Cabozantinib plus Nivolumab and Ipilimumab in Renal-Cell Carcinoma
1. The probability of progression-free survival at 12 months was 0.57 in the experimental group (cabozantinib plus nivolumab and ipilimumab) vs 0.49 in the control group (placebo plus nivolumab and ipilimumab, where the HR was 0.73.
2. Adverse events (grade 3 or higher) occurred in 79% of the experimental group and 56% in the control group, with differences highlighted in liver enzymes and hypertension.
Evidence Rating Level: 1 (Excellent)
Study Rundown: In the treatment of clear-cell, advanced renal-cell carcinoma, tyrosine kinase inhibitors (TKIs) and immune checkpoint inhibitors (ICIs) are commonly used either alone or in combination. Past research had shown that first-line therapy with nivolumab and ipilimumab (ICIs) improved outcome measures, but a subset of those patients had progressive disease as the best response. Cabozantinib is a TKI which demonstrated promising outcomes in previous trials as a single agent and in combination with nivolumab. This phase 3 trial assessed the efficacy of cabozantinib vs. placebo in combination with nivolumab and ipilimumab in previously untreated patients with advanced renal-cell carcinoma and intermediate or poor risk. The primary endpoint was progression-free survival (PFS) and secondary endpoints included overall survival (OS), objective response rate (ORR), duration of response (DoR), and safety. The probability of PFS at 12 months was 0.57 in the experimental group and 0.49 in the control group, with an HR of 0.73. The ORR was 43% in the experimental group and 36% in the control, with 3% of the patients in both groups achieving a complete response. With regards to safety, grade 3 or higher adverse event occurred in 79% of the experimental group and 56% in the control group. Adverse event differences included increased alanine aminotransferase level (27% in the experimental group and 6% in the control group), increased aspartate aminotransferase level (20% and 5%), and hypertension (10% and 3%). This led to the discontinuation of any component of treatment in 45% of the experimental group and 24% in the control group. The strengths of this study included its methodology and the limitations included short follow-up time, and immature data (including for OS). Overall, the addition of cabozantinib to nivolumab and ipilimumab demonstrated improved PFS in patients with previously untreated advanced renal-cell carcinoma and poor prognostic risk, although it was associated with higher rates of adverse events and treatment discontinuations.
Click to read the study in NEJM
In-Depth [randomized controlled trial]: This international, randomized, double-blinded, placebo-controlled phase 3 trial assessed cabozantinib plus nivolumab and ipilimumab (n = 428) vs placebo plus nivolumab and ipilimumab (n = 427) in untreated adult patients with histologically confirmed clear-cell advanced renal-cell carcinoma. The median follow-up time was 20.2 months. Median PFS was conducted in a smaller subgroup of patients and was not reached in the experimental group (95%CI, 14.0 months to NA) and was 11.3 months (95%CI, 7.7 to 18.2) in the control group, but PFS at 12 months was 0.57 (95%CI, 0.50 to 0.63) in the experimental group and 0.49 (95%CI, 0.42 to 0.55) in the control group, with HR 0.73 (95%CI, 0.57 to 0.94, p=0.01). The ORR was 43% (95%CI, 37 to 49) in the experimental group and 36% (95%CI, 30 to 42) in the control, with 3% of the patients in both groups achieving a complete response. With regards to safety, grade 3 or higher adverse event occurred in 79% of the experimental group and 56% in the control group, with adverse event differences including increased alanine aminotransferase level (27% in the experimental group and 6% in the control group), increased aspartate aminotransferase level (20% and 5%), and hypertension (10% and 3%). This led to the discontinuation of any component of treatment in 45% of the experimental group and 24% in the control group. Overall, the addition of cabozantinib to nivolumab and ipilimumab demonstrated improved PFS, although it was associated with higher rates of adverse events and treatment discontinuations.
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