Trametinib + Dabrafenib Improves PFS in BRAFV600E/K Mutant Metastatic Melanoma

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Trametinib + Dabrafenib Improves PFS in BRAFV600E/K Mutant Metastatic Melanoma
Trametinib + Dabrafenib Improves PFS in BRAFV600E/K Mutant Metastatic Melanoma

CHICAGO, IL—Patients with BRAFV600E/K mutant metastatic melanoma had a significant improvement in progression-free survival (PFS) when trametinib was added to first-line dabrafenib, results of the phase 3 COMBI-d study reported at the 2014 American Society of Clinical Oncology (ASCO) Annual Meeting.

This is the first melanoma phase 3 double-blind randomized controlled trial with an active control arm,” said Georgina V. Long, BSc PhD MBBS, of the Melanoma Institute Australia, Sydney. “As monotherapies, the BRAF inhibitor dabrafenib and the MEK inhibitor trametinib demonstrated superior PFS versus chemotherapy in patients with BRAFV600 mutant, metastatic melanoma,” she added.

However, most patients develop resistance to treatment and experience oncogenic toxicities, such as cutaneous squamous carcinoma, associated with BRAF inhibition. Previously, a phase 1/ 2 study of dabrafenib plus trametinib versus dabrafenib alone found the simultaneous inhibition of BRAF and MEK mitigated these effects, demonstrating an improvement in overall response rate (ORR) and PFS as well as reducing cutaneous squamous carcinoma.

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The study randomly assigned 423 patients with unresectable or metastatic BRAFV600E/K mutation-positive cutaneous melanoma to dabrafenib (150 mg twice daily) plus trametinib (2 mg once daily; n=211) or dabrafenib plus placebo (n=212). The primary endpoint was investigator-assessed PFS. Secondary endpoints were overall survival (OS), ORR, duration of response, and safety. Cross-over was prohibited. The study has 95% power and a one-sided α=0.025 to detect a PFS hazard ratio (HR) of 0.59.

Median follow-up was 9 months (range, 0-16 months). The HR for 6-month investigator-assessed PFS was 0.75 (95% CI: 0.57-0.99; P = 0.035), in favor of dabrafenib plus trametinib. Median PFS was 9.3 months for the dabrafenib plus trametinib arm versus 8.8 months for the dabrafenib plus placebo arm.

For the dabrafenib plus trametinib arm, confirmed ORR was 67%, with a complete response of 10%, versus 51% with a complete response of 9% for dabrafenib plus placebo (P = 0.0015). The interim OS HR was 0.63 (95% CI: 0.42-0.94; P = 0.023), in favor of dabrafenib plus trametinib (40 vs. 55 deaths).

Dr. Long noted that rates of adverse events (AEs) were similar for both arms; however, more patients in the dabrafenib plus trametinib arm had AEs that led to dose modifications. The combination also resulted in an increased incidence (51% vs. 28%) and severity (grade 3, 6% vs. 2%) of pyrexia compared with dabrafenib plus placebo. Dr. Long said that she educates her patients with respect to the potential for pyrexia and, if they experience a second event, to stop the medication for two days. She said she has not found premedication or dose reduction helpful; however, for the small percentage of patients who are recalcitrant, corticosteroids may be indicated.

Patients in the dabrafenib plus trametinib arm had fewer cutaneous hyperproliferative events compared with dabrafenib plus placebo: cutaneous squamous carcinoma was observed in 2% versus 9% and hyperkeratosis in 3% versus 32%, respectively, which are considered BRAF-inhibitor related AEs.

Dr. Long emphasized that the COMBI-d study is continuing, with an updated OS planned at 70% death events. The PFS analysis will also be updated.


  1. Long GV, Stroyakovsky DL, Gogas H et al. Abstract 9011. Presented at: 2014 American Society of Clinical Oncology (ASCO) Annual Meeting; May 30-June 3, 2014; Chicago, IL.

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