Trial of Triplet Regimen With Cabozantinib Plus Immunotherapy Is Planned in RCC


Investigators see potential in adding targeted therapy to dual immunotherapy for intermediate- and poor-risk patients with renal cell carcinoma. In the phase III COSMIC-313 trial, investigators aim to evaluate cabozantinib, nivolumab, and ipilimumab in patients with untreated advanced RCC.

Gisela Schwab, MD

Investigators see potential in adding targeted therapy to dual immunotherapy for intermediate- and poor-risk patients with renal cell carcinoma (RCC).1 In the phase III COSMIC-313 trial (NCT03937219), investigators aim to evaluate cabozantinib (Cabometyx), nivolumab (Opdivo), and ipilimumab (Yervoy) in patients with untreated advanced RCC.

The double-blind, controlled study will recruit up to 676 patients and randomize them 1:1 to receive cabozantinib in combination with nivolumab and ipilimumab or nivolumab and ipilimumab plus matched placebo (Figure).

“COSMIC-313 is notable for being the first phase III pivotal trial to compare a [tyrosine kinase inhibitor]/checkpoint inhibitor combination with the combination of nivolumab and ipilimumab already approved in the first-line RCC setting,” Gisela Schwab, MD, president of product development and medical affairs and chief medical officer for Exelixis, said in an interview with OncologyLive®.

The rationale for the trial derives from preliminary data from a phase IB study (NCT02496208), which contrasted cabozantinib and nivolumab with and without ipilimumab in patients with previously treated advanced genitourinary cancers, including RCC. In both arms, and across tumor types, data from the study, conducted by the National Cancer Institute and its Experimental Therapeutics Clinical Trials Network, showed promising antitumor activity.

The objective response rate was 53.9% (7 of 13) for patients with advanced RCC who received either the doublet or triplet combination, and the remaining patients in this subgroup had stable disease (46.1%).2 Moreover, median progression-free survival (PFS) for this cohort was 18.4 months.

Investigators concluded that further development of both combinations in metastatic RCC is warranted. “The mechanisms of action of single-agent cabozantinib and the combination of nivolumab and ipilimumab are complementary, and each has demonstrated efficacy in advanced [RCC],” Schwab said in a press release.1 “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.”

Cabozantinib's Climb

The FDA approved cabozantinib as a firstline treatment for patients with advanced RCC in December 2017. This decision followed the agent’s initial April 2016 approval, which authorized its use for treatment of patients with advanced RCC following 1 prior antiangiogenic therapy.

Frontline approval was based on data from the phase II CABOSUN trial (NCT03541902), in which cabozantinib demonstrated superiority over sunitinib (Sutent) among 157 patients with intermediate- and poor-risk advanced RCC. Cabozantinib yielded a 52% reduction in the risk of disease progression or death versus sunitinib.3 Patients were randomized 1:1 to receive cabozantinib at 60 mg once daily (n = 79) or standard-of-care sunitinib 50 mg daily in a schedule of 4 weeks on/2 weeks off (n = 78).

In this trial, the median PFS with cabozantinib was 8.6 months compared with 5.3 months for sunitinib (HR, 0.48; 95% Cl, 0.31-0.74; P = .0008). Partial responses were observed in 20% (16 of 79) of patients who received cabozantinib and 9% (7 of 78) who received sunitinib. In poorrisk patients, there was a 69% reduction in disease progression or death (HR, 0.31; 95% Cl, 0.11-0.92). In the intermediate-risk group, the hazard ratio for PFS was 0.52, favoring cabozantinib (95% CI, 0.32-0.82).

Nivolumab and Ipilimumab: An Effective Pair

Figure. COSMIC-313 Trial Evaluates Cabozantinib in Combination With Immunotherapy Duo

In April 2018, the FDA gave the green light to the combination of nivolumab and ipilimumab as a frontline treatment for intermediate- and poor-risk patients with advanced RCC. The approval was based on findings from Bristol-Myers Squibb’s phase III CheckMate214 study (NCT02231749), which demonstrated a 32% reduction in risk of death for patients with metastatic disease who received the immunotherapy combination versus sunitinib.4 In addition, the risk reduction was 37% for patients with intermediate- and poor-risk RCC, who composed approximately 75% of the intent-to-treat population. CheckMate214 randomized treatment-naïve patients with advanced or metastatic clear cell RCC at a 1:1 ratio. Patients received either nivolumab 3 mg/ kg plus ipilimumab 1 mg/kg every 3 weeks for 4 doses, followed by nivolumab 3 mg/kg every 2 weeks or oral sunitinib 50 mg daily for 4 weeks in 6-week cycles.

