Combining Two Types of Targeted Therapy Improves Survival in Some Patients with Advanced Melanoma (Updated)

In two phase III trials, patients with metastatic melanoma whose tumors have specific mutations in the BRAF gene lived longer following treatment with dabrafenib (Tafinlar®), a BRAF inhibitor, plus trametinib (Mekinist®), a MEK inhibitor, than following treatment with a BRAF inhibitor alone. The results of both trials were published in November 2014 in the New England Journal of Medicine (NEJM).

In previous clinical trials, both dabrafenib and another BRAF inhibitor, vemurafenib (Zelboraf®), improved progression-free survival when used alone to treat patients with advanced melanoma whose tumors bear specific mutations in the BRAF gene. These mutations, which affect an amino acid in the BRAF protein (V600), cause strong growth-promoting signals and are often found in advanced melanomas.

Unfortunately, tumors frequently develop resistance to BRAF inhibitors within 6 to7 months. Studies have shown that resistance develops, at least in part, because tumors are able to activate the mitogen-activated protein kinase (MAP kinase/MEK) signaling pathway, which allows the tumors to resume growing. By combining dabrafenib with trametinib, a drug that inhibits the activity of MEK proteins, researchers hope to prevent tumors from using this escape mechanism.

In the larger of the two trials, led by Caroline Robert, M.D., Ph.D., of the Institut Gustave Roussy, 704 patients with metastatic melanoma bearing a BRAF V600 mutation were randomly assigned to receive either a combination of dabrafenib plus trametinib or vemurafenib alone. Patients in the combination-therapy group had a 12-month survival rate of 72 percent, compared with 65 percent in the vemurafenib group. The dabrafenib-trametinib group also had a better median progression-free survival than the vemurafenib group: 11.4 months versus 7.3 months, respectively.

Five patients (1 percent) who received dabrafenib plus trametinib developed cutaneous squamous-cell carcinoma—a serious and common complication in patients treated with BRAF inhibitors—compared with 63 of the patients (18 percent) who received vemurafenib alone. The most common adverse events in this trial were pyrexia (fever), fatigue, nausea, headaches, and chills. The proportion of patients in the combination group discontinuing treatment due to adverse events was similar to that of the vemurafenib group (13 percent versus 12 percent).

In a separate trial, led by Georgina V. Long, M.D., Ph.D., of the Melanoma Institute Australia, 423 previously untreated patients with advanced melanoma were randomly assigned to receive either a combination of dabrafenib plus trametinib daily or dabrafenib plus placebo. Patients in the combination-therapy group had an overall response rate of 67 percent and a 6-month survival rate of 93 percent, whereas patients in the dabrafenib and placebo group had a 51 percent response rate and 6-month survival rate of 85 percent. Median progression-free survival was longer in the combination group than the dabrafenib group: 9.3 months versus 8.8 months, respectively. [See the update below for results on overall survival.]

Five patients in the trial who received dabrafenib plus trametinib (2 percent) developed cutaneous squamous-cell carcinoma, compared with 20 of the patients who received dabrafenib alone (9 percent). The most common adverse events were similar to those observed in the larger trial and contributed to the discontinuation of treatment by 9 percent of patients in the combination group versus 5 percent in the dabrafenib and placebo group.

Both trials were funded by GlaxoSmithKline, the manufacturer of dabrafenib and trametinib. The Food and Drug Administration (FDA) approved both drugs in 2013 for use as single agents in patients with BRAF mutation-positive melanomas, and the FDA approved the dabrafenib-trametinib combination in 2014.

Data from clinical trials that have tested a BRAF and MEK inhibitor in combination have convincingly shown that “the combination of a BRAF and MEK inhibitor is better than either drug alone, and safer with regard to the risk of cutaneous squamous carcinoma,” said Howard Streicher, M.D., of NCI’s Cancer Therapy Evaluation Program.

The impact of these trials on patient outcomes could be important, suggested Brendan Curti, M.D., of the Providence Cancer Center, in an accompanying editorial in NEJM.

“The good news is that we now have agents with a much higher potential to induce clinically meaningful melanoma regression, as compared with therapies used before,” Dr. Curti wrote. However, since melanoma adapts and develops drug resistance very quickly, Dr. Curti cautioned that more work remains to be done to develop therapeutic strategies that are better able to address treatment resistance.

Update: In a follow-up report, Dr. Long and her colleagues published results on overall survival, which was a secondary endpoint of their study. The median overall survival for patients in the dabrafenib-plus-trametinib group was 25.1 months, versus 18.7 months for patients in the dabrafenib-only group, the researchers reported May 29, 2015, in The Lancet. The improvement in progression-free survival and overall survival with the combination treatment, and the fact that it was seen in all subgroups of patients analyzed, “support the choice of combined dabrafenib and trametinib as the standard targeted treatment, rather than single drug BRAF inhibition, for the patients with BRAF Val600 mutation-positive metastatic melanoma,” the authors concluded.