Phase III Trial Launches to Investigate Cabozantinib Plus Nivolumab/Ipilimumab in Frontline RCC

A phase III clinical trial evaluating cabozantinib (Cabometyx) in combination with nivolumab (Opdivo) and ipilimumab (Yervoy) in patients with previously untreated advanced renal cell carcinoma has been initiated, according to Exelixis, the developer of cabozantinib.

Gisela Schwab, MD

A phase III clinical trial evaluating cabozantinib (Cabometyx) in combination with nivolumab (Opdivo) and ipilimumab (Yervoy) in patients with previously untreated advanced renal cell carcinoma (RCC) has been initiated, according to Exelixis, the developer of cabozantinib.1

The phase III COSMIC-313 trial, a multicenter, international, double-blinded, controlled study, will enroll approximately 676 intermediate- or poor-risk patients with previously untreated advanced RCC, across 150 sites. Patients will be randomized 1:1 to receive cabozantinib in combination with nivolumab/ipilimumab or to a control arm of nivolumab/ipilimumab in combination with matched placebo.

The primary endpoint of the trial is progression-free survival (PFS); secondary endpoints are overall survival (OS) and objective response rate (ORR).

“Clinical observations suggest cabozantinib promotes an immune-permissive environment, which could present an opportunity for additive or synergistic effects with immune checkpoint inhibitors,” Gisela Schwab, MD, president, Product Development and Medical Affairs and chief medical officer, Exelixis, said in a press release.

“The mechanisms of action of single-agent cabozantinib and the combination of nivolumab and ipilimumab are complementary, and each has demonstrated efficacy in advanced renal cell carcinoma. The further combination of these agents as a triplet regimen may offer promise to previously untreated patients with intermediate- or poor-risk disease, who are known to have poor treatment outcomes,” added Schwab.

This trial was initiated based on preliminary data from an ongoing phase Ib study (NCT02496208) of cabozantinib plus nivolumab with or without ipilimumab in patients with previously treated advanced genitourinary cancers, including RCC. The phase Ib study is being conducted by the National Cancer Institute, as well as centers from its Experimental Therapeutics Clinical Trials Network.

Data from the trial demonstrated that there was promising antitumor activity in both arms, and initial safety findings were confirmed, which showed that grade 3/4 adverse event (AE) rates were 62% with cabozantinib/nivolumab and 71% with cabozantinib/nivolumab plus ipilimumab.2

Cabozantinib in the first-line setting was approved by the FDA in December 2017 for patients with advanced RCC. This decision followed its initial April 2016 approval, which was specifically for patients with advanced RCC following one prior antiangiogenic therapy.

The frontline approval was based on data from the phase II CABOSUN trial, which demonstrated a 52% reduction in the risk of progression or death versus sunitinib (Sutent) for patients with advanced RCC.3

In CABOSUN, 157 patients with poor- and intermediate-risk advanced RCC were randomized to receive cabozantinib at 60 mg once daily (n = 79) or sunitinib at 50 mg daily for a 4-weeks-on/2-weeks-off schedule (n = 78). Intermediate-risk patients comprised 81% of the study population, and baseline characteristics were similar between the 2 arms.

Results also showed that the median PFS with cabozantinib was 8.6 months compared with 5.3 months for sunitinib (HR, 0.48; 95% CI, 0.31-0.74;P= .0008). Moreover, the ORRs were 20% and 9% with cabozantinib and sunitinib, respectively. When including those with stable disease, the disease control rate was 75% with cabozantinib and 47% for sunitinib. An 80% reduction in target lesion size of any magnitude was recorded for those who received cabozantinib versus 50% with sunitinib.

The median OS was 26.6 months (95% CI, 14.6-not evaluable) with cabozantinib versus 21.2 months (95% CI, 16.3-27.4) with sunitinib, which demonstrated a 20% reduction in the risk of death (HR, 0.80; 95% CI, 0.53-1.21;P= 0.29), which was not statistically significant, after 30.8 months of follow-up.

