Treatment with the combination of trametinib (Mekinist) and dabrafenib (Tafinlar) significantly improved overall survival (OS) compared to vemurafenib monotherapy in previously untreated patients with BRAF V600E/K mutation-positive metastatic melanoma, without increased overall toxicity, according to a study published in the New England Journal of Medicine.
COMBI-v, a phase 3, randomized, open-label study that compared the combination of dabrafenib and trametinib, to vemurafenib in subjects with unresectable (Stage IIIC) or metastatic (Stage IV) BRAF V600E/K mutation-positive cutaneous melanoma. The primary objective of the study was to evaluate the superiority of dabrafenib and trametinib combination therapy over vemurafenib with respect to OS. Secondary objectives evaluated and compared dabrafenib and trametinib combination therapy versus vemurafenib with respect to PFS, overall response rate and duration of response.
The pre-planned interim overall survival (OS) analysis -performed after 77% of the total number of expected events-demonstrated a hazard ratio (HR) for survival of 0.69 (95% CI, 0.53–0.89; 2-sided P=.005) resulting in a 31% decrease in the risk of death for the trametinib and dabrafenib combination compared to vemurafenib. Median OS for the vemurafenib arm was 17.2 months; median OS for the combination arm has not yet been reached. Additional results include:
· Treatment with the combination also increased median progression-free survival (PFS) by 11.4 months compared to 7.3 months for the vemurafenib arm (HR 0.56; 95% CI, 0.46–0.69; P<.001). This translated into a 44% reduction in risk of disease progression among patients treated with the combination compared to vemurafenib monotherapy.
· The objective response rate was 64% (95% CI. 59.1% to 69.4%) for the combination and 51% (95% CI, 46.1% to 56.8%) for vemurafenib (P<.001); with a median duration of response of 13.8 months (95% CI, 11.0 to not reached) vs. 7.5 months (95% CI, 7.3–9.3), respectively.
· After 6 months, 92% of patients treated with the combination were alive versus 87% in the vemurafenib arm.
· 13% of patients treated with the combination achieved a complete response, compared to 8% of patients in the vemurafenib arm.
The independent data monitoring committee (IDMC) recommended stopping the study early since the combination therapy arm demonstrated benefit with regard to the primary endpoint, OS, over vemurafenib based on pre-defined stopping criteria. The secondary endpoints-PFS, ORR and OS in subgroups-did not have pre-specified stopping criteria (per protocol).
Following the IDMC’s recommendation, a protocol amendment was released on August 7, 2014 allowing eligible study patients who were randomly assigned to the vemurafenib arm the option to cross over to receive treatment with the trametinib and dabrafenib combination.
COMBI-v was conducted to answer an important scientific question about the safety and efficacy of combination vs monotherapy in patients with BRAF mutant metastatic melanoma, according to Bernadette King, spokesperson GlaxoSmithKline.
“COMBI-v adds to the body of evidence our phase 3 program has provided thus far, and helps to more fully characterize the efficacy and safety profile of this combination,” she said.
The study was sponsored by GSK.