SUMMARY: The American Cancer Society estimates that 79,000 new cases of kidney cancers will be diagnosed in the United States in 2022 and about 13,920 people will die from this disease. Clear Cell Renal Cell Carcinoma (RCC) is by far the most common type of kidney cancer in adults. Modifiable risk factors include smoking, obesity, workplace exposure to certain substances and high blood pressure. The five-year survival of patients with advanced RCC is about 14% and there is a significant unmet need for improved therapies for this disease.
OPDIVO® (Nivolumab) is a fully human, immunoglobulin G4 monoclonal antibody that binds to the PD-1 receptor and blocks its interaction with PD-L1 and PD-L2, whereas YERVOY® (Ipilimumab) is a fully human immunoglobulin G1 monoclonal antibody that blocks Immune checkpoint protein/receptor CTLA-4 (Cytotoxic T-Lymphocyte Antigen 4, also known as CD152). Blocking the Immune checkpoint proteins unleashes the T cells, resulting in T cell proliferation, activation, and a therapeutic response. The FDA in 2018, granted approvals to OPDIVO® and YERVOY® in combination, for the treatment of Intermediate or Poor-risk, previously untreated advanced Renal Cell Carcinoma.
CABOMETYX® (Cabozantinib) is an oral, small-molecule Tyrosine Kinase Inhibitor (TKI), which targets Vascular Endothelial Growth Factor Receptors (VEGFR), as well as tyrosine kinases MET and AXL. Both MET and AXL are upregulated in Renal Cell Carcinoma as a consequence of VHL inactivation, and increased expression of MET and AXL is associated with tumor progression and development of resistance to VEGFR inhibitors. Further, CABOMETYX® promotes an immune-permissive environment, which may enhance response to checkpoint inhibitors. CABOMETYX® was approved by the FDA in 2016 for the treatment of advanced Renal Cell Carcinoma.
COSMIC-313 is a global, multicenter, randomized, double-blinded, controlled, ongoing Phase III pivotal trial, conducted to evaluate the triplet combination of Cabozantinib, Nivolumab and Ipilimumab versus the doublet combination of Nivolumab and Ipilimumab, in patients with previously untreated advanced Intermediate or Poor-risk Renal Cell Carcinoma. COSMIC-313 was designed to answer whether adding Cabozantinib to dual checkpoint inhibition can improve outcomes among patients with Intermediate and Poor-risk advanced Renal Cell Carcinoma.
In this trial, 855 treatment naïve, advanced clear cell Renal Cell Carcinoma patients of IMDC (International Metastatic RCC Database Consortium) Intermediate or Poor risk were randomized 1:1 to receive Cabozantinib plus Nivolumab and Ipilimumab (N=428) or placebo plus Nivolumab and Ipilimumab (N=427). Patients in the study group received Cabozantinib 40 mg, orally once daily in combination with Nivolumab 3 mg/kg IV and Ipilimumab 1 mg/kg IV once every 3 weeks for 4 doses total followed by Cabozantinib 40 mg orally once daily and Nivolumab 480 mg/kg flat dose IV, once every 4 weeks for up to 2 years. Patients in the control group received the same regimen, but instead of Cabozantinib, received a matched placebo. Both treatment groups were well balanced. The median patient age was 60 years, 75% were men, 63% had PD-L1 expression of less than 1%, 75% had Intermediate-risk disease, 25% were Poor risk, and 65% had prior nephrectomy. The Primary endpoint was Progression Free Survival (PFS), as assessed by Blinded Independent Radiology Committee (BIRC). Secondary endpoints included Overall Survival (OS), Objective Response Rate (ORR) and Safety. The median follow up was 20.2 months.
The study met the Primary endpoint and the median PFS was not reached in the Cabozantinib group and was 11.3 months in the placebo group (HR=0.73; P=0.013). Patients treated with the Cabozantinib three-drug combination had a 27% lower risk of disease progression or death compared to those on the two drug immunotherapy combination. This PFS benefit was predominantly noted in the Intermediate-risk group. The Objective Response Rate was 43% with the Cabozantinib combination versus 36% in the placebo plus dual immunotherapy group, with 3% of patients achieving a Complete Response in both treatment groups. The Disease Control Rate was 86% and 72%, respectively. The median Duration of Response was not reached in either treatment group. Grade 3/4 adverse events occurred in 73% of patients treated with the combination of Cabozantinib, Nivolumab and Ipilimumab, and in 41% of patients treated with the Nivolumab and Ipilimumab combination. Discontinuation of all treatment agents due to adverse events occurred in 12% and 5% of patients, respectively.
The authors concluded that this is the first study to show that a TKI added to dual checkpoint inhibition significantly improved Progression Free Survival, in patients with untreated, Intermediate or Poor risk advanced kidney cancer, compared to doublet immunotherapy. Follow-up for Overall Survival is ongoing.
Phase III study of cabozantinib (C) in combination with nivolumab (N) and ipilimumab (I) in previously untreated advanced renal cell carcinoma (aRCC) of IMDC intermediate or poor risk (COSMIC-313). Choueiri TK, Powles TB, Albiges L, et al. Annals of Oncology (2022) 33 (suppl_7): S808-S869. 10.1016/annonc/annonc1089. LBA8