Additionally, cabozantinib was superior to sunitinib across all prespecified patient subgroups, including risk, bone metastases, andMETstatus. In poor-risk patients, there was a 69% reduction in disease progression or death (HR, 0.31; 95% Ci, 0.11-0.92). In the intermediate group, the HR for PFS was 0.52, favoring cabozantinib (95% CI, 0.32-0.82).

Regarding safety, the rate of grade 3/4 AEs was 68% with cabozantinib and 65% with sunitinib. All-cause grade 5 AEs were experienced by 4% of patients in the cabozantinib arm compared with 10% in the sunitinib group.

In April 2018, the FDA approved the combination of nivolumab and ipilimumab as a frontline treatment for intermediate- and poor-risk patients with advanced RCC. This decision was based on findings from the phase III CheckMate-214 study, in which the frontline combination reduced the risk of death by 32% versus sunitinib for patients with metastatic disease. Additionally, the risk reduction was 37% in patients with intermediate- and poor-risk RCC, who comprised approximately 75% of the intent-to-treat population.4

In CheckMate-214, treatment-naïve patients with advanced or metastatic clear cell RCC were randomized 1:1 to nivolumab at 3 mg/kg plus ipilimumab at 1 mg/kg every 3 weeks for 4 doses, followed by 3 mg/kg of nivolumab every 2 weeks; or to receive oral sunitinib at 50 mg daily for 4 weeks in 6-week cycles. Patients were stratified by risk group and region, and treatment was continued until disease progression or unacceptable toxicity.

The median OS in the overall population was not reached with the combination versus 32.9 months with sunitinib (HR, 0.68; 99.8% CI, 0.49-0.95;P= .0003). In those patients with intermediate- and poor-risk RCC, the median OS was not reached in the nivolumab and ipilimumab arm and was 26.0 months with sunitinib (HR, 0.63; 99.8% CI, 0.44-0.89; P<.0001). In those with favorable-risk disease, there was no benefit for the combination compared with sunitinib.

Moreover, AEs leading to discontinuation occurred in 22% of patients in the nivolumab/ipilimumab arm compared with 12% with sunitinib. The most common grade 3/4 AEs in the combination group were fatigue (4%) and diarrhea (4%); the most common grade 3/4 AEs with sunitinib were hypertension (16%), fatigue (9%), and Palmar-plantar erythrodysesthesia syndrome (9%). Seven treatment-related deaths occurred in the combination group compared with 4 in the sunitinib group.


  1. Exelixis Initiating Phase 3 Pivotal Trial (COSMIC-313) of Cabozantinib in Combination with Nivolumab and Ipilimumab Versus Nivolumab and Ipilimumab in Previously Untreated Advanced Renal Cell Carcinoma. Exelixis. Published May 1, 2019. Accessed May 2, 2019.
  2. Nadal RM, Mortazavi A, Stein M, et al. Results of phase I plus expansion cohorts of cabozantinib (Cabo) plus nivolumab (Nivo) and CaboNivo plus ipilimumab (Ipi) in patients (pts) with metastatic urothelial carcinoma (mUC) and other genitourinary (GU) malignancies.J Clin Oncol. 2018;36(6):515.
  3. Choueiri TK, Hessel C, Halabi S, et al. Progression-free survival (PFS) by independent review and updated overall survival (OS) results from Alliance A031203 trial (CABOSUN): Cabozantinib versus sunitinib as initial targeted therapy doe patients (pts) with metastatic renal cell carcinoma (mRCC). Presented at: 2017 ESMO Congress; September 8-12, 2017; Madrid, Spain. Abstract LBA38.
  4. Escudier B, Tannir NM, McDermott DF, et al. CheckMate 214: Efficacy and safety of nivolumab plus ipilimumab vs sunitinib for treatment-naive advance or metastatic renal cell carcinoma, including IMDC risk and PD-L1 expression subgroups. Presented at: 2017 ESMO Congress; Madrid, Spain; September 8-12, 2017. Abstract LBA5.