Adjuvant Nivolumab/Ipilimumab Not Recommended for Localized RCC With High-Risk Features

Robert J. Motzer, MD

Adjuvant treatment with nivolumab (Opdivo) plus ipilimumab (Yervoy) did not show improvement in disease-free survival (DFS) compared with placebo in patients with localized renal cell carcinoma (RCC) who were at high risk of recurrence following nephrectomy.

Limited research exists on approaches for adjuvant therapy that can provide durable disease control and long-term survival advantages for patients with RCC. It is known, however, that immune checkpoint blockade has been effective in patients with first-line RCC, and the benefit appears to be durable. Investigators led by Robert J. Motzer, et al considered that the durability of benefit shown with immune checkpoint inhibition may extend to the advanced stages.

To investigate this hypothesis, the double-blind, randomized, phase 3 CheckMate 914 trial (NCT03138512) was conducted. In part A of the study, the median DFS shown with nivolumab plus ipilimumab in the study was not reached compared with 50.7 months in the placebo arm (hazard ratio [HR], 0.92; 95% CI, 0.71-1.19; P = .53), at a median follow-up of 37.0 months (IQR, 31.3-43.7 months). The HR and P value shown for the primary end point were well beyond the significance threshold at 0.65 and 0.05, respectively.

In CheckMate 914, 1153 patients were assessed for eligibility. All patients were required to have completely resected renal cell carcinoma, advanced disease, be post-nephrectomy with no macroscopic residual disease or distant metastases and have an ECOG performance status of 0-1. Following the eligibility assessment, 816 patients were randomized 1:1 to received nivolumab plus ipilimumab (n = 405) or placebo (n = 411). There were 5 treatment arms total. In addition to DFS, these patients were assessed for the secondary end points of overall survival (OS) and safety determined by the incidence of adverse event (AEs).

Patients had a median age of 58 years (range, 51-65 years) in the combination arm and 57 years (range, 50-65 years) in the placebo arm. Most patients, including 71% of the combination arm and 72% of the placebo arm, were male. Seventy-five percent of patients in the combination arm identified as White, as did 78% of the placebo arm. The population was 23% and 16% Asian in the combination arm and the placebo arm, respectively.

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Patients were stratified by their baseline TNM stage and type of nephrectomy received. The TNM stage for most patients in the study was pT3, G any, N0 M0 for 78% of patients in the nivolumab plus ipilimumab group and 77% of the placebo group. TNM stage pT2a G3 or G4, N0 M0/pT2b, G any, N0 M0 was the second most common followed by pT4, G any, N0 M0/pT any, G any, N1 M0. Ninety-three percent of patients in each arm underwent radical nephrectomy vs partial nephrectomy.

At the time data from CheckMate 914 were published, OS data were immature and therefore, Kaplan-Meier estimates were not reported. In terms of safety, grade 1/2 AEs occurred in 59% of the nivolumab plus ipilimumab arm compared with 78% of the placebo arm. Grade 3/4 AEs were seen in 38% of the nivolumab plus ipilimumab arm vs 10% of the placebo arm. The most common all-cause AEs in the nivolumab/ipilimumab arm vs the placebo were pruritis (31% v 17%), fatigue (30% v 27%), diarrhea (24% v 20%), and rash (21% v 9%).

Immune-mediated AEs were observed in both arms with the most common being hypothyroidism in 19% of the nivolumab/ipilimumab arm vs 3% of the placebo arm, and rash in 15% vs 2%, respectively. Few of these AEs were grade 3/4 in severity.

Treatment-related AEs (TRAEs) led to treatment discontinuation in 29% of the nivolumab/ipilimumab arm vs 1% of the placebo arm. The most common TRAEs that led to treatment discontinuation among patients treated with nivolumab plus ipilimumab were hypophysitis (2%) and increased alanine aminotransferase (2%). In the placebo group, the most common TRAES leading to treatment discontinuation were increased alanine aminotransferase (1%), increased aspartate aminotransferase (1%), increased blood creatinine (1%), rash (1%), and eczema (1%).

Based on these findings, investigators of CheckMate 914 do not support the use of nivolumab plus ipilimumab in in patients with localized RCC at a high risk of recurrence following nephrectomy. Investigators noted that the number treatment discontinuation that occurred along with the length of exposure to treatment may have negatively impacted efficacy.

Pembrolizumab remains the most optimal treatment for this patient population in the adjuvant setting, according to findings from KEYNOTE-564 (NCT03142334). Compared with placebo, pembrolizumab was shown to improve DFS (HR, 0.68; 95% CI, 0.53-0.87; 2-sided P = .002).

_REFERENCE:

_{1. Motzer RJ, Russo P, Grunwald V, et al. Adjuvant nivolumab plus ipilimumab versus placebo for localised renal cell carcinoma after nephrectomy (CheckMate 914): a double-blind, randomised, phase 3 trial. Lancet. 2023;402(10379):812-832. doi:10.1016/S0140-6736(22)02574-0}

_{2. Choueiri TK, Tomczak P, Park SH, et al. Adjuvant pembrolizumab after nephrectomy in renal-cell carcinoma. N Engl J Med. 2021; 385(8):683-694. doi:10.1056/NEJMoa2106391}