COSMIC-313 highlights benefit of triplet regimen in RCC

In the COSMIC-313 trial, the addition of the tyrosine kinase inhibitor (TKI) cabozantinib to the immune checkpoint inhibitor (ICI)-doublet regimen comprising nivolumab and ipilimumab (NIVO/IPI) improved progression-free survival (PFS) in patients with previously untreated, advanced renal-cell carcinoma (RCC) who had intermediate or poor prognostic risk according to the IMDC* category.

“In this randomized, double-blind, phase III trial [evaluating this subgroup of] RCC patients … PFS was significantly longer with cabozantinib in combination with NIVO/IPI than with NIVO/IPI alone,” said the researchers.

The intention-to-treat (ITT) population comprised 855 patients (median age 60 years, 75 percent male) who were randomized 1:1 to NIVO/IPI with oral cabozantinib 40 mg QD (experimental arm) or matched placebo (control arm). Nivolumab 3 mg/kg and ipilimumab 1 mg/kg were administered intravenously once Q3W for four cycles. Nivolumab was then administered at a dose of 480 mg Q4W for up to 2 years as maintenance therapy. [N Engl J Med 2023;388:1767-1778]

In the PFS population**, the probability of PFS at 12 months was 0.57 in the experimental arm and 0.49 in the control arm (hazard ratio [HR] for disease pro­gression or death, 0.73; p=0.01). Median PFS was not reached in the experimental arm and 11.3 months in the control arm.

On prespecified subgroup analyses, the PFS benefit with the triplet regimen was sustained, except in the subgroup of patients with poor IMDC risk. “[However,] interpretability is limited by the small subgroup size and differences in populations confound comparisons across trials. Exploratory analyses according to individual IMDC risk factors may provide further insight into patient characteristics associated with outcomes,” said the researchers.

In the supportive analyses of the PFS population, median PFS was longer with the experimental vs control regimen, both on BIR*** (16.9 vs 11.3 months; HR for progression or death, 0.74) and investigator assessment (13.8 vs 11.2 months; HR for progression or death, 0.79). A similar trend favouring the experimental regimen was seen in the ITT cohort (median PFS by BIR, 15.3 vs 11.3 months; HR for progression or death, 0.74).

In the PFS cohort, more patients on the experimental regimen had an objective response vs those in the control arm as per BIR (43 percent vs 36 percent). Three percent of patients in both arms had a complete response.

Safety analysis

There were more grade 3/4 adverse events (AEs) in the experimental vs the control arm (79 percent vs 56 percent), the most common being increased ALT^# (27 percent vs 6 percent) and AST^# levels (20 percent vs 5 percent) and hypertension (10 percent vs 3 percent).

Compared with the control arm, the experimental arm had more dose modifications due to AEs (91 percent vs 71 percent), dose delays of any regimen component (90 percent vs 70 percent), and dose reductions of cabozantinib or placebo (54 percent vs 20 percent).

Almost all experimental regimen recipients had AEs (73 percent grade 3/4) that were deemed related to the trial regimen; in the control arm, the corresponding rate was 91 percent (41 percent grade 3/4).

In the experimental arm, 28 percent discontinued cabozantinib due to AEs, 26 percent discontinued NIVO, and 30 percent discontinued IPI. The corresponding rates in the control arm were 14 percent (placebo), 18 percent (NIVO), and 12 percent (IPI).

“These observations emphasize the importance of frequent routine monitoring after treatment initiation, dose modifications, and supportive care for AE management,” the researchers noted.

Spotlight on TKI-ICI combo

Although the study may have been limited by the short follow-up and immature overall survival data, COSMIC-313 underpinned the benefit of a combination regimen comprising a TKI and an ICI doublet in RCC patients with intermediate or poor IMDC risk.

Phase III trials evaluating TKI and ICI combinations – either as a triplet or sequential regimen – are underway. “[The results of these studies] may further inform the use of combination therapies,” said the researchers.