PD-1–Blocking Nivolumab Shows Impressive Responses in Melanoma

October 2014, Vol 5 , No 8

Madrid, Spain—Immunotherapy marches on, showing continued progress in treating advanced melanoma. At the 2014 European Society for Medical Oncology (ESMO) Congress, first reports from a phase 3 clinical trial showed that the monoclonal anti–PD-1 antibody nivolumab achieved superior responses and longer progression-free survival (PFS) and overall survival (OS) compared with standard chemotherapy in the second- or third-line treatment of patients whose melanoma progressed with ipilimumab therapy.

“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 and overall survival, but the data are not yet mature,” said lead investigator Jeffrey S. Weber, MD, PhD, Director, Donald A. Adam Comprehensive Melanoma Research Center of Excellence, Moffitt Cancer Center, Tampa, FL.

Ipilimumab was the first immunotherapy to be approved for the 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.

Study Details
This is the first phase 3 clinical trial of nivolumab in patients with melanoma 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.

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

The patients were stratified prospectively according to PD-1 ligand 1 (PD-L1) expression, a potential biomarker for response, BRAF status, and best overall response to previous anti–CTLA-4 therapy (ie, ipilimumab). Overall, 30% of patients had BRAF mutations and had also previously received a BRAF inhibitor.

Overall response rate (ORR) was 32% for nivolumab versus 11% with ICC by RECIST criteria. Among the responses, 95% were ongoing in the nivolumab arm at the time of the analysis, and the median duration of response in that arm had not yet been reached by the time of presentation at ESMO 2014. The median duration of response in the ICC arm was 3.6 months.

No deaths were attributed to 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,” Dr Weber said. PFS and OS results will be reported when the data are more mature.

A New Drug Application for ni­volumab has been submitted to the FDA, which has designated it as breakthrough therapy. A similar drug, pembrolizumab, received FDA approval for melanoma based on less robust response data than in the nivolumab trial (ie, 22% ORR), Dr Weber said.

A course of treatment with ipilimumab is estimated to cost $120,000. If nivolumab receives FDA approval, its cost is estimated 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,” Dr Weber said in a separate interview.

Expert Discussion
Formal discussant of this trial, Ignacio Melero, MD, PhD, of the University of Navarra, Pamplona, Spain, called this “very exciting clinical data with impressive responses.”

“I am disappointed that the sur­vival data are not available yet,” Dr Melero said.

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 with PD-L1 disease.

As for potential biomarkers, “We will learn a lot when we get correlative data from this trial,” Dr Melero said. He mentioned that pembroliz­umab is also showing good responses in melanoma.

“The treatment of melanoma is changing,” Dr Melero said. “If a patient is BRAF wild-type, treatment is with chemotherapy or ipilimumab or the reverse, 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 upfront 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,” Dr Melero said.

“My main conclusion is that immunotherapy in cancer is no longer a quixotic task,” he concluded.

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