FDA Approves Nivolumab for Advanced Melanoma


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The FDA has approved the PD-1 inhibitor nivolumab for patients with unresectable or metastatic melanoma following treatment with ipilimumab or a BRAF inhibitor.

Richard Pazdur, MD

The FDA has approved the PD-1 inhibitor nivolumab (Opdivo) for patients with unresectable or metastatic melanoma following treatment with ipilimumab or a BRAF inhibitor, based on data from the phase III CheckMate-037 trial.

In the study, the fully human IgG4 monoclonal antibody nivolumab demonstrated an overall response rate (ORR) of 32% compared with 11% in patients treated with chemotherapy. At the 6-month analysis, 95% of responses were ongoing, with a median duration of response not yet reached. Additionally, fewer serious adverse events were reported with nivolumab compared with chemotherapy.

The deadline for the FDA's decision on nivolumab was scheduled for March 30, 2015. The accelerated approval was granted under the FDA's breakthrough therapy and priority review designations. Nivolumab is the second PD-1 inhibitor to gain approval in 2014.

“Opdivo is the seventh new melanoma drug approved by the FDA since 2011,” Richard Pazdur, MD, director of the Office of Hematology and Oncology Products in the FDA’s Center for Drug Evaluation and Research, said in a statement. “The continued development and approval of novel therapies based on our increasing understanding of tumor immunology and molecular pathways are changing the treatment paradigm for serious and life-threatening diseases.”

The open-label CheckMate-037 trial randomized 405 patients with advanced melanoma in a 2:1 ratio to nivolumab at 3 mg/kg every 2 weeks (n = 268) or investigator's choice of chemotherapy (n = 102). The chemotherapies utilized in the trial included dacarbazine at 1,000 mg/m2 or intravenous carboplatin at AUC6 plus paclitaxel at 175 mg/m2 administered every 3 weeks

Patients in the trial were pretreated with ipilimumab or a BRAF inhibitor, if BRAF-mutation positive. The primary endpoints were ORR and overall survival. 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.

Early findings for ORR were presented at the 2014 ESMO Congress for 120 patients treated with nivolumab and 47 treated with chemotherapy. The complete response rate with nivolumab was 3%, partial response rate was 28%, and 23% of patients had stable disease. Of the 38 patients (32%) who responded to nivolumab, 82% experienced a greater than 50% reduction in target lesion burden compared with 60% in the 5 patients (11%) who responded to chemotherapy.

The median time to response in nivolumab treated patients was 2.1 versus 3.5 months with chemotherapy. The median duration of response was not reached with nivolumab versus 3.6 months with chemotherapy.

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.

Grade 3/4 adverse events occurred in 9% of patients treated with nivolumab compared with 31% in the chemotherapy arm. Fewer patients discontinued treatment with nivolumab as a result of adverse events compared with chemotherapy (2% vs 8%). Serious drug-related adverse events of any grade occurred in 6% of nivolumab-treated patients compared with 10% with chemotherapy.

“The approval of Opdivo gives patients and physicians an important new treatment option for a population where they were once very limited,” CheckMate-037 lead investigator Jeffrey S. Weber, MD, PhD, director of the Donald A. Adam Comprehensive Melanoma Research Center at Moffitt Cancer Center, said in a statement. “For the first time, a PD-1 blocking antibody has shown a response rate of 32% in a phase III randomized clinical trial of patients with unresectable or metastatic melanoma, who have progressed following first line therapy.”

Nivolumab continues to be explored across a variety of settings, including non-small cell lung cancer (NSCLC) and renal cell carcinoma. Earlier this year, the company developing the drug, Bristol-Myers Squibb, announced that it planned to initiate a rolling submission for nivolumab as a third-line treatment for patients with squamous cell NSCLC.

Nivolumab has been explored across a variety of settings for patients with advanced melanoma. In the phase III CheckMate-066 trial, treatment with nivolumab improved OS by 58% and PFS by 57% compared with dacarbazine. Following the demonstration of an improvement in survival at the interim analysis, the study was unblinded and patients being treated with chemotherapy were allowed to receive nivolumab. In PD-L1-positive patients, OS was improved by 70% and ORR was 52.7% versus 10.8%, for nivolumab and dacarbazine, respectively. Moreover, grade 3/4 side effects were less common in the nivolumab arm.

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