Adjuvant Nivolumab Misses DFS End Point in Locally Advanced High-Risk RCC

Because the primary endpoint was not met, no formal overall survival analysis will be performed.

Treatment with adjuvant nivolumab (Opdivo) monotherapy did not meet the primary end point of disease-free survival (DFS) when compared with placebo when treating patients with localized renal cell carcinoma who are at high risk of relapse after nephrectomy, according to findings from part B of the phase 3 CheckMate 914 trial (NCT03138512) presented at the 2024 Genitourinary Cancers Symposium.¹

At a median follow-up of 27.0 months (95% CI, 18.0-42.4), the median DFS per blinded independent central review (BICR) was not reached in either the nivolumab arm or the placebo arm (HR, 0.87; 95% CI, 0.62-1.21; P = .3962). The 18-month DFS rates were 78.4% in the nivolumab arm and 75.4% in the placebo arm.

When evaluated via investigator, the median DFS was also not reached in either arm (HR, 0.80; 95% CI, 0.58-1.12; P = .1936), and the 18-month rates of DFS were 81.1% and 75.0%, respectively.

Because the primary endpoint of DFS per BICR was not met, no formal overall survival (OS) analysis will be performed, lead study author, Robert J. Motzer, MD, said in an oral presentation during the meeting.

However, patient subgroups that favored nivolumab vs placebo included patients with sarcomatoid features (HR, 0.42; 95% CI, 0.17-1.07), PD-L1 expression of 1% or greater (HR, 0.53; 95% CI, 0.22-1.29), and those with lower limit of normal hemoglobin at baseline (HR, 0.49; 95% CI, 0.25-1.49).

“Subgroup analysis from CheckMate 914 part A, which have been published previously, and presented previously, and part B suggest that there are tumor-specific characteristics that may influence outcomes for adjuvant nivolumab plus ipilimumab and nivolumab monotherapy treatment,” said Motzer, section head, Kidney Cancer, Genitourinary Oncology Service, and Jack and Dorothy Byrne Chair in Clinical Oncology, Memorial Sloan Kettering Cancer Center.

Part A of the CheckMate 914 study was designed to evaluate the efficacy of adjuvant nivolumab plus ipilimumab (Yervoy) compared with placebo in patients with surgically resected stage II/III clear cell RCC with a high risk of relapse. At median follow up of 37.0 months (range, 15.4-58.0), part A did not meet the primary endpoint of DFS for the treatment combination, with a median DFS of NR with nivolumab/ipilimumab and 50.7 months with placebo (95% CI, 48.1-NE).² The 18-month DFS rates were 78.8% and 76.6%, respectively.

Part B of the double-bind, randomized, phase 3 CheckMate 914 trial included 825 patients with radical or partial nephrectomy with negative surgical margins, predominant clear cell histology, no clinical or radiological evidence of residual disease or distant metastases after nephrectomy, and an ECOG performance status of 0 or 1. Pathologic TNM staging had to be pT2a, G3 or G4, N0 M0; pT2b, G any, N0 M0; pT3, G any, N0 M0; pT4, G any, N0 M0; or pT any, G any, N1 M0.

Patients were randomized 2:1:1 to receive either 240 mg of intravenous (IV) nivolumab every 2 weeks for 12 doses plus placebo every 6 weeks for 4 doses (n = 411), IV placebo every 2 weeks for 12 doses plus placebo every 6 weeks for 4 doses (n = 208), or 240 mg of IV nivolumab every 2 weeks for 12 doses plus ipilimumab every 6 weeks for 4 doses (n = 206). Randomization occurred between 4 and 12 weeks after surgery.

Stratification factors included pathologic TNM staging and type of nephrectomy.

Secondary endpoints for this trial included DFS for nivolumab/ipilimumab vs nivolumab alone, OS for nivolumab vs placebo and nivolumab/ipilimumab vs nivolumab alone, and safety. An exploratory outcome was health-related quality of life. The data cutoff date was September 8, 2023.

The median ages of patients in the nivolumab monotherapy, placebo, and nivolumab/ipilimumab arms were 59 years (range, 25-86), 59 years (range, 25-80), and 60 years (range, 29-81), respectively. Ninety-three percent, 93%, and 94% of patients in each respective arm had a radical nephrectomy. In addition, most patients had pathological TNM staging of pT3, G any, N0 M0 at 82%, 81%, and 82%, respectively. Most patients also had a PD-L1 expression of less than 1% or not evaluable (85%, 89%, and 86%, respectively).

The median duration of therapy for all 3 arms was 5.1 months (range, <0.1-8.3). Overall, 327, 182, and 118 patients completed treatment in each respective arm. Discontinuations occurred in 20% of the nivolumab-alone arm, 12% of the placebo arm, and 42% of the combination arm; 11%, 1%, and 31% of patients discontinued due to study drug toxicity, respectively.

All-grade treatment-related adverse events (TRAEs) occurred in 73% of patients in the monotherapy arm, 52% of patients in the placebo arm, and 85% in the combination arm. Grade 3/4 TRAEs occurred in 9%, 2%, and 20% of patients in each respective arm. No patients died due to study drug toxicity.

The most common all-grade TRAEs in the nivolumab monotherapy, placebo, and combination arm, respectively, were pruritus (21% vs 15% vs 25%), fatigue (19% vs 16% vs 22%), hyperthyroidism (11% vs 1% vs 16%), hypothyroidism (11% vs 3% vs 21%), diarrhea (11% vs 9% vs 19%), rash (10% vs 6% vs 17%), asthenia (9% vs 8% vs 8%), arthralgia (8% vs 8% vs 11%), myalgia (5% vs 6% vs 9%), nausea (5% vs 5% vs 7%), headache (5% vs 3% vs 4%), alanine aminotransferase increase (5% vs 1% vs 10%), and maculopapular rash (5% vs <1% vs 7%).

Motzer noted that 6% of patients in the nivolumab monotherapy arm required corticosteroids to manage any-grade immune-mediated AEs vs 2% in the placebo arm and 19% in the nivolumab/ipilimumab arm.

The mean changes from FKSI-19 and EQ-5D-3L baseline scores were similar in both treatment arms and were not found to be meaningful.

References

1. Bex A, Russo P, Tomita Y, et al. A phase III, randomized, placebo-controlled trial of nivolumab or nivolumab plus ipilimumab in patients with localized renal cell carcinoma at high-risk of relapse after radical or partial nephrectomy (CheckMate 914). J Clin Oncol. 2024;42(suppl; abstr LBA358). doi:10.1200/jco.2020.38.15_suppl.tps5099
2. Motzer RJ, Russo P, Grünwald 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;401(10379):821-832. doi:10.1016/S0140-6736(22)02574-0.