Dabrafenib plus trametinib as a first-line treatment demonstrated long-term survival benefit for approximately one-third of patients who had unresectable or metastatic melanoma with a BRAF V600E or V600K mutation, a 5-year pooled analysis of two phase III trials revealed. The findings were recently published in the New England Journal of Medicine.
“Patients who have unresectable or metastatic melanoma with a BRAF V600E or V600K mutation have prolonged progression-free survival and overall survival when receiving treatment with BRAF inhibitors plus MEK inhibitors,” the study authors explained. “However, long-term clinical outcomes in these patients remain undefined.”
The pooled analysis included extended-survival data from the COMBI-d and COMBI-v trials, both of which included treatment-naïve patients with unresectable or metastatic melanoma who were randomized to receive either dabrafenib plus trametinib or BRAF inhibitor monotherapy. Specifically, the COMBI-d trial used dabrafenib plus placebo as the comparator arm and the COMBI-v trial used vemurafenib alone as the comparator arm.
For primary endpoints, the COMBI-d trial used progression-free survival and COMBI-v used overall survival. Between the COMBI-d (n=211) and the COMBI-v (n=352), a total of 563 patients were included who received dabrafenib plus trametinib.
Overall, at 4 years, 21% of patients (95% CI, 17%–24%) did not have disease progression and 37% of patients (95% CI, 33%–42%) remained alive. At 5 years, 19% of patients (95% CI, 15%–22%) did not have disease progression and 34% of patients (95% CI, 30%–38%) remained alive.
In a previous pooled analysis of the COMBI-d and COMBI-v trials, the 3-year progression-free survival (PFS) rate was 23% (95% CI, 20%–27%) and the overall survival (OS) rate was 44% (95% CI, 40%–49%).
“Of note, the survival curves appear to plateau from 3 to 5 years,” the study authors asserted. “This finding suggests stabilization of rates of progression-free survival and overall survival over time in this population.”
In addition, several characteristics at baseline were found in a multivariate analysis to be significantly associated with a longer PFS and OS. Characteristics included older age, female sex, BRAF V600E genotype, better performance status, normal lactate dehydrogenase level, and fewer than three disease sites.
Specifically, the 5-year PFS rate for patients with normal lactate dehydrogenase level at baseline was 25% (95% CI, 20%–30%) compared with a PFS rate of 8% (95% CI, 4%–13%) for patients with an elevated level. The 5-year OS rate was 43% (95% CI, 38%–49%) for patients with normal lactate dehydrogenase level at baseline and 16% (95% CI, 11%–22%) for patients with an elevated level.
Nearly all patients (98%) had an adverse event, but no “unexpected” adverse events were reported, according to the study authors. No patients died from a treatment-related adverse event.