Targeted Therapy Combo Boosts Survival for Advanced Melanoma Patients

Metastatic melanoma patients treated with a combination of the BRAF inhibitor dabrafenib and the MEK inhibitor trametinib experienced a median overall survival of 23.8 months (HR = 0.73, P = .24) compared with 20.2 months for dabrafenib alone. The results are not statistically significant partly due to the crossover of patients from the monotherapy arm to the combination arm.

The 18-month overall survival rate is 63% for the combination.

“The rationale for this combination is compelling,” said Adil Daud, MD, director of melanoma clinical research at the Helen Diller Family Comprehensive Cancer Center at the University of San Francisco, during his presentation. “While BRAF inhibitor monotherapy is highly effective, resistance does develop. The median progression-free survival (PFS) for the monotherapy is about 5 to 6 months.”

Both preclinical and clinical results so far show that adding a MEK inhibitor to BRAF inhibitor therapy can not only boost PFS but can also reduce the hyper-proliferative skin phenotype that occurs in patients treated with a BRAF inhibitor alone.

Dr. Daud presented the data from the randomized, three-arm phase II portion of the phase I/II trial of the combination at the 10th International Congress of the Society for Melanoma Research (SMR) held in Philadelphia.

The trial included 160 patients. The initial PFS data were published in the New England Journal of Medicine.

The current update is after a median follow-up of 24 months. Crossover from the monotherapy arm to the combination treatment arm occurred in 83% of patients.

“There are other types of exciting therapies that are being developed, but for now, this stands as a new landmark in melanoma treatment,” Daud told Cancer Network. “I remember the days when a 6-month PFS was the best we could do. So this is really a major milestone in this disease.”

Patients in the phase II portion of the trial were randomized evenly to receive either 150 mg of dabrafenib twice daily, or one of two dose combinations of concurrent dabrafenib plus trametinib, including a 150 mg dose of dabrafenib twice daily plus 2 mg of trametinib once daily (150/2; a combination that is currently being tested in phase III clinical trials).

Forty-four percent (26) of patients receiving the 150/2 combination dose were on treatment for at least 12 months compared with 7% (4) of patients in the monotherapy arm.

The most frequent adverse events included pyrexia (23% in the monotherapy arm compared with 67% in the 150/2 treatment arm) and chills (15% in the monotherapy arm and 53% in the 150/2 treatment arm). The pyrexia tended to be episodic and got better after a short break from the therapy, said Daud.

As previously reported, skin rash was a non-additive toxicity. Patients in the combination arm had lower incidence of rash (22%) compared with those in the monotherapy arm (36%). High grade toxicities were limited to grade 3 pyrexia in three combination-treated patients (5%) and cutaneous squamous cell carcinoma (17% in the monotherapy arm compared with 7% in the 150/2 combination treatment arm).

Both dabrafenib and trametinib are approved as monotherapies to treat metastatic melanoma harboring a V600 BRAF mutation. Another BRAF inhibitor, vemurafenib, is also approved as a single agent to treat this subpopulation of metastatic melanoma patients. The combination of dabrafenib and trametinib is now being tested in two phase III trials in this patient population.

The combination of dabrafenib and trametinib is being developed by GlaxoSmithKline. In September, the combination of dabrafenib plus trametinib received a priority review from the US Food and Drug Administration based on submission of phase II data.