Nivolumab: Impressive Responses in Melanoma

Jeffrey Weber, MD, PhD

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Immunotherapy marches on showing continued progress in treating advanced melanoma. At the recent ESMO 2014 Congress, first reports from a phase 3 study showed that the monoclonal anti–PD-1 antibody nivolumab achieved superior responses and longer duration of response compared with standard chemotherapy in the second- or third-line treatment of patients whose melanoma progressed on treatment with ipilimumab.

“Patients who progress on previous treatment have limited options. In this study, nivolumab had impressive responses and duration of response, and these data suggest that the drug can prolong progression-free survival (PFS) and overall survival (OS), but the data are not yet mature,” said lead author Jeffrey Weber, MD, PhD, director of the Donald A. Adam Comprehensive Melanoma Research Center of Excellence at the Moffitt Cancer Center, Tampa, FL.

Like ipilimumab, the first immunotherapy to be approved for treatment of advanced melanoma, nivolu­mab is a PD-1–blocking antibody, referred to as a “check­point inhibitor,” because it releases a brake placed on the immune system by the tumor itself. Once the brake is released, the immune system goes into action mounting an antitumor response and shrinking the tumor.
This is the first phase 3 trial of nivolumab in melanoma patients with progressive disease despite treatment with ipilimumab. The study randomized 405 patients with unresectable melanoma in a 2:1 ratio to intravenous nivolumab 3 mg/kg versus investigator’s choice of chemotherapy (ICC). Patients were treated until disease progression or unacceptable toxicity.

Weber explained that the control arm was designed to accommodate differences in preferred chemotherapy regimens between North America and Europe (carboplatin/paclitaxel or dacarbazine, respectively).

The patients were stratified prospectively according to expression of PD-L1, a potential biomarker for response, BRAF status, and best overall response to prior anti–CTLA-4 (ipilimumab). Thirty percent had BRAF mutations and had previously received a BRAF inhibitor.

Overall response rate (ORR) was 32% for nivolumab versus 11% with ICC using a RECIST definition. Ninety-five percent of responses (36 of 38) were ongoing in the nivolumab arm at the time of the analysis, and median duration of response in that arm had not yet been reached at the time of ESMO 2014. Median duration of response in the ICC arm was 3.6 months.

No deaths were attributed to study drug toxicity. One patient in the nivolumab group experienced grade 5 hypoxia, possibly pneumonitis, and this cause of death was classified as “other” rather than “study drug toxicity,” Weber said.

PFS and OS will be reported when the data are more mature.

The company has filed for FDA approval in the United States, and the drug has breakthrough status. A similar drug, pembrolizumab, received FDA approval for melanoma based on less robust response data than those seen in the nivolumab trial (ie, 22% ORR), Weber said.

A course of treatment with ipilimumab is estimated at $120,000. If nivolumab is approved, the cost is likely to be at least as high.

“This appears to be the death knell of chemotherapy, at least in second and third line. I hate using chemotherapy in melanoma, and I hope this study puts to rest that it should be used as a comparator arm in clinical trials. In the US, you won’t be able to do this anymore,” Weber said in a separate interview.

Discussion

Formal discussant of this trial, Ignacio Melero, MD, Pamplona, Spain, called this “very exciting clinical data with impressive responses. I am disappointed that the survival data are not available yet.”

He said that the study included patients with brain metastases, and he is looking forward to hearing the specific outcome in that subgroup as well as in the 50% of patients who were PD-L1 positive.

“We will learn a lot [about potential biomarkers] when we get correlative data from this trial,” he said.

He mentioned that pembrolizumab is also showing good responses in melanoma. “The treatment of melanoma is changing,” Melero said.

“If a patient is BRAF wild type, treatment is with chemotherapy or ipilimumab or a clinical trial. With BRAF-mutated melanoma, it is more entangled. Patients have the option of targeted therapy or immunotherapy. The trend is to move anti–PD-1 agents up front and get rid of chemotherapy. It is important to study immunotherapy combinations, but we need good biomarkers,” he stated.

“I believe that melanoma treatment with anti–PD-1 will be the tip of the iceberg. Many other indications for this treatment are emerging, including lung cancer, head and neck cancer, and bladder cancer,” Melero said.

“My main conclusion is that immunotherapy in cancer is no longer an exotic task,” he said.

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