Results from an general proviso III hearing uncover that nivolumab improves altogether participation compared with a chemotherapy drug dacarbazine in patients with metastatic cancer whose tumors do not have a turn in a BRAF gene.
New England Journal of Medicine, Nov 16, 2014 (See a abstract.)
Approximately half of patients with metastatic cancer have tumors with mutations in a gene called BRAF. These patients are mostly treated with one of several targeted therapies authorized by a 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 miss BRAF mutations are mostly treated with an immune-based therapy, ipilimumab (Yervoy®). Ipilimumab, that inhibits a protein on T cells called CTLA-4, was a initial representative from a category of drugs famous as defence checkpoint inhibitors to be authorized by a FDA.
Based on certain results from an early-phase clinical trial, another checkpoint inhibitor, pembrolizumab (Keytruda®), was authorized by a FDA for a diagnosis of patients with modernized melanoma. Pembrolizumab targets a opposite checkpoint protein, called PD-1. Nivolumab is an investigational PD-1 inhibitor that, when administered both alone and in combination with ipilimumab, has shown guarantee in early-stage clinical trials of patients with modernized melanoma.
In a CheckMate-066 trial, 418 patients with untreated metastatic cancer whose tumors did not have BRAF mutations were incidentally reserved to accept possibly nivolumab or dacarbazine, a chemotherapy drug mostly used to provide patients with modernized melanoma.
All patients had growth samples tested for a participation of PD-L1—a ligand, or contracting partner, for a PD-1 checkpoint protein on T cells—to establish either a participation competence envision softened altogether participation following diagnosis with nivolumab.
The trial’s primary endpoint was altogether survival. Secondary endpoints enclosed how prolonged patients lived but their illness surpassing (progression-free survival) and how many patients gifted some rebate in a distance of their tumors (response rate).
Caroline Robert, M.D., Ph.D., of a Institut Gustave Roussy in France, led a trial, that was saved by Bristol-Myers Squibb, a manufacturer of nivolumab.
At a time of publication, a median altogether participation had not nonetheless been reached for patients who perceived 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 participation rate was 72.9 percent and 42.1 percent, respectively. Patients treated with nivolumab also had longer progression-free participation (5.1 months contra 2.2 months) and a aloft design response rate (40.0 percent contra 13.9 percent).
As of Aug 5, 2014, 46 percent of patients in a trial’s nivolumab arm and 6 percent of patients in a dacarbazine arm were still receiving a diagnosis to that they had creatively been assigned. A estimable series of patients who stopped receiving their reserved treatment—either since their illness began to swell or since of side effects—went on to accept some form of systemic treatment, a many common being ipilimumab.
The rate of side effects in both hearing arms was similar, nonetheless fewer patients treated with nivolumab gifted class 3 or 4 side effects than those treated with dacarbazine (11.7 percent contra 17.6 percent). The many common side effects in patients who perceived nivolumab were fatigue, greatly tingling skin (pruritus), and nausea. Fewer patients treated with nivolumab stopped holding a drug since of diagnosis side effects than patients treated with dacarbazine.
Treatment with nivolumab reduced a risk of genocide by 58 percent, a authors explained, a advantage that was “consistent opposite all a prespecified subgroups, including patients with bad premonitory factors.”
Dacarbazine was comparison as a comparison treatment, they continued, “because, until recently, it was a customary first-line diagnosis in many countries for patients who had cancer but a BRAF mutation.”
Based on certain commentary from prior early-stage trials, a formula from this proviso III hearing “confirm a expectations,” pronounced Howard Streicher, M.D., of NCI’s Cancer Therapy Evaluation Program.
The estimable series of patients who knowledge “durable, long-lasting responses” with nivolumab is an considerable 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 opposite settlement of responses” with immunotherapies, he said.
In an concomitant editorial, Mario Sznol, M.D., of a Yale Cancer Center, and Dan Longo, M.D., of Harvard Medical School, wrote that a trial’s commentary “strongly support a capitulation and preference of anti–PD-1 therapy as first-line diagnosis for metastatic cancer in patients with tumors containing unmutated BRAF.”
Although fewer patients treated with nivolumab gifted critical side effects than those treated with dacarbazine, Dr. Streicher cautioned that clinicians and patients should be wakeful of a intensity for immune-related side effects with nivolumab, including “events that can be really serious.”