Cabozantinib Plus Nivolumab/Ipilimumab Under Exploration in Intermediate-, Poor-Risk RCC

November 14, 2020 - A novel combination comprised of the TKI cabozantinib plus the PD-1 inhibitor nivolumab and the CTLA-4 inhibitor ipilimumab is under exploration in treatment-naïve patients with intermediate or poor risk advanced or metastatic renal cell carcinoma in the phase 3 COSMIC-313 trial.

A novel combination comprised of the TKI cabozantinib (Cabometyx) plus the PD-1 inhibitor nivolumab (Opdivo) and the CTLA-4 inhibitor ipilimumab (Yervoy) is under exploration in treatment-naïve patients with International Metastatic RCC Database Consortium (IMDC) intermediate or poor risk advanced or metastatic renal cell carcinoma (RCC) in the phase 3 COSMIC-313 trial (NCT03937219), according to a poster revealed during the 2020 SITC Annual Meeting.1

“Preclinical and clinical studies show that cabozantinib may have immunomodulatory activity and may promote an immune-permissive tumor environment that enhances response to immune checkpoint inhibitors,” first author Toni Choueiri, MD, who is the director of the Lank Center for Genitourinary Oncology, director of the Kidney Cancer Center, and senior physician at Dana-Farber Cancer Institute, and colleagues, wrote in the poster.

Treatment with TKIs and immune checkpoint inhibitors have become the standard of care for patients with advanced disease. The TKI cabozantinib was developed to hinder tyrosine kinases that play a role in tumor progression, angiogenesis, metastasis, and immune regulation, including the MET, VEGFR, and TAM kinases.

In December 2017, cabozantinib was approved by the FDA for use in treatment-naïve patients with advanced RCC, based on a meaningful improvement in progression-free survival (PFS) versus sunitinib (Sutent) in the CABOSUN trial (NCT01835158).2 The agent also received regulatory approval in Europe in May 2018 for previously untreated patients with intermediate- or poor-risk advanced disease based on data from the trial. Specifically, the TKI was found to reduce the risk of progression or death by 52% versus sunitinib in this population; the median PFS was 8.6 months and 5.3 months, respectively (HR, 0.48; 95% CI, 0.31-0.74; P =.0008).3

The anti–PD-1 monoclonal antibody nivolumab is approved for use as a monotherapy in patients with advanced disease who have received prior antiangiogenic therapy;4 it is also approved for use in combinationwith the anti–CTLA-4 monoclonal antibody ipilimumab in treatment-naïve patients with advanced intermediate or poor-risk RCC, based on data from the phase 3 CheckMate-214 trial.5 Here, nivolumab plus ipilimumab reduced the risk of death by 32% compared with sunitinib in patients with metastatic disease. The risk reduction was 37% in patients with intermediate- and poor-risk RCC.

Findings from early-phase clinical trials have indicated that the combination of cabozantinib and immune checkpoint inhibitors such as nivolumab (Opdivo) and atezolizumab (Tecentriq) is safe and has clinical activity.6,7 Notably, data from the phase 3 CheckMate-9ER trial demonstrated that the frontline combination of cabozantinib and nivolumab was found to significantly improve PFS, overall survival (OS), and objective response rate (ORR) when compared with sunitinib in patients with advanced RCC.8 The FDA has since granted a priority review designation to a supplemental biologics license application and supplemental new drug application for the combination.

Now, in the global, randomized, double-blind, placebo-controlled, phase 3 COSMIC-313 trial, investigators are examining the safety and efficacy of cabozantinib in combination with nivolumab plus ipilimumab versus nivolumab/ipilimumab in approximately 676 treatment-naïve patients with intermediate- or poor-risk metastatic or advanced RCC.

To be eligible for enrollment, patients needed to be 18 years of age or older, have advanced RCC with a clear cell component, be intermediate or poor risk per IMDC, and have measurable disease via RECIST v1.1 criteria. Patients also had to have archival or fresh tumor tissue available for analysis, a Karnofsky Performance Status of 70% or greater, and acceptable organ and marrow function.

If they had received previous systemic therapy for advanced disease, radiation treatment within 4 weeks or within 2 weeks for bone metastasis, or uncontrolled and significant illnesses such as autoimmune diseases, they were excluded. Patients with brain metastases or cranial epidural disease were not permitted unless they were adequately treated. Moreover, patients who not be receiving concomitant oral anticoagulants except for low-dose aspirin. Anticoagulation with low-dose low-molecular-weight heparin was permitted, but corticosteroid use was not.

In the trial, patients are randomized in a 1:1 fashion. Those on the investigational arm will receive oral cabozantinib at 40 mg once daily, intravenous (IV) nivolumab at 3 mg/kg every 3 weeks for 4 cycles, and IV ipilimumab at 1 mg/kg every 3 weeks for 4 cycles; this is then followed by oral cabozantinib at 40 mg once daily and IV nivolumab at 480 mg every 4 weeks. Those in the control arm will receive placebo plus nivolumab/ipilimumab at the same dose and schedule as the investigational arm.

