Combined immunotherapy improves survival in metastatic melanomaBMJ 2015; 350 doi: https://doi.org/10.1136/bmj.h2993 (Published 02 June 2015) Cite this as: BMJ 2015;350:h2993
A combination of two immunotherapy agents acting on different steps in activation of the immune system considerably improves the time to disease progression in patients with previously untreated metastatic melanoma when compared with either drug alone, first study to investigate this dual approach has shown.
The international study, reported in the New England Journal of Medicine,1 randomly assigned 945 patients with unresectable stage III or IV melanoma to treatment with either nivolumab alone, nivolumab plus ipilimumab, or ipilimumab alone.
Results showed that median progression-free survival was 11.5 months (95% confidence interval 8.6 to 16.7 months) with combination therapy, which was nearly twice as long as with nivolumab alone (6.9 months (4.3 to 9.5)). Median progression-free survival with ipilimumab was 2.9 months (2.8 to 3.4).
The two agents block two different immune checkpoints that prevent the immune system from recognising and destroying cancer cells. Nivolumab is a programmed death 1 (PD-1) checkpoint inhibitor, which blocks the interaction between excess PD-L1 receptors expressed by tumour cells and PD-1 receptors on T cells, enabling them to bind and kill tumour cells. Ipilimumab, which has been used to treat melanoma for some time, inhibits anti-cytotoxic T lymphocyte associated antigen 4 (CTLA-4) to lift the brake that it puts on anti-tumour immunity.
Researchers measured the expression of PD-1 ligand (PD-L1) in tumour tissues from patients taking part in the study. They found that the median progression-free survival was similar with combination immunotherapy or with nivolumab alone (both 14.0 months) in patients with tumours that were positive for this ligand. But patients expressing low levels of PD-L1 (<5%) had longer progression-free survival with the combination (11.2 months (8.0 to not yet reached)) than with nivolumab monotherapy (5.3 months (2.8 to 7.1)).
“Nivolumab alone and in combination with ipilimumab significantly improved progression-free survival and overall response rate compared to ipilimumab alone in patients with previously untreated melanoma,” reported Jedd Wolchok, lead author, from the Memorial Sloan Kettering Cancer Center in New York, USA. He added, “The combination represents a means to improve outcomes compared to nivolumab alone, particularly for patients whose tumours have less than 5% PD-L1 expression.” He said that the use of PD-L1 as a biomarker may allow more informed decisions about the benefit-risk ratio of the combination versus monotherapy.
Serious adverse events (grade 3 or 4) related to treatment were more common with the combination therapy, affecting 55% of patients, compared with 16.3% of patients treated with nivolumab and 27.3% of those in the ipilimumab group.
Cite this as: BMJ 2015;350:h2993