Nivolumab Beats Chemotherapy as Second-Line Treatment for Advanced Melanoma

Jeffrey S. Weber, MD, PhD

Treatment with nivolumab (Opdivo) demonstrated superior objective response rates (ORR) and longer durations of response compared with chemotherapy in a phase III trial of patients with previously treated advanced metastatic melanoma, reported Jeffrey Weber, MD, at the 2014 ESMO Congress.

Nivolumab is a fully human IgG4 PD-1 immune checkpoint inhibitor antibody with durable antitumor activity. Patients in the trial were previously treated with anti-CTLA-4 therapy with ipilimumab and a BRAF inhibitor, if they were positive for a BRAF mutation. In phase I trials of pretreated patients with metastatic melanoma, nivolumab induced tumor regression and showed promise in extending overall survival (OS), with OS rates of 63%, 48%, and 41% at 1-, 2-, and 3-years, respectively.

“Nivolumab is superior to chemotherapy for patients that have failed prior ipilimumab, and in my view, should replace chemotherapy in routine practice as second-line or even third-line therapy in melanoma,” said Weber, the director of the Donald A. Adam Comprehensive Melanoma Research Center of Excellence at the Moffitt Cancer Center, Tampa. “The idea is that an antibody that can block the interaction between PD-1 and its ligand PD-L1 might allow the immune system to proceed in an unfettered manner and cause tumor regression.”

The open-label phase III trial included 405 patients with advanced melanoma whose disease progressed after treatment with ipilimumab and, if their tumor was positive for the BRAF V600 mutation, a BRAF inhibitor. Patients were randomized in a 2:1 ratio to either intravenous nivolumab at 3 mg/kg every other week or the investigator’s choice of chemotherapy (either dacarbazine at 1,000 mg/m² or intravenous carboplatin at AUC6 plus paclitaxel at 175 mg/m² administered every 3 weeks).

Treatment continued until progression of disease or unacceptable toxicity. The primary endpoints were ORR and OS. Results were stratified by PD-L1 expression, BRAF status, and best overall response to anti-CTLA-4 therapy. PD-L1 positivity was defined as ≥5% tumor cell membrane staining measured using a proprietary immunohistochemistry assay.

A planned preliminary assessment of ORR was based on the first 120 nivolumab- and 47 chemotherapy-treated patients with at least 6 months of follow-up. In this preliminary analysis, using RECIST v1.1 by central review, ORR was 32% in the nivolumab arm versus 11% in the chemotherapy arm. With nivolumab, the complete response rate was 3%, partial response rate was 28%, and 23% of patients experienced stable disease.

The median time to response favored nivolumab at 2.1 months compared with 3.5 months in the chemotherapy arm. Treatment responses were also longer-lasting in the nivolumab arm. The median duration of response was 3.6 months in the chemotherapy and had not been reached in the nivolumab arm. “The vast majority of responders [95%] who stayed in remission got nivolumab,” Weber said.

Responses with nivolumab were observed regardless of pretreatment PD-L1 expression status, BRAF mutation status, and prior anti-CTLA-4 benefit.

“A patient with a BRAF mutation who has rapidly progressing disease on an anti-CTLA-4 antibody will most likely be treated with a BRAF inhibitor,” said Weber. “For the patient with a BRAF mutation and slow-growing disease, who tend to do well over the long term, the choice between a BRAF inhibitor or an anti-PD-1 agent as second-line therapy is less clear.”

In patients with BRAF-mutated melanoma, the ORR was 23% with nivolumab compared with 9% for chemotherapy. In BRAF wild-type patients, the ORR was 34% with nivolumab versus 11% with chemotherapy. Patients with PD-L1 positive tumors (n = 77) experienced an ORR of 44% versus 20% for PD-L1-negative.

“In terms of side effects and toxicity, there was a clear edge to nivolumab,” said Weber.

The rates of drug-related grade 3/4 adverse events were 9% in the nivolumab arm compared with 31% in the chemotherapy arm. The rates of treatment-related adverse events that led to discontinuation also favored nivolumab over chemotherapy (2% vs. 8%). Serious drug-related adverse events of any grade occurred in 6% of nivolumab-treated patients compared with 10% with chemotherapy.

“I hope this is, at least for second- and third-line therapy, the death knell for chemotherapy in melanoma,” said Weber. “You can get occasional responses with chemotherapy…and I hope this puts to rest that it should be a comparator arm in a large study. That’s good for patients.”

Weber J, Minor D, D'Angelo SP, et al. A phase 3 randomized, open-label study of nivolumab (anti-PD-1; BMS-936558; ONO-4538) versus investigator’s choice chemotherapy (ICC) in patients with advanced melanoma with prior anti-CTLA-4 therapy. Presented at: ESMO 2014 Congress; September 26-30, 2014; Madrid, Spain. Abstract LBA3.

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