'Impressive' Duration of Response With Nivolumab in Melanoma

Zosia Chustecka

September 29, 2014

MADRID — In the first phase 3 trial to be reported with the investigational immunotherapy nivolumab, the drug showed an "impressive" duration of response when used as a second- or third-line therapy in patients with advanced melanoma, said Jeffrey Weber, MD, from the Comprehensive Melanoma Research Centers of Excellence at the Moffitt Cancer Center in Tampa, Florida. These data have been filed for approval in both Europe and the United States, where the drug has breakthrough status.

Dr. Jeffrey Weber

Dr. Weber was speaking at a press briefing here at the European Society for Medical Oncology (ESMO) Congress 2014, ahead of the presidential session where he presented preliminary results from the phase 3 trial, known as CheckMate-037.

The trial compared nivolumab with chemotherapy in 405 patients with unresectable advanced or metastatic melanoma who had previously been treated with ipilimumab (Yervoy). About 30% of these patients harbored BRAF mutations, and this group had also received treatment with a BRAF inhibitor. These patients currently have few treatment options, he commented.

One of the primary end points of the trial was overall response rate, and this was achieved by 32% of patients on nivolumab vs 11% on chemotherapy.

Dr. Weber highlighted the duration of response results, which show a median of 3.6 months for patients on chemotherapy, but the median has not yet been reached with nivolumab. Some patients have been responding for more than 10 months, he said.

Of the patients who responded to nivolumab, 36 of 38 (95%) are still responding, he said.

"The impressive data on duration of response suggest that there will be significant prolongation of progression-free and overall survival when the analysis of those data is mature," Dr. Weber commented in a statement.

These survival data are not available yet. Overall survival is the other primary end point, and there is great anticipation about whether a benefit will be seen, as is expected, and also about how much of a benefit will be seen.

Dr. Weber said the data so far on response rates and duration of response, as well as the fact the drug is well tolerated, should be sufficient for approval of nivolumab in this setting of second- or third-line therapy for melanoma, and he hopes that US Food and Drug Administration (FDA) approval will be forthcoming in the next few months.

A rival similar drug, pembrolizumab (Keytruda), has just been FDA approved for this indication on the basis of what he considers to be weaker data. They come from a nonrandomized study in 89 patients that was an extension of a phase 1/2 trial, which showed a response rate of 22% to pembrolizumab.

The data on nivolumab show a response rate of 32% and they come from a randomized phase 3 study in 405 patients, which is a "more definitive assessment of efficacy," he told Medscape Medical News.

Nivolumab has already been approved in Japan, and the indication there is for unresected melanoma. In Japan, nivolumab is marketed as Opdivo by Ono Pharmaceuticals; it is licensed elsewhere to Bristol-Myers Squibb, which has said that it will use the same trade name for the drug, Opdivo.

End of Chemo in Melanoma?

In this study, nivolumab was tolerated much better than chemotherapy. Grade 3/4 drug-related adverse events were seen in 9% of patients on nivolumab vs 31% on chemotherapy, and discontinuations due to drug-related adverse events occurred in 2.2% and 7.8% of patients, respectively.

Among nivolumab-treated patients, 10 patients (8.3%) had immune-related response patterns, Dr. Weber reported.

The chemotherapy used in this trial was left to investigator choice, and could be either dacarbazine (1000 mg/m²) or carboplatin AUC6 plus paclitaxel (175 mg/m²).

Dr. Weber said that he hardly ever uses chemotherapy now for melanoma in his clinical practice. "I haven't used dacarbazine for many years, and haven't used carboplatin for months," he told journalists. "We have better drugs, thank God," he added.

The immunomodulator ipilimumab is now approved for first-line use in melanoma, and Dr. Weber said he often uses this drug in patients who are not BRAF-mutation positive.

More immunomodulators are on their way. As well as pembrolizumab and nivolumab, there are several more similar agents that act on the program death (PD) pathway.

In the BRAF-mutation positive population (about 40% of melanoma), he said that he would consider BRAF inhibitor combinations for patients with rapidly growing tumors, but for those with slow-growing tumors and a low disease burden, he would consider an immunomodulator. "I would give the patient the choice," he added.

Commenting on the findings, Olivier Michielin, MD, from the Department of Oncology at the University of Lausanne in Switzerland, said, "These results add another piece of evidence that PD blockade is rapidly becoming a central part in our armamentarium against melanoma, progressively replacing chemotherapy with more effective and less toxic options."

"These results demonstrate that PD blockade, contrary to a common and old dogma of immunotherapy, can produce rapid and deep responses even in advanced and bulky disease. This opens exciting new opportunities to widen the scope of application of immuno-oncology for the treatment of stage IV melanoma," Dr. Michielin commented in an ESMO statement.

The trial was funded by Bristol-Myers Squibb, the manufacturer of nivolumab. Dr. Weber reports serving on the advisory boards of Bristol-Myers Squibb, Merck, and Genentech. His institution receives research funding from Bristol-Myers Squibb and Genentech

European Society for Medical Oncology (ESMO) Congress 2014: Abstract LBA3_PR. Presented September 29, 2014.

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