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Nivolumab Improves Overall Survival in Patients with Metastatic Melanoma without a BRAF Mutation


Results from an international phase III trial show that nivolumab (Opdivo®) improves overall survival compared with the chemotherapy drug dacarbazine in patients with metastatic melanoma whose tumors do not have a mutation in the BRAF gene.


New England Journal of Medicine, November 16, 2014 (See the abstract.)


Approximately half of patients with metastatic melanoma have tumors with mutations in a gene called BRAF. These patients are often treated with one of several targeted therapies approved by the Food and Drug Administration (FDA), including vemurafenib (Zelboraf®), dabrafenib (Tafinlar®), and trametinib (Mekinist®).

These treatments, however, are not effective in patients whose tumors do not have BRAF mutations. Patients whose tumors lack BRAF mutations are often treated with an immune-based therapy, ipilimumab (Yervoy®). Ipilimumab, which inhibits a protein on T cells called CTLA-4, was the first agent from a class of drugs known as immune checkpoint inhibitors to be approved by the FDA.

Based on positive results from an early-phase clinical trial, another checkpoint inhibitor, pembrolizumab (Keytruda®), was approved by the FDA for the treatment of patients with advanced melanoma. Pembrolizumab targets a different checkpoint protein, called PD-1. Nivolumab is an investigational PD-1 inhibitor that, when administered both alone and in combination with ipilimumab, has shown promise in early-stage clinical trials of patients with advanced melanoma.

The Study

In the CheckMate-066 trial, 418 patients with untreated metastatic melanoma whose tumors did not have BRAF mutations were randomly assigned to receive either nivolumab or dacarbazine, a chemotherapy drug often used to treat patients with advanced melanoma.

All patients had tumor samples tested for the presence of PD-L1—a ligand, or binding partner, for the PD-1 checkpoint protein on T cells—to determine whether its presence might predict improved overall survival following treatment with nivolumab.

The trial’s primary endpoint was overall survival. Secondary endpoints included how long patients lived without their disease progressing (progression-free survival) and how many patients experienced some reduction in the size of their tumors (response rate).

Caroline Robert, M.D., Ph.D., of the Institut Gustave Roussy in France, led the trial, which was funded by Bristol-Myers Squibb, the manufacturer of nivolumab.


At the time of publication, the median overall survival had not yet been reached for patients who received nivolumab (median follow-up 8.9 months) and was 10.8 months in patients treated with dacarbazine (median follow-up 6.8 months). The 1-year survival rate was 72.9 percent and 42.1 percent, respectively. Patients treated with nivolumab also had longer progression-free survival (5.1 months versus 2.2 months) and a higher objective response rate (40.0 percent versus 13.9 percent).

Among patients in the trial’s nivolumab arm there was no difference in survival between those whose tumors were positive for PD-L1 and those whose tumors were negative.

As of August 5, 2014, 46 percent of patients in the trial’s nivolumab arm and 6 percent of patients in the dacarbazine arm were still receiving the treatment to which they had originally been assigned. A substantial number of patients who stopped receiving their assigned treatment—either because their disease began to progress or because of side effects—went on to receive some form of systemic treatment, the most common being ipilimumab.

The rate of side effects in both trial arms was similar, although fewer patients treated with nivolumab experienced grade 3 or 4 side effects than those treated with dacarbazine (11.7 percent versus 17.6 percent). The most common side effects in patients who received nivolumab were fatigue, intensely itchy skin (pruritus), and nausea. Fewer patients treated with nivolumab stopped taking the drug because of treatment side effects than patients treated with dacarbazine.


Treatment with nivolumab reduced the risk of death by 58 percent, the authors explained, a benefit that was “consistent across all the prespecified subgroups, including patients with poor prognostic factors.”

Dacarbazine was selected as the comparison treatment, they continued, “because, until recently, it was a standard first-line treatment in many countries for patients who had melanoma without a BRAF mutation.”

Based on positive findings from previous early-stage trials, the results from this phase III trial “confirm our expectations,” said Howard Streicher, M.D., of NCI’s Cancer Therapy Evaluation Program.

The substantial number of patients who experience “durable, long-lasting responses” with nivolumab is an impressive finding, Dr. Streicher continued. Some of these responses “occur late, what have typically been termed atypical responses, so we’re going to have to get used to a different pattern of responses” with immunotherapies, he said.

In an accompanying editorial, Mario Sznol, M.D., of the Yale Cancer Center, and Dan Longo, M.D., of Harvard Medical School, wrote that the trial’s findings “strongly support the approval and selection of anti–PD-1 therapy as first-line treatment for metastatic melanoma in patients with tumors containing unmutated BRAF.”

Although fewer patients treated with nivolumab experienced serious side effects than those treated with dacarbazine, Dr. Streicher cautioned that clinicians and patients should be aware of the potential for immune-related side effects with nivolumab, including “events that can be very serious.”

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