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Long-Term Outcomes of Treatment With Nivolumab Plus Ipilimumab in Patients With Advanced Melanoma
abstract
This abstract is available on the publisher's site.
Access this abstract nowBACKGROUND
Previous results from this trial showed longer overall survival after treatment with nivolumab plus ipilimumab or with nivolumab monotherapy than with ipilimumab monotherapy in patients with advanced melanoma. Given that patients with advanced melanoma are living longer than 7.5 years, longer-term data were needed to address new clinically relevant questions.
METHODS
We randomly assigned patients with previously untreated advanced melanoma, in a 1:1:1 ratio, to one of the following regimens: nivolumab (1 mg per kilogram of body weight) plus ipilimumab (3 mg per kilogram) every 3 weeks for four doses, followed by nivolumab (3 mg per kilogram) every 2 weeks; nivolumab (3 mg per kilogram) every 2 weeks plus placebo; or ipilimumab (3 mg per kilogram) every 3 weeks for four doses plus placebo. Treatment was continued until the occurrence of disease progression, unacceptable toxic effects, or withdrawal of consent. Randomization was stratified according to BRAF mutation status, metastasis stage, and programmed death ligand 1 expression. Here, we report the final, 10-year results of this trial, including results for overall survival and melanoma-specific survival, as well as durability of response.
RESULTS
With a minimum follow-up of 10 years, median overall survival was 71.9 months with nivolumab plus ipilimumab, 36.9 months with nivolumab, and 19.9 months with ipilimumab. The hazard ratio for death was 0.53 (95% confidence interval [CI], 0.44 to 0.65) for nivolumab plus ipilimumab as compared with ipilimumab and was 0.63 (95% CI, 0.52 to 0.76) for nivolumab as compared with ipilimumab. Median melanoma-specific survival was more than 120 months with nivolumab plus ipilimumab (not reached, with 37% of the patients alive at the end of the trial), 49.4 months with nivolumab, and 21.9 months with ipilimumab. Among patients who had been alive and progression-free at 3 years, 10-year melanoma-specific survival was 96% with nivolumab plus ipilimumab, 97% with nivolumab, and 88% with ipilimumab.
CONCLUSIONS
The final trial results showed a continued, ongoing survival benefit with nivolumab plus ipilimumab and with nivolumab monotherapy, as compared with ipilimumab monotherapy, in patients with advanced melanoma. (Funded by Bristol Myers Squibb and others; CheckMate 067 ClinicalTrials.gov number, NCT01844505.).
Additional Info
Disclosure statements are available on the authors' profiles:
Final, 10-Year Outcomes with Nivolumab plus Ipilimumab in Advanced Melanoma
N. Engl. J. Med 2024 Sep 15;[EPub Ahead of Print], JD Wolchok, V Chiarion-Sileni, P Rutkowski, CL Cowey, D Schadendorf, J Wagstaff, P Queirolo, R Dummer, MO Butler, AG Hill, MA Postow, C Gaudy-Marqueste, T Medina, CD Lao, J Walker, I Márquez-Rodas, JBAG Haanen, M Guidoboni, M Maio, P Schöffski, MS Carlino, S Sandhu, C Lebbé, PA Ascierto, GV Long, C Ritchings, A Nassar, M Askelson, MP Benito, W Wang, FS Hodi, J LarkinFrom MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
The final 10-year analysis of the seminal CheckMate 067 study1 by Wolchok et al reflects the huge impact of this pivotal trial, which has clearly established the current benchmark for first-line treatment in advanced (unresectable stage III or metastatic stage IV) melanoma.
The study compared the outcomes of patients treated with either single-agent nivolumab (NIVO; 3 mg/kg every 2 weeks) plus placebo or the combination of ipilimumab (IPI; 3 mg/kg) and NIVO (1 mg/kg) every 3 weeks for four doses (IPI-NIVO), followed by NIVO maintenance (3 mg/kg every 2 weeks) or the comparator of single-agent IPI (3 mg/kg every 3 weeks) for four doses plus placebo. The study was only designed to compare NIVO with IPI and IPI-NIVO with IPI and did not allow a comparison of IPI-NIVO with NIVO.
The main findings, which had already been shown previously, demonstrated the statistically significant benefit of either NIVO-containing regimen (both single-agent and combination) versus IPI. There was a numerical benefit of IPI-NIVO over NIVO alone. The 10-year results show this sustained benefit; the 10-year melanoma-specific survival (MSS) rate was 52% with IPI-NIVO, 44% with NIVO, and 23% with IPI.
Interestingly, several new observations were made. First of all, the overall survival rates were 43%, 37%, and 19%, respectively, indicating that patients are now starting to die from other causes after surviving their advanced melanoma diagnosis. Second, patients who were free from progression within the first 3 years hardly ever died of melanoma later (10-year MSS rate of 97%–96%), indicating these patients have a high likelihood of cure. Third and final, among patients who developed grade 3/4 adverse events, the 10-year MSS rate was 71% with NIVO versus 54% with IPI-NIVO, suggesting that patients in the combination therapy arm were treated with more significant immunosuppression when these adverse events occurred, potentially nullifying the immune response.
In conclusion, the final 10-year results from CheckMate 067 confirm that nearly 50% of patients with advanced melanoma can be cured with combination immunotherapy with IPI-NIVO, which is now the first-line standard-of-care option for these patients. The challenge is to identify the best second-line options for patients with refractory disease and/or to improve upon this benchmark in the first line.
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