Novartis announced data from a phase III study showing a significant survival benefit for patients with BRAF V600E/K mutation-positive advanced melanoma when treated with the first-line combination of Tafinlar (dabrafenib) + Mekinist (trametinib) compared to Tafinlar monotherapy.
The results from the COMBI-d three-year follow-up analysis represent one of the longest survival follow-up studies to date with BRAF mutation-positive advanced melanoma patients. Results were presented at the 52nd Annual Meeting of the American Society of Clinical Oncology (ASCO) in Chicago.
Results from the COMBI-d study of 423 patients found the estimated three-year survival rate to be 44% for patients receiving the combination of Tafinlar + Mekinist (95% CI, 36.4%-50.5%) compared with 32% who received Tafinlar alone (95% CI, 25.4%-38.3%). There were 26 patients who crossed over from the monotherapy arm to the combination arm after the combination demonstrated a significant overall survival (OS) benefit in a prior analysis. Additionally, the estimated three-year progression-free survival rate was 22% (95% CI, 16.2%-28.0%) for the combination arm and 12% (95% CI, 7.1%-18.0%) for the monotherapy arm. In an analysis of patients with normal lactate dehydrogenase (LDH) levels and fewer than three disease sites, the three-year survival rate for combination was 62% (95% CI, 49.3%-72.0%) compared with 45% who received Tafinlar alone (95% CI, 34.9%-55.1%). In advanced melanoma, a patient's LDH level is often predictive of prognosis and may be a predictor of treatment response.
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, vomiting, joint pain (arthralgia), hypertension, cough and peripheral edema.
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 as first-line therapy 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 progression-free survival (PFS). Secondary endpoints included overall survival (OS), overall response rate (ORR), duration of response (DoR), and safety. There were 26 patients who crossed over from the monotherapy group to the combination group after the combination demonstrated a significant OS benefit in a prior analysis.
At three years of follow up, the combination of Tafinlar + Mekinist continued to demonstrate a benefit on the measures of DoR and ORR, in line with results seen at the two-year follow up analysis. 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.
