Research in context
Evidence before this study
To identify other studies of inhibitors of PD-1 or PD-L1 in advanced cancers, including melanoma, we did a detailed search of PubMed and congress abstracts from the annual meetings of the American Society of Clinical Oncology, European Society of Medical Oncology/European Cancer Congress, and Society for Melanoma Research, between Jan 1, 2010 and Jan 13, 2015. We used the search terms “PD-1”, “PD-L1”, “nivolumab”, “MK-3475”, “pembrolizumab”, “lambrolizumab”, “MPDL3280A”, and “MEDI4736”. Our search identified several non-randomised, non-controlled phase 1/2 studies with promising levels of antitumour response for PD-1 and PD-L1 inhibitors in patients with advanced solid tumours, including melanoma. Although these data suggest activity for PD-1 inhibition in patients with melanoma that have progressed after ipilimumab and BRAF inhibitors, the sample sizes were too small to allow firm conclusions to be drawn on the efficacy and safety of PD-1 inhibition. Our review identified only one randomised, controlled, phase 3 study comparing an anti-PD-1 drug (nivolumab) with dacarbazine, but this study was done in treatment-naive patients who had BRAF wild-type tumours.
Added value of this study
For the patient population investigated in this study, treatment options are very restricted, and no prospective, randomised, controlled trial comparing an anti-PD-1 drug with any approved treatment has been done. Our data show that nivolumab led to clinically meaningful improvements in the proportion of patients achieving an objective response and provided a manageable safety profile when compared with chemotherapy.
Implications of all the available evidence
Nivolumab can now be deemed a new treatment option for patients that have progressed after ipilimumab, or a BRAF inhibitor and ipilimumab if their melanoma is BRAFV600-mutated. These data resulted in the accelerated approval of nivolumab by the US Food and Drug Administration for this indication in December, 2014.