Frontline BRAF/MEK Combo Improves Survival in Melanoma

Combination MEK/BRAF inhibition with trametinib and dabrafenib reduced the risk of death by 29% in patients with BRAF-mutant advanced melanoma.

Georgina V. Long, BSc, PhD, MBBS

Combination therapy with the MEK inhibitor trametinib (Mekinist) and the BRAF inhibitor dabrafenib (Tafinlar) reduced the risk of death by 29% in patients with BRAF-mutant advanced melanoma, according to the final results from the COMBI-d phase III trial, which were presented at the 2015 ASCO Annual Meeting and simultaneously published in The Lancet.

“Dabrafenib combined with trametinib represents a new targeted therapy standard of care for BRAF V600 metastatic melanoma,” said lead author Georgina V. Long, BSc, PhD, MBBS, clinical researcher at the Melanoma Institute Australia and Westmead Hospital in Sydney.

The COMBI-d study randomized 423 treatment-naïve adults with unresectable stage IIIC/IV melanoma expressing a BRAF V600E or V600K mutation to 150 mg of dabrafenib twice daily plus 2 mg of trametinib daily (n = 211) or placebo (n = 212).

All patients had an ECOG performance status of 0 or 1. The median patient age in the overall trial population was approximately 56 years. Eighty-five percent (n = 179) and 15% (n = 32) of patients in the combination arm had V600E and V600K mutations, respectively, with rates of 85% and 14% for the two mutations, respectively, in the placebo arm. Approximately one-third of patients in each arm had elevated LDH levels. Patients with brain metastases were excluded from enrollment unless the metastases was definitively treated with local therapy and the patient was stable for at least 12 weeks.

The primary endpoint of the study was investigator-assessed progression-free survival (PFS) and secondary endpoints included overall survival (OS), overall response rate (ORR), duration of response, and safety.

A primary analysis was conducted in August 2013 following 213 PFS events and 95 OS events. At a median follow-up of 9 months, the PFS was 9.3 months with the combination versus 8.8 months for dabrafenib alone (HR = 0.75; P = .035). The combination reduced the risk of death by 37% versus single-agent dabrafenib (HR = 0.63; P = .023).

After the primary analysis, the study continued per protocol, with no crossover allowed and site staff and patients remained blinded. The final analysis was conducted in January 2015 after 222 OS events and a median follow-up of 20 months in the combination arm and 16 months in the control arm.

The final results showed that OS was 25.1 months in the combination arm compared with 18.7 months with single-agent dabrafenib (HR = 0.71; 95% CI, 0.55-0.92; P = .011). The 1- and 2-year OS rates were 74% and 51%, respectively, with dabrafenib plus trametinib and 68% and 42%, respectively, with dabrafenib alone.

“Subgroup analysis for the overall survival showed that every subgroup benefited from the combination compared with dabrafenib monotherapy, including subgroups analyzed by age, BRAF mutation genotype, tumor stage, LDH, and number of disease sites,” Long said.

In the final analysis, median PFS was 11.0 months for dabrafenib plus trametinib versus 8.8 months for dabrafenib plus placebo (HR = 0.67; 95% CI, 0.53-0.84; P <.001).

ORR with the combination was 69% versus 53% with dabrafenib alone (P = .001). The complete and partial response rates with the combination were 16% and 53%, respectively, versus 13% and 40% with dabrafenib alone. Duration of response was 12.9 and 10.6 months in the combination and monotherapy arms, respectively.

Long said that toxicities were manageable and there were no new or unexpected adverse events with an additional 17 months of follow-up. All-grade adverse events (AEs) occurred in 90% and 87% of the control and combination arms, respectively. AEs leading to dose interruption, reduction, or permanent treatment discontinuation were higher in the combination arm. The most common AE with the combination was pyrexia at 52% of patients versus 25% in patients receiving dabrafenib alone.

“Grade 3 AEs occurred in 30% of patients in each arm,” said Long. “There was no predominant adverse event of grade 3 except pyrexia, which occurred in 7% of patients in the combination arm.”

Patients in the combination arm were less likely to develop noncutaneous malignancies and new primary melanomas.

Approximately 30% of patients in each arm continued study treatment after progression. Fifty-one percent of patients in the control arm received subsequent anticancer therapy versus 33% in the combination arm. Subsequent treatments included “anticancer therapies known to prolong overall survival, including ipilumimab, and the anti-PD-1 antibodies pembrolizumab and nivolumab. But despite this, we still see an overall survival benefit for the combination of dabrafenib and trametinib,” said Long.

Long GV, Stroyakovsky DK, Gogas H, et al. COMBI-d: a randomized, double-blinded, phase III study comparing the combination of dabrafenib and trametinib to dabrafenib and trametinib placebo as first-line therapy in patients (pts) with unresectable or metastatic BRAFV600E/K mutation-positive cutaneous melanoma. J Clin Oncol. 2015;33 (suppl; abstr 102).


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