD

Peter J. Van Veldhuizen, MD

Peter J. Van Veldhuizen, MD

The trial—COSMIC-313—randomly assigned patients with advanced clear cell RCC to receive standard doublet therapy with nivolumab and ipilimumab (427 patients) vs an experimental combination of nivolumab and ipilimumab plus 40 mg of cabozantinib daily (428 patients).3

Results from the trial were highly anticipated given increasing interest among renal oncologists as well as patients about the potential benefits of triplet therapy, said Peter J. Van Veldhuizen, MD, of the University of Rochester Medical Center and Co-Chair of the Expert Panel.

“I think there’s a tendency to think more is better,” Dr. Van Veldhuizen said. “We were getting a lot of questions and queries from community physicians thinking, is triplet therapy the new standard of care? I think it was really because of that question that we thought we needed to update the guideline, as this was the first study looking at triplet therapy for kidney cancer.”

Thanks to advances in immunotherapy, renal cancer treatments have evolved from monotherapy to doublet therapy with either immunotherapy plus another immunotherapy or immunotherapy in combination with a tyrosine kinase inhibitor. Given positive survival and tolerability outcomes with doublet therapy—now the standard of care—oncologists and researchers have logically wondered whether adding a third drug would further improve outcomes.4

In terms of survival benefits, COSMIC-313 did show the probability of progression-free survival at 12 months was significantly higher in the experimental group (hazard ratio for disease progression or death = 0.73, 95% confidence interval = 0.57–0.94; P = .01).1 However, this was juxtaposed against what the Expert Panel thought was a disappointing safety profile. Namely, 79% of patients in the experimental arm and 56% in the control arm had grade 3 or 4 adverse events.1

Additionally, the trial revealed what Dr. Singer called “a surprisingly low number” of complete responses in both arms of patients at only 3%—vs the greater than 10% rate he was expecting to see. “The complete response rates were lower than those reported in previous pivotal trials that only looked at two drug combinations,” he added. “So, we had a lower complete response rate, a lot more toxicity, and a lot more dose reductions. Those all raised our concern.”

Consequently, the Expert Panel recommended against oncologists using triplet therapy for metastatic clear cell RCC for now. Dr. Van Veldhuizen also warned that the doublet immunotherapy combination control arm tested in COSMIC-313 is currently used less frequently than it was at the time COSMIC-313 was initiated. Whether the triplet combination assessed in the trial is better than more commonly used doublet therapies, such as combination treatments with tyrosine kinase inhibitors, remains to be seen, he said.

Looking Ahead, Future Trials

Longer-term follow-up for COSMIC-313 is still underway, and overall survival outcomes will be forthcoming. Although Dr. Van Veldhuizen noted the survival benefit may still bear out with more time and data, the lack of difference in complete response rates observed thus far makes differences in long-term durable response rates less likely.

But the findings from COSMIC-313 aren’t necessarily the end of the road for triple combination drugs in renal carcinoma. “If oncologists are trying to enroll patients on clinical trials, they have other options for triplet therapies,” Dr. Van Veldhuizen said. “And I do think with longer-term follow-up, there is a survival advantage such that one could revisit a triplet combination. So, I don’t know I would say this is open and shut.”

Related clinical trials currently underway include the phase III PDIGREE trial examining nivolumab and ipilimumab followed by nivolumab plus cabozantinib ( identifier NCT03793166); the single-arm phase II ICONIC trial looking at combination ipilimumab/cabozantinib/nivolumab (NCT03866382); and a phase I dose-escalation study looking at cabozantinib and nivolumab with or without ipilimumab (NCT02496208).

“I think we just need to wait a little more and dig a little deeper to see, for example, are there subpopulations who might benefit from triplet therapy? Similarly, are there subpopulations who might be more at risk for adverse events?” Dr. Singer added. “This is an exciting and important topic for the treatment for kidney cancer. I’m still very optimistic.” 


1. Singer EA, Rumble RB, Rathmell WK, et al: Management of metastatic renal clear cell cancer: ASCO guideline rapid recommendation update. J Clin Oncol. October 9, 2023 (early release online).

2. Rathmell WK, Rumble RB, Van Veldhuizen PJ, et al: Management of metastatic clear cell renal cell carcinoma: ASCO guideline. J Clin Oncol 40:2957-2995, 2022.

3. Choueiri TK, Powles T, Albiges L, et al: Cabozantinib plus nivolumab and ipilimumab in renal-cell carcinoma. N Engl J Med 388:1767-1778, 2023.

4. Fahey CC, Shevach JW, Flippot R, et al: Triplet strategies in metastatic clear cell renal cell carcinoma: A worthy option in the first-line setting? Am Soc Clin Oncol Educ Book 43:e389650, 2023.

Originally published in ASCO Daily News © American Society of Clinical Oncology. ASCO Daily News. October 11, 2023. All rights reserved.