Cumulatively, the CABOSUN and CheckMate-214 trials led to regulatory approvals that addressed intermediate- and poor-risk patients with RCC. These FDA authorizations contributed to what Schwab calls the “rapidly changing” nature of the RCC treatment landscape. “Until recently, single-agent sunitinib and pazopanib [Votrient] had been considered standard frontline treatments in the intermediate- [and] poor-risk setting,” Schwab said.

Despite the strides made in the development of treatments for this patient population, further options are needed.

Seeking Promise for Untreated Patients

In addition to the phase IB study findings, the impetus for the COSMIC-313 trial is fueled by the FDA and European Union approvals of cabozantinib and of the combination of nivolumab and ipilimumab for treatment-naïve patients considered intermediate or poor risk by the International Metastatic Renal Cell Carcinoma Database Consortium. Schwab said that pairing cabozantinib with immune checkpoint inhibitors such as nivolumab and ipilimumab is appealing given that cabozantinib tends to make tumor cells more sensitive to immune-mediated attack.

She also noted that cabozantinib is believed to inhibit kinases that suppress macrophage activity. “The TAM kinases— TYRO3, AXL, and MER—are potently inhibited by cabozantinib and are believed to play a role in maintaining tumor-associated macrophages in an immunosuppressive state,” Schwab said. “We are exploring the possibility that cabozantinib might promote a ‘switch’ in the macrophage phenotype to a more immune-permissive state that could then promote antitumor immune response.”

Cabozantinib is currently the clinical focus of several other studies. Notably, investigators are exploring the effect of cabozantinib plus nivolumab versus sunitinib in patients with previously untreated advanced or metastatic RCC in the phase III CheckMate 9ER trial (NCT03141177). Also, Exelixis is concurrently evaluating cabozantinib with an anti—PD-L1 agent in the phase III COSMIC-312 trial (NCT03755791), which began in December 2018. The pivotal trial compares a dual regimen of cabozantinib and atezolizumab (Tecentriq) with use of the single-agent sorafenib (Nexavar) in treatment-naïve patients with advanced hepatocellular carcinoma.

“We anticipate starting further late-stage immune checkpoint inhibitor combination studies in indications that could potentially include bladder cancer, non—small cell lung cancer, and other promising tumor types identified through our ongoing phase IB trial of cabozantinib plus atezolizumab, COSMIC-021,” Schwab said.5

Looking Forward

With respect to adverse events, the doublet and triplet regimens used in the phase IB study demonstrated an acceptable tolerability profile. Now, investigators look forward to a trial that could bring about a promising new treatment option for patients with advanced RCC.

“Although we announced the [COSMIC- 313’s] initiation just [recently], the response from the clinical oncology community has been strong,” Schwab said. “We are looking forward to enrolling the trial and to evaluating the potential for this combination regimen to benefit appropriate patients.”

Exelixis’ collaborator, Bristol-Myers Squibb, will provide nivolumab and ipilimumab for use in the COSMIC-313 trial.


  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 [news release]. Alameda, CA: Exelixis; May 1, 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. doi: 10.1200/JCO.2018.36.6_suppl.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 for patients (pts) with metastatic renal cell carcinoma (mRCC). Presented at: ESMO 2017 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: ESMO 2017 Congress; Madrid, Spain; September 8-12, 2017. Abstract LBA5.
  5. Exelixis Announces Further Expansion to Clinical Research Protocol for Phase 1b COSMIC-021 Trial of Cabozantinib in Combination with Anti-PD-L1 Immunotherapy in Patients with Locally Advanced or Metastatic Solid Tumors [news release]. South San Francisco, CA: Exelixis; June 1, 2018.
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