Combination immunotherapy boosts survival in advanced melanoma

By Nicola Garrett

2 Oct 2019

A combination of ipilimumab and nivolumab has a significant impact on the five year median overall survival and progression free survival of patients with advanced melanoma compared to either drug alone, the latest analysis from CheckMate 067 shows.

The Phase III study randomised 945 patients with previously untreated stage III or IV melanoma in a 1:1:1 ratio to 1) nivolumab plus ipilimumab; 2) nivolumab plus placebo; or 3) ipilimumab plus placebo until progression or unacceptable toxicity. Each nivolumab arm was compared to ipilimumab monotherapy.

Results showed that the median overall survival was more than 60.0 months (median not reached) in patients receiving  nivolumab-plus-ipilimumab and 36.9 months in those receiving nivolumab alone.

This compared with 19.9 months in the ipilimumab group (hazard ratio for death with nivolumab plus ipilimumab vs. ipilimumab, 0.52; hazard ratio for death with nivolumab vs. ipilimumab, 0.63).

Overall survival at 5 years was 52% in the nivolumab-plus-ipilimumab group and 44% in the nivolumab group, as compared with 26% in the ipilimumab group.

Median progression-free survival was 11.5 months in the nivolumab-plus-ipilimumab group, 6.9 months  in the nivolumab group, and 2.9 months in the ipilimumab group.

Five-year progression-free survival was 36%, 29%, and 8% in the nivolumab-plus-ipilimumab, nivolumab, and ipilimumab groups, respectively.

The trial was presented here at ESMO congress 2019 and published simultaneously in the NEJM

Study author Professor James Larkin, Royal Marsden NHS Foundation Trust, London, UK said the results were a major improvement on what had been seen historically.

“Ten years ago, the five-year survival for melanoma was around 5%. With ipilimumab monotherapy, which has been used for around ten years, around 20% of patients are long-term survivors and the remainder live for just six to nine months,” he said.

A total of 46%, 59%, and 75% of all patients who were randomly assigned to nivolumab plus ipilimumab, nivolumab, and ipilimumab, respectively, received subsequent systemic therapy.

Excluding patients who died and had not received subsequent therapy, the median time from randomization to subsequent systemic therapy was more than 60.0 months (median not reached) in the nivolumab-plus-ipilimumab group, 25.2 months in the nivolumab group, and 8.0 months in the ipilimumab group

“We know that the two immunotherapy drugs together can have significant side-effects and some patients even need to discontinue treatment,” said Larkin.

“But for those patients who did stop treatment because of side-effects, it did not impair the success of the therapy.

Commenting on the trial results, Dr Teresa Amaral, Centre for Dermato-oncology, Eberhard Karls University Tuebingen, Germany, noted that the difference in overall survival rates between the nivolumab arms had steadily increased with each year of follow-up and was now 8%. For the large subgroup of patients with a BRAF mutation the five-year overall survival rates were 30% with ipilimumab, 46% with nivolumab, and 60% with nivolumab plus ipilimumab.

“When the BRAF mutation is present, clinicians need to decide whether individual patients are best served with immunotherapy or targeted therapy,” she said.

“While this study was not powered to compare the nivolumab arms, the results suggest that if patients harbouring a BRAF mutation are to receive immunotherapy, they might derive greater benefit with combination immunotherapy.

Caution is needed when comparing the results to other trials, but the five-year overall survival rate with combined targeted therapy in the COMBI-d and COMBI-v trials was 34%.”

“Further research is needed to identify the patients who are resistant to immunotherapy and will not derive any benefit. This is important not only because of the toxicity related to the therapy but also for the most effective use of resources,” she added.

The trial was funded by Bristol Myers Squibb.


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