Advanced Melanoma Nivolumab–Ipilimumab Survival Benefit Lasts For 5 years

medwireNews: Five-year trial results confirm that combining nivolumab with ipilimumab significantly improves the long-term overall survival (OS) of patients with stage III or IV melanoma, the CheckMate 067 investigators reported at the ESMO 2019 Congress in Barcelona, Spain.  

“The current results of the CheckMate 067 trial set a new foundation on which to make improvements in long-term efficacy outcomes with the combination of nivolumab plus ipilimumab”, summarise the researchers in a simultaneously published article in The New England Journal of Medicine. 

After a minimum of 60 months of follow-up, median OS was more than 60 months for the 314 patients with treatment-naïve unresectable or metastatic disease who were randomly assigned to receive nivolumab 1 mg/kg plus ipilimumab 3 mg/kg every 3 weeks for four doses, followed by nivolumab 3 mg/kg every 2 weeks. 

“Nivolumab plus ipilimumab is […] currently the only treatment for metastatic melanoma for which median overall survival has not been reached at 5 years”, the investigators emphasize, noting that the OS curve plateaued at around 3 years. 

This duration of OS was significantly longer than the median 36.9 months for the 316 patients who were given nivolumab 3 mg/kg every 2 weeks plus placebo and the 19.9 months for the 315 patients who instead received four cycles of ipilimumab 3 mg/kg every 3 weeks plus placebo.  

The hazard ratios (HRs) for death were 0.83 and 0.52 in favour of combination therapy versus nivolumab or ipilimumab alone, while the HR was 0.63 in favour of nivolumab over ipilimumab monotherapy, report presenting author James Larkin, from the Royal Marsden NHS Foundation Trust in London, UK, and co-workers. 

Median progression-free survival in the combination, nivolumab and ipilimumab arms was 11.5, 6.9 and 2.9 months, respectively, with HRs for progression or death of 0.79 for combination treatment versus nivolumab, 0.42 for combination treatment versus ipilimumab and 0.53 for nivolumab versus ipilimumab, all of which were significant. 

The 5-year rate of OS with nivolumab plus ipilimumab was 52%, reducing to 44% with nivolumab and 26% with ipilimumab, while 5-year PFS rates were 36%, 29% and 8%, respectively. 

Toxicity was comparable with earlier results for the study, with grade treatment-related 3–4 events occurring in 59%, 23% and 28% of the combination, nivolumab and ipilimumab arms; there were no new toxicity-related deaths or long-term adverse events. 

Furthermore, EQ-5D-3L results indicate that patients taking nivolumab–ipilimumab or nivolumab did not experience a “sustained deterioration of health-related quality of life” during or after treatment, whereas this outcome was more common in patients taking ipilimumab monotherapy. 

Overall, 46% of the combination group received systematic therapy after discontinuing nivolumab–ipilimumab, 21% radiotherapy and 21% surgery. The corresponding rates for the nivolumab group were 59%, 29% and 23%, and for the ipilimumab arm 75%, 40% and 30%. The median time to subsequent treatment for survivors was more than 60 months (unreached), 25 and 8 months, respectively. 

James Larkin et al therefore conclude: “Among patients with advanced melanoma, sustained long-term overall survival at 5 years was observed in a greater percentage of patients who received nivolumab plus ipilimumab or nivolumab alone than in those who received ipilimumab alone, with no apparent loss of quality of life in the patients who received regimens containing nivolumab.” 

References 

Larkin JMG, Chiarion-Sileni V, Gonzalez R, et al. 5-year survival outcomes of the CheckMate 067 phase 3 trial of nivolumab plus ipilimumab (NIVO+IPI) combination therapy in advanced melanoma. ESMO 2019 Congress; Barcelona, Spain: 27 September – 1 October. LBA68_PR 

Larkin J, Chiarion-Sileni V, Gonzalez R, et al. Five-year survival with combined nivolumab and ipilimumab in advanced melanoma. N Engl J Med; Advance online publication 28 September 2019. DOI: 10.1056/NEJMa1910836.