MADRID – The investigational anti-PD-1 drug nivolumab bested investigator’s choice of chemotherapy in pretreated advanced melanoma in the phase III CheckMate-037 trial.
The coprimary end point of objective response rate by central review was 32% with nivolumab vs. 11% with investigator’s choice chemotherapy among patients with unresectable metastatic melanoma that progressed despite prior ipilimumab or a BRAF inhibitor, if BRAF mutation-positive.
The median duration of response for chemotherapy was 3.6 months, but has not been reached with nivolumab. Five patients on chemotherapy continue to respond, whereas 95% of nivolumab responders (36/38) continue in remission with a minimum follow-up of 24 weeks, Dr. Jeffrey Weber reported during a presidential symposium at the European Society for Medical Oncology Congress.
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Nivolumab should replace chemotherapy for second-line or even third-line melanoma, said Dr. Jeffrey Weber.
Grade 3-4 treatment-related adverse events also were significantly lower with nivolumab than with chemotherapy (9% vs. 31%), as were toxicity-related treatment discontinuations (2% vs. 8%).
“Overall nivolumab was superior to chemotherapy in terms of toxicity and response rate in patients that fail prior ipilimumab and in my view should replace chemotherapy in practice for second-line or even third-line melanoma,” said Dr. Weber, director of the Donald A. Adam Comprehensive Melanoma Research Center of Excellence, Moffitt Cancer Center, Tampa, Fla.
Survival data are pending, but the impressive data on duration of response suggest there will be significant prolongation of progression-free and overall survival with the programmed death (PD)-1 blocking antibody when the analysis of those data is mature, Dr. Weber said in a statement.
Nivolumab is under priority review with the Food and Drug Administration and accelerated assessment with the European Medicines Agency based on these data. The drug is already approved for unresectable melanoma in Japan, where it is sold under the trade name Opdivo.
Dr. Weber told reporters in a press briefing that he rarely uses chemotherapy in his practice for patients with melanoma. This sentiment was echoed by invited discussant Ignacio Melero of the University of Navarra, Pamplona, Spain. “The trends that one can foresee are that we will be moving PD-1 blockade up front in treatment and will probably get rid of chemotherapy or save it as a last-ditch effort,” said Dr. Melero.
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"We will be moving PD-1 blockade up front" and saving chemotherapy "as a last-ditch effort", said Dr. Ignacio Melero.
He added that the “best is yet to come,” and that this is particularly true about immunotherapy combinations. Dr. Melero highlighted recent phase I data for pembrolizumab (Keytruda), which just gained approval in September as the first PD-1 checkpoint inhibitor in the United States in advanced melanoma. The overall response rate with pembrolizumab was in the same range as nivolumab at 26% and overall survival was “impressive,” with the median not yet reached after 14 months in patients who also had ipilimumab-refractory advanced melanoma (Lancet 2014;384:1109-17).
CheckMate-037 randomized 405 patients in a 2:1 fashion to intravenous nivolumab 3 mg/kg or investigator’s choice of chemotherapy regimens: dacarbazine 1,000 mg/m2 or carboplatin AUC 6 plus paclitaxel 175 mg/m2 . Response data were based on 120 patients in the nivolumab and 47 in the chemotherapy arm, and safety data were based on the entire population. The best overall response in the nivolumab arm was complete response in 3%, partial response in 28%, and stable disease in 23%, compared with 0%, 11%, and 34%, respectively, in the chemotherapy arm.
Subgroup analysis revealed consistently higher clinical activity with nivolumab regardless of pretreatment PD-ligand 1 expression status, BRAF mutation status, or prior ipilimumab benefit, Dr. Weber said.
Ten patients (8%) given nivolumab had an immune-related response pattern involving 30% or more reduction in target lesion tumor burden.
Dr. Weber reported serving on the advisory board for Genentech, Merck, and the study sponsor, Bristol-Myers Squibb. His institution also receives research funding from BMS and Genentech.