The phase 3 CheckMate 914 clinical trial missed one of its primary endpoints of improved disease-free survival (DFS) with Opdivo (nivolumab) compared with placebo in patients with localized renal cell carcinoma at high risk of relapse after nephrectomy (removal of the kidney), according to findings from part B of the trial that were presented at the 2024 Genitourinary Cancers Symposium.
At a median follow-up of 27 months, the median DFS, which is the time patients live without progression or complications from their cancer, was not reached in either the Opdivo arm or the placebo arm. The 18-month DFS rates by blinded review were 78.4% in the Opdivo arm and 75.4% in the placebo arm. There was no statistically significant difference among the two DFS rates, meaning that the researchers could not say with certainty that one truly outperformed the other.
When evaluated by researchers, the median DFS was also not reached in either arm, 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; time from treatment until death of any cause) analysis will be performed, lead study author, Dr. Robert J. Motzer, said in an oral presentation during the meeting.
However, patient subgroups that favored Opdivo vs placebo included patients with sarcomatoid features, PD-L1 expression of 1% or greater, and those with a lower limit of normal hemoglobin at baseline.
“Subgroup analysis from CheckMate 914 part A, which has been published previously, and presented previously, and part B suggest that there are tumor-specific characteristics that may influence outcomes for adjuvant (Opdivo) plus (Yervoy [ipilimumab]) and (Opdivo) 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 Opdivo plus Yervoy compared with placebo in patients with surgically resected stage 2/3 clear cell RCC with a high risk of relapse. At a median follow-up of 37 months, part A did not meet the primary endpoint of DFS for the treatment combination, with a median DFS of NR with Opdivo/Yervoy and 50.7 months with placebo. The 18-month DFS rates were 78.8% and 76.6%, respectively.
Part B of the double-blind, 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, indicating that they can perform all of most of their daily tasks independently.
Patients were randomly assigned to receive either 240 mg of intravenous (IV) Opdivo every two weeks for 12 doses plus placebo every six weeks for four doses (411 patients), IV placebo every two weeks for 12 doses plus placebo every six weeks for four doses (208 patients), or 240 mg of IV Opdivo every two weeks for 12 doses plus Yervoy every six weeks for four doses (206 patients). Randomization occurred between 4 and 12 weeks after surgery.
Patients were analyzed in groups based on the stage of their disease and the type of nephrectomy they underwent.
Secondary endpoints for this trial included DFS for Opdivo/Yervoy versus Opdivo alone, OS for Opdivo versus placebo and Opdivo/Yervoy versus Opdivo alone, and safety. An exploratory outcome was health-related quality of life. The data cutoff date was Sept. 8, 2023.
The median ages of patients in the Opdivo monotherapy, placebo, and Opdivo/Yervoy 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 three 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 Opdivo-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 side effects 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 (moderate to severe) side effects 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 side effect in the Opdivo monotherapy, placebo, and combination arm, respectively, were itching (21% versus 15% versus 25%), fatigue (19% versus 16% versus 22%), hyperthyroidism (11% versus 1% versus 16%), hypothyroidism (11% versus 3% versus 21%), diarrhea (11% versus 9% versus 19%), rash (10% versus 6% versus 17%), weakness (9% versus 8% versus 8%), joint pain (8% versus 8% versus 11%), muscle aches/pain (5% versus 6% versus 9%), nausea (5% versus 5% versus 7%), headache (5% versus 3% versus 4%), alanine aminotransferase increase, which could indicate liver disease (5% versus 1% versus 10%), and maculopapular rash (5% versus <1% versus 7%).
Motzer noted that 6% of patients in the Opdivo monotherapy arm required corticosteroids to manage any grade immune-mediated side effects, compared with 2% in the placebo arm and 19% in the nivolumab/ipilimumab arm.
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