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Renal Cell Carcinoma · Medical Oncology · Updated 14 October 2026

COSMIC-313

In previously untreated advanced clear-cell RCC with IMDC intermediate- or poor-risk disease, does adding cabozantinib to nivolumab plus ipilimumab improve outcomes over nivolumab plus ipilimumab alone?

Population
855 patients with untreated advanced clear-cell RCC; IMDC intermediate risk 75%, poor risk 25%.
Experimental arm
Cabozantinib 40 mg orally daily + nivolumab 3 mg/kg IV + ipilimumab 1 mg/kg IV every 3 weeks for 4 cycles; then nivolumab 480 mg IV every 4 weeks for up to 2 years.
Comparator
Placebo + nivolumab/ipilimumab, followed by nivolumab.
Design
Double-blind, randomized phase III trial; primary endpoint PFS, secondary endpoint OS.

Final efficacy and safety

Median PFS: 16.6 vs 11.2 months; HR 0.82 (95% CI 0.69–0.98) after median follow-up of 45 months.

Triplet median PFS
16.6 months
Nivolumab/ipilimumab median PFS
11.2 months

Overall survival: no significant difference; OS HR 1.02 (95% CI 0.85–1.23; P=0.84). Median OS was 41.9 vs 42.0 months.

Grade 3–4 treatment-related adverse events: 75% vs 43%, an absolute increase of 32 percentage points with the triplet.

Absolute-effect interpretation: COSMIC-313 preserved a modest PFS advantage but did not demonstrate an OS advantage in the intention-to-treat population and markedly increased severe treatment-related toxicity. The PFS hazard ratio is not converted into an NNT.

Critical appraisal

The final report reinforces the primary PFS signal but changes the clinical balance: the triplet adds a VEGFR/MET/AXL-targeting TKI to an established dual-checkpoint regimen, with a substantial increase in grade 3–4 toxicity. Exploratory M2-like macrophage findings are hypothesis-generating and are not a validated treatment-selection biomarker.

Interpret subgroup signals cautiously; the overall randomized population did not show improved OS. Toxicity included increased ALT and AST, and grade 5 treatment-related events occurred in approximately 1% in each group.

Current-practice context

As of 14 October 2026, COSMIC-313 should not be treated as establishing routine triplet therapy for all intermediate/poor-risk patients. Nivolumab/ipilimumab and approved IO–TKI combinations remain established first-line choices; triplet selection requires careful discussion of the lack of demonstrated OS benefit and greater toxicity, alongside local guideline and regulatory status.

Freshness note: targeted review of the 2026 final publication; broader guideline reconciliation remains ongoing.

Sources