Cabozantinib Plus Nivolumab and Ipilimumab Provides PFS Benefit in Advanced RCC


The addition of cabozantinib to nivolumab and ipilimumab led to improved progression-free survival vs nivolumab and ipilimumab alone in patients with treatment-naïve advanced renal cell carcinoma; however, the rate of grade 3/4 adverse effects with the triplet was 79%.

Toni K. Choueiri, MD

Toni K. Choueiri, MD

The addition of cabozantinib (Cabometyx) to nivolumab (Opdivo) and ipilimumab (Yervoy) led to improved progression-free survival (PFS) vs nivolumab and ipilimumab alone in patients with treatment-naïve advanced renal cell carcinoma (RCC); however, the rate of grade 3/4 adverse effects (AEs) with the triplet was 79%, according to results from the phase 3 COSMIC-313 study (NCT03937219).1

The findings, published in the New England Journal of Medicine, showed that among patients in the experimental arm (n = 428), the probability of 12-month PFS was 0.57. In the control arm of nivolumab/ipilimumab alone, the probability of 12-month PFS was 0.49 (HR, 0.73; 95% CI, 0.57-0.94; P = .01). The median PFS in the experimental arm was not reached (95% CI, 14.0-not estimable [NE]) vs 11.3 months (95% CI, 7.7-18.2) in the control arm (HR, 0.73; 95% CI, 0.57-0.94; P= .01). The PFS benefit was consistent across the prespecified subgroups, except for those with poor International Meta­static Renal-Cell Carcinoma Database Consor­tium (IMDC; HR, 1.04; 95% CI, 0.65-1.69).

The overall response rate between the 2 groups was 43% (95% CI, 37-49) vs 36% (95% CI, 30-42) in the investigative and control arms, respectively. In both groups, 3% had a complete response. Response rates were worse among those who were 65 years of age or older, had poor IMDC risk, or had a PD-L1 tumor proportion score of at least 1%. Overall survival (OS) data are not yet mature.

The rate of grade 3/4 AEs was 79% with the addition of cabozantinib and 56% without. Grade 3/4 AEs that were more common with cabozantinib arm included increased levels of alanine aminotransferase (ALT) and aspartate aminotransferase (AST), and hypertension. The rates of these events, between the 2 arms, were 27% vs 6%; 20% vs 5%; and 10% vs 3%, respectively.

“Among patients with previously untreated ad­vanced renal cell carcinoma who had intermediate or poor prognostic risk, treatment with cabozantinib plus nivolumab and ipilimumab resulted in significantly longer PFS than treatment with nivolumab and ipi­limumab alone,” Toni K. Choueiri, MD, Jerome and Nancy Kohlberg Professor of Medicine at Harvard Medical School and director of the Lank Center for Genitourinary Oncology at Dana-Farber Cancer Institute, and co-investigators, wrote in the study. “Adverse events and discontinua­tions were more frequent in the experimental group than in the control group.”

In the study, investigators wrote that TKIs and immune checkpoint inhibitors (ICIs) are standard treatment for patients with advanced RCC. Cabozantinib is a TKI that targets multiples tyrosine kinases, including VEGF, MET, and the TAM family of kinases. Moreover, in the CABOSUN trial (NCT01835158), cabozantinib improved outcomes over sunitinib in patients with untreated, advanced RCC.

This phase 3, double-blind trial enrolled treatment-naïve patients with advanced clear cell RCC that were randomized to receive either 40 mg of cabozantinib or placebo daily, both in addition to nivolumab and ipilimumab. Patients received nivolumab at 3 mg/kg and ipilimumab at 1 mg/kg every 3 weeks for 4 cycles. Nivolumab maintenance therapy was given at a dose of 480 mg once every 4 weeks for up to 2 years. PFS, as determine by blinded independent review, was the primary endpoint. The secondary end point is OS.

Supportive PFS analyses reported a median PFS, which comprising all events that occurred by the data cutoff and as determined by blinded independent review, of 16.9 months (95% CI, 11.5-NE) vs 11.3 months (95% CI, 7.7-14.0) in the experimental and control arms, respectively (HR, 0.74; 95% CI, 0.58-0.94). Investigator review reported the median PFS to be 13.8 months (95% CI, 9.7-15.9) and 11.2 months (95% CI, 7.6-14.0) between the 2 arms, respectively (HR, 0.79; 95% CI, 0.63-0.98).

Regarding safety, treatment-related adverse events (TRAEs) occurred in 99% of patients in the experimental group and 91% of those in the control group. In the cabozantinib arm, 45% of patients had AEs that led to treatment discontinuation; 28% specifically discontinued cabozantinib. Twenty-four percent of patients discontinued treatment in the control arm and 14% discontinued placebo. The AEs that most frequently resulted in treatment discontinuation, of any component, in the experimental and control arms, respectively, were increased ALT (19% vs 4%) and AST levels (15% vs 3%), and immune-mediated hepatitis (5% vs 1%).

AEs of special interest occurred in 83% with the addition of cabozantinib and in 65% of patients in the control group. Among them, respectively, were increased ALT level (42% vs 16%, respectively), increased AST level (38% vs 14%), and diarrhea (26% vs 13%).

Furthermore, 58% in the cabozantinib group required concomitant high-dose glucocorticoid treatment (at least 40 mg or more of prednisone or equivalent) vs 35% of patients in the control group. This treatment was necessary for at least 30 days or more in 18% vs 10% of patients, respectively. Treatment-related deaths occurred in 1% of the experimental group (n = 5), and in 1% (n = 4) in the control arm.

Trial limitations, according to investigators, include the relatively short duration of follow-up and the lack of mature OS data. They also acknowledge that it is difficult to attribute which AEs were caused by cabozantinib or ICIs, as both can cause hepatic and gastrointestinal toxicities.

Other ongoing phase 3 trials are assessing TKIs in combination with ICIs—both as a triplet regimen (NCT04736706), and in sequencing (NCT03793166).2,3

Editor’s Note: This trial was funded by Exelixis.


  1. Choueiri TK, Powles T, Albiges L; COSMIC-313 Investigators. Cabozantinib plus nivolumab and ipilimumab in renal-cell carcinoma. N Engl J Med. 2023;388(19):1767-1778. doi:10.1056/NEJMoa2212851
  2. Choueiri TK, Plimack ER, Powles T, et al. Phase 3 study of first-line treatment with pembrolizumab + belzutifan + lenvatinib or pembrolizumab/quavonlimab + lenvatinib versus pembrolizumab + lenvatinib for advanced renal cell carcinoma (RCC). J Clin Oncol. 2022;40(suppl 6):TPS399. doi:10.1200/JCO.2022.40.6_suppl.TPS399
  3. Zhang T, Ballman KV, Dipankar Choudhury A; PDIGREE investigators. PDIGREE: an adaptive phase III trial of PD-inhibitor nivolumab and ipilimumab (IPI-NIVO) with VEGF TKI cabozantinib (CABO) in metastatic untreated renal cell cancer (Alliance A031704). J Clin Oncol. 2021;39(6):TPS366. doi: 10.1200/JCO.2021.39.6_suppl.TPS366
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