From the Journals

Nivolumab-ipilimumab nets long-term survival in advanced melanoma



Combination therapy with the immune checkpoint inhibitors nivolumab and ipilimumab has durable efficacy in patients with untreated advanced melanoma, with more than half still alive at 5 years and almost three-fourths of them no longer on any treatment, found an update of the CheckMate 067 trial. The combination also had a manageable safety profile and generally maintained health-related quality of life in the long term.

“The apparent plateau with nivolumab plus ipilimumab has continued with longer follow-up … nivolumab plus ipilimumab is … currently the only treatment for metastatic melanoma for which median overall survival has not been reached at 5 years,” noted the investigators, led by James Larkin, FRCP, PhD, a consultant medical oncologist at the Royal Marsden National Health Service Foundation Trust, London. “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.”

The phase 3, randomized, controlled trial pitted nivolumab (Opdivo) plus ipilimumab (Yervoy) combination therapy and nivolumab monotherapy against ipilimumab monotherapy among 945 adults with previously untreated or unresectable metastatic melanoma. Initial results at a median follow-up of about 1 year showed a progression-free survival benefit of the nivolumab regimens (N Engl J Med. 2015;373:23-34), a pattern that has persisted in updates and has been augmented by an overall survival benefit, as seen most recently at a median follow-up of about 4 years (Lancet Oncol. 2018;19:1480-92).

Dr. Larkin and colleagues performed another update, now at a minimum follow-up of 5 years in all patients. This update additionally looked at subsequent therapies and health-related quality of life.

Results reported in the New England Journal of Medicine showed that median overall survival was now 19.9 months with ipilimumab. In comparison, it was not reached with nivolumab-ipilimumab (hazard ratio for death, 0.52) and was 36.9 months with nivolumab alone (HR, 0.63). The 5-year overall survival rate was 26%, compared with 52% and 44%, respectively.

In all groups, complete response rates continued an increase seen since the trial’s initial results were reported. “[T]his indicates that the best response can improve over time with immune checkpoint inhibitors,” Dr. Larkin and coinvestigators maintained.

“The treatment-free interval continued to lengthen in the nivolumab-plus-ipilimumab group, and the percentage of patients who were alive and not receiving treatment continued to increase across the groups,” they further noted. As of the update, the median treatment-free interval was 18.1 months with nivolumab-ipilimumab, 1.8 months with nivolumab, and 1.9 months with ipilimumab. The percentage of those alive who were not receiving any trial treatment or subsequent systemic therapy was 74%, 58%, and 45%, respectively.

Meanwhile, the data did not show any new safety signals. And health-related quality of life, measured with European Quality of Life 5-Dimensions 3-Level questionnaire, was generally sustained during and after treatment, with limited fluctuations outside a 0.08-point clinically meaningful boundary, in the combination-therapy group and the nivolumab group, whereas it deteriorated more often in the ipilimumab group.

Dr. Larkin disclosed grants and personal fees from numerous pharmaceutical companies. The trial was supported by Bristol-Myers Squibb, a grant from the National Cancer Institute, and a grant (to Dr. Larkin) from the National Institute for Health Research Royal Marsden–Institute of Cancer Research Biomedical Research Centre.

SOURCE: Larkin J et al. N Engl J Med. 2019 Sep 28. doi: 10.1056/NEJMoa1910836.

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