Dabrafenib/Trametinib Combo Improves Survival Over Vemurafenib in Phase III COMBI-v Trial

Caroline Robert, MD

Patients with unresectable melanoma had a significant improvement in the odds of survival when treated in first line with a combination of BRAF and MEK inhibitors, as opposed to anti-BRAF monotherapy, according to findings from the phase III COMBI-v trial presented at the 2014 ESMO Congress.

A preliminary survival analysis of more than 700 patients showed a 31% reduction in the hazard for survival in patients treated with dabrafenib (Tafinlar) and trametinib (Mekinist) versus vemurafenib (Zelboraf) monotherapy. Median survival had yet to be reached in the combination arm, whereas vemurafenib treatment led to a median survival of 17.2 months.

Treatment with the combination was associated with a 44% reduction in the hazard for progression or death, said Caroline Robert, MD, a medical oncologist at Gustave Roussy Institute in Villejuif, France.

“We observed significant improvement across all efficacy endpoints in favor of the dabrafenib-trametinib combination, including overall survival, progression-free survival, overall response rate, and duration of response,” Robert said during an ESMO press briefing. “The safety profile of the combination arm was consistent with previously reported studies and, in general, rates of adverse events and serious adverse events were similar across both treatment arms.”

The trial ended prematurely as a result of the demonstration of a significant reduction in the survival hazard.

Robert presented findings from the COMBI-v trial, which involved patients with newly diagnosed unresectable BRAF-mutated stage IIIC/IV melanoma. Eligible patients had received no prior therapy for advanced or metastatic disease.

Investigators in the international trial randomized patients in a 1:1 ratio to 150 mg of dabrafenib twice daily plus 2 mg of trametinib once daily or to vemurafenib at 960 mg twice daily. The trial had a primary endpoint of overall survival (OS). Secondary objectives included progression-free survival (PFS), overall response rate, duration of response, and safety.

The trial design included a prespecified interim analysis of overall survival after 202 deaths and a final analysis of the primary endpoint after 288 deaths.

The interim survival analysis yielded a survival hazard of 0.69 for the combination arm versus vemurafenib monotherapy (P = .005), which met the protocol-defined stopping point for the trial.

Analysis of the secondary endpoints showed that patients in the combination arm had a median PFS of 11.4 months versus 7.3 months with vemurafenib, resulting in a hazard ratio of 0.56 in favor of combination therapy (P <.001).

Examination of best response by treatment assignment showed that 13% of the combination arm versus 8% of the vemurafenib group achieved complete responses. Partial responses were documented in 51% of the combination group and 44% of the vemurafenib patients. Additionally, 26% and 30% of the groups, respectively, met criteria for stable disease.

“The combination therapy was associated with an overall response rate of 64% compared with 51% for vemurafenib alone,” said Robert. “The 13% absolute difference was highly significant (P <.001). The mean duration of response was 13.8 months with the combination and 7.5 months with vemurafenib.”

The most common adverse events (all grades) in the combination arm were pyrexia (53%), nausea (35%), diarrhea (32%), chills (31%), fatigue (29%), headache (29%), vomiting (29%), hypertension (26%), arthralgia (24%), and rash (22%). The most frequent grade 3 adverse events were hypertension (14%) and pyrexia (4%).

Arthralgia (51%), rash (43%), alopecia (39%), diarrhea (38%), nausea (36%), and fatigue (33%) were most common in the vemurafenib group. The most frequently reported grade 3 adverse events were hypertension and rash (9% each).

“There were fewer cutaneous malignancies with the combination (1%) than with vemurafenib (18%),” said Robert. “Hyperproliferative events and photosensitivity also were less frequent in the combination arm.”

The data are consistent with results from multiple studies that have demonstrated substantially better efficacy with combination targeted therapy in advanced melanoma, said Jeffrey Weber, MD, head of Melanoma Research at the H. Lee Moffitt Cancer Center. Collectively, the favorable data have sounded the “death knell” for chemotherapy in advanced melanoma.

“I haven’t used dacarbazine in more than a year and carboplatin-paclitaxel in months,” said Weber. “We all know that the next step will be to move combination therapy into earlier stages of the disease to see whether we can have an even greater effect on disease progression and survival.”

Robert C, Karaszewska B, Schachter J, et al. COMBI-v: A randomised, open-label, phase III study comparing the combination of dabrafenib (D) and trametinib (T) with vemurafenib (V) as first-line therapy in patients (pts) with unresectable or metastatic BRAF V600E/K mutation-positive cutaneous melanoma. Presented at: ESMO Congress 2014; September 26-30, 2014; Madrid, Spain. Abstract LBA4.

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