Novartis announced data from the phase III COMBI-d study showing a significant survival benefit for patients with BRAF V600E/K mutation-positive metastatic melanoma when treated with the combination of Tafinlar (dabrafenib) and Mekinist (trametinib) compared to Tafinlar monotherapy alone. This is the first combination of BRAF/MEK inhibitors to demonstrate a statistically significant overall survival benefit for this patient population in two phase III studies.

Results presented at the 51st Annual Meeting of the American Society of Clinical Oncology (ASCO) in Chicago.

"This final analysis from COMBI-d confirms prior results showing a statistically significant improvement in overall survival among patients with BRAF V600E/K mutation-positive metastatic melanoma receiving the combination of dabrafenib and trametinib compared to dabrafenib monotherapy," said Georgina Long, medical oncologist, Melanoma Institute Australia, The University of Sydney. "These findings further reinforce the rationale for the treatment of metastatic melanoma with this combination."

The final analysis included the 423 patients enrolled in COMBI-d and showed that the combination of Tafinlar and Mekinist achieved a statistically significant overall survival (OS) benefit compared to Tafinlar monotherapy (median of 25.1 months vs 18.7 months). The analysis for the combination also showed median progression-free survival (PFS) of 11.0 months, overall response rate (ORR) of 69%, and median duration of response (DoR) of 12.9 months. The safety results were consistent with the profile observed to date for the combination and consistent with the profile observed for Tafinlar monotherapy; no new safety concerns were observed. The most common adverse events (>=20%) in the combination arm were pyrexia, fatigue, nausea, headache, chills, diarrhoea, rash, joint pain (arthralgia), hypertension, vomiting, cough and peripheral edema.

"We are very pleased to have entered into a new disease area with the acquisition of two medicines that are making a positive impact on the lives of people with this serious form of skin cancer," said Bruno Strigini, president, Novartis Oncology. "These COMBI-d data prove that these medicines can significantly extend the lives of people with BRAF V600E/K mutation-positive melanoma, and we are proud to be part of the progress in this disease."

In addition to results from the COMBI-d study, long-term data from a phase I-II study showed a three-year OS rate of 38% (95% CI, 25%, 51%) after treatment with the combination of Tafinlar and Mekinist in all patients with BRAF V600 E/K mutation-positive metastatic melanoma. Safety results from this study were consistent with those observed in other trials evaluating the combination.

Other data being presented at the meeting, including oral presentations related to the investigational use of dabrafenib and trametinib, include studies in BRAF V600E-mutated metastatic colorectal cancer (CRC), non-small cell lung cancer (NSCLC), and other rare cancers.

COMBI-d is a pivotal phase III randomized, double-blinded study (NCT01584648) comparing the combination of the BRAF inhibitor, Tafinlar, and the MEK inhibitor, Mekinist, to single agent therapy with Tafinlar and placebo in patients with unresectable (Stage IIIC) or metastatic (Stage IV) BRAF V600E/K mutation-positive cutaneous melanoma. The study randomized 423 patients from investigative sites in Australia, Europe and North and South America. The primary endpoint of this study was investigator-assessed PFS. Secondary endpoints included OS, ORR, DoR, and safety. There was no crossover between treatment arms.

The final OS analysis showed that the combination of Tafinlar and Mekinist achieved a statistically significant OS benefit compared to Tafinlar monotherapy (median of 25.1 months vs 18.7 months; Hazard Ratio [HR] 0.71 [95% Confidence Interval (CI), 0.55-0.92], p=0.011). A 33% reduction in the risk of progression or death was demonstrated with the combination therapy compared to monotherapy (median PFS of 11.0 months in the 211 patients receiving combination therapy vs 8.8 months in the 212 patients receiving monotherapy; HR 0.67 [95% CI, 0.53-0.84], p<0.001). The combination achieved ORR of 69% compared to 53% for monotherapy [difference=15% (95% CI, 6.0%-24.5%), p=0.001]. The median DoR for the 144 responders receiving combination therapy was 12.9 months [95% CI, 9.4-19.5] compared to 10.6 months in the 113 responders receiving monotherapy [95% CI, 9.1-13.8].

The safety results were consistent with the profile observed to date for the combination and consistent with the profile observed for Tafinlar monotherapy; no new safety concerns were observed. The most common adverse events (>=20%) in the combination arm were pyrexia, fatigue, nausea, headache, chills, diarrhea, rash, joint pain (arthralgia), hypertension, vomiting, cough and peripheral edema. More patients had AEs leading to dose modifications in the combination arm compared to Tafinlar monotherapy. Increased incidence (57% vs 33%) and severity (grade 3, 7% (n=15) vs 2% (n=4)) of pyrexia occurred with combination treatment as compared to Tafinlar monotherapy. There was a lower incidence of cutaneous squamous cell carcinoma (cuSCC) including keratoacanthoma with the combination arm (3% (n=6)) compared to the Tafinlar monotherapy arm (10% (n=22)). Discontinuation of treatment due to adverse events occurred in 11% (n=24) vs 7% (n=14) of patients in the combination group and the monotherapy group, respectively.

Completion of COMBI-d is a post-marketing requirement for the FDA's accelerated approval for the combination in the US.

Combination use of Tafinlar and Mekinist in patients with unresectable or metastatic melanoma who have BRAF V600E/K mutation is approved in the US, Australia, Chile and Canada.

Tafinlar and Mekinist target two different serine/threonine kinases - BRAF and MEK, respectively - in the RAS/RAF/MEK/ERK pathway, which is implicated in NSCLC and melanoma, among other cancers. When Mekinist is used with Tafinlar, the combination has been shown to slow tumor growth more effectively compared with either drug alone. The combination of Tafinlar and Mekinist is currently being investigated in an ongoing clinical trial program conducted in study centers worldwide.

In 2015, Novartis, as successor in interest to GlaxoSmithKline, purchased the worldwide exclusive rights to develop, manufacture, and commercialize trametinib from Japan Tobacco Inc. (JT). JT retains co-promotion rights in Japan.

Tafinlar and Mekinist are registered trademarks of Novartis