Adjuvant Nivolumab Plus Ipilimumab Combination Does Not Improve RFS Over Nivolumab Alone in Patients with Stage IIIB-D or IV Melanoma

In a randomised, double-blind, phase III CheckMate 915 study, adjuvant nivolumab 240 mg once every 2 weeks plus ipilimumab 1 mg/kg once every 6 weeks did not improve recurrence-free survival (RFS) compared with nivolumab 480 mg once every 4 weeks in patients with resected stage IIIB-D or IV melanoma in the all randomised population or in patients with tumour PD-L1 expression < 1%. The safety and tolerability of both treatments were consistent with their known safety profiles. Health-related quality of life was comparable in both arms, with no clinically meaningful changes from baseline. The findings are published by Dr. Jeffrey S. Weber of the Laura and Isaac Perlmutter Cancer Center, NYU Langone Health in New York, NY, US and colleagues on 26 September 2022 in the Journal of Clinical Oncology.

The authors wrote in the study background that previous studies demonstrated that adjuvant nivolumab and ipilimumab each provide clinical benefit in patients with resected stage III or IV melanoma. The phase III CheckMate 915 study compared nivolumab 240 mg once every 2 weeks plus ipilimumab 1 mg/kg once every 6 weeks with nivolumab monotherapy 480 mg once every 4 weeks as adjuvant treatment for ≤ 1 year in patients with completely resected stage IIIB-D or IV melanoma. This dosing was designed to optimise adjuvant treatment benefit and risk profiles.

CheckMate 915 dual primary endpoints were RFS in the all randomised population and in patients with tumour PD-L1 expression < 1%. A total, 916 patients received nivolumab 240 mg once every 2 weeks plus ipilimumab 1 mg/kg once every 6 weeks and 917 patients received nivolumab 480 mg once every 4 weeks for ≤ 1 year. After random assignment, patients were stratified by tumour PD-L1 expression and stage.

At a minimum follow-up of approximately 23.7 months, there was no significant difference between treatment groups for RFS in the all randomly assigned patient population (hazard ratio [HR] 0.92; 95% confidence interval [CI] 0.77 to 1.09; p = 0.269) or in patients with PD-L1 expression < 1% (HR 0.91; 95% CI 0.73 to 1.14). In all patients, 24-month RFS rates were 64.6% in the combination arm and 63.2% in the nivolumab alone arm.

Treatment-related grade 3 or 4 adverse events were reported in 32.6% of patients in the combination arm and 12.8% in the nivolumab arm. Treatment-related deaths were reported in 0.4% of patients in the combination arm and in no patients treated with nivolumab alone.

These results reaffirm nivolumab as a standard of care for adjuvant treatment of melanoma. The authors commented that combination dosing in the adjuvant setting requires further refinement and investigation to determine the optimal balance between benefit and side effects.

In an accompanied editorial article, Ryan C. Augustin and Jason J. Luke of the UPMC Hillman Cancer Center and Department of Medicine, University of Pittsburgh in Pittsburgh, PA, US wrote that CheckMate 915 data emphasise the need for optimisation of ipilimumab dose and schedule as monotherapy, but particularly in combination with anti–PD1. The cumulative ipilimumab induction dose used in this study was too low and seemingly negated the potential benefits of combination treatment. These results call also into question ipilimumab dosing regimens in other cancers pursuing administration at intervals longer than 3 weeks, e.g. in non-small cell lung cancer and mesothelioma.

The CheckMate 915 study was supported by Bristol Myers Squibb.

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