Investigators will conduct a tumor assessment at week 10 of the trial, then every 8 weeks for the first 50 weeks, followed by every 12 weeks thereafter. Treatment will continue until either loss of clinical benefit or unacceptable toxicity. However, nivolumab will be given for a maximum of 2 years. Also, if a clinical benefit is present per investigator assessment, patients may receive treatment beyond disease progression.

The primary end point of the trial is PFS per RECIST v1.1 criteria by blinded independent radiology committee (BIRC), while the secondary end point is OS. Additional end points to be evaluated in this trial include PFS per RECIST v1.1 criteria by investigator assessment; ORR and duration of response per RECIST v1.1 criteria, BIRC, and investigator; PFS and ORR per RECIST v1.1 criteria by BIRC, according to PD-L1 status; safety; and pharmacokinetics of cabozantinib. Moreover, the immunogenicity of nivolumab and ipilimumab will be examined, along with the correlation of biomarkers and clinical outcomes. Health-related quality of life (HRQoL) and healthcare resource utilization serves as an additional end point of the trial.


Investigators will evaluate radiographic response and disease progression in patients through the use of RECIST v1.1 criteria. A CT of the chest, abdomen, and pelvis or a CT of the chest and an MRI of the abdomen and pelvis will be completed at baseline, week 10 of the trial, and then every 8 weeks through week 50; this will then be done every 12 weeks thereafter until radiographic disease progression.

Safety of the combination will be examined through the incidence of toxicities, performance status, vital signs, electrocardiograms, and standard laboratory tests. Adverse effects will be evaluated by the investigators and severity will be graded per the National Cancer Institute Common Terminology Criteria for Adverse Events v5.0.

Moreover, at week 1 day 1 (W1D1), W4D1, W7D1, W10D1, W14D1, and W26D1, investigators will collect blood samples from patients to conduct pharmacokinetic and immunogenicity assessments; this will also be done 30 days and 100 days after study treatment has be stopped. Specifically, these samples will be analyzed to learn more about cabozantinib plasma concentrations and antibodies to nivolumab and ipilimumab. Serum concentrations for nivolumab/ipilimumab will also be measured.

Tumor samples will also be collected from patients at baseline. Optional tumor biopsies can potentially be collected at 6 weeks following the first dose of treatment. Here, investigators will look at potential biomarkers and PD-L1 tumor expression.

Finally, using the EuroQoL Health questionnaire instrument EQ-5D-5L, investigators will perform HRQoL assessments at baseline and every 3 weeks following randomization; this will continue until week 10. Then, these will be done every 4 weeks thereafter until the date of the last tumor assessment.

"The COSMIC-313 study is open for enrollment in North America, Europe, Asia-Pacific region, and South America," the authors of the poster concluded.


  1. Choueiri TK, Albiges L, Powles T, et al. A phase 3 study (COSMIC-313) of cabozantinib in combination with nivolumab and ipilimumab in patients with previously untreated advanced renal cell carcinoma of intermediate or poor risk. Presented at: 2020 SITC Annual Meeting; November 9-14, 2020; Virtual. Abstract 342.
  2. Choueiri TK, Halabi S, Sanford BL, et al. Cabozantinib versus sunitinib as initial targeted therapy for patients with metastatic renal cell carcinoma of poor or intermediate risk: The Alliance A031203 CABOSUN trial. J Clin Oncol. 2017;35(6):591-597. doi:10.1200/JCO.2016.70.7398
  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). Ann Oncol. 2017;28(suppl 5):623. doi:10.1093/annonc/mdx440.032
  4. Motzer RJ, Escudier B, McDermott DF, et al. Nivolumab versus everolimus in advanced renal-cell carcinoma. N Engl J Med. 2015;373(19):1803-1813. doi:10.1056/NEJMoa1510665
  5. 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.
  6. Apolo AB, Nadal R, Girardi DM, et al. Phase 1 study of cabozantinib and nivolumab alone or with ipilimumab for advanced or metastatic urothelial carcinoma and other genitourinary tumors. J Clin Oncol. 2020;38(31):3672-3684. doi:10.1200/JCO.20.01652
  7. Pal S, Tsao C, Suarez C, et al. Cabozantinib (C) in combination with atezolizumab (A) as first-line therapy for advanced clear cell renal cell carcinoma (ccRCC): results from the COSMIC-021 study. Ann Oncol. 2020;31(suppl 4):550. doi:10.1016/annonc/annonc274
  8. Choueiri TK, Powles T, Burotto M, et al. Nivolumab + cabozantinib vs sunitinib in first-line treatment for advanced renal cell carcinoma: first results from the randomized phase 3 CheckMate 9ER trial. Ann Oncol. 2020;31(4). doi:10.1016/j.annonc.2020.08.2257