Long-Term Outcomes of Dabrafenib/Trametinib in BRAF V600–Mutated Advanced Melanoma

Findings from a pooled analysis of two phase III trials, COMBI-d and COMBI-v, centered on outcomes with first-line dabrafenib plus trametinib vs either agent alone.

First-line treatment with dabrafenib plus trametinib yielded durable, long-term improved outcomes in patients with BRAF V600–mutated unresectable or metastatic melanoma compared with dabrafenib or trametinib alone, according to data (abstract 9507) presented at the 2019 American Society of Clinical Oncology (ASCO) Annual Meeting in Chicago.

“This is a pooled analysis of two studies, the COMBI-d and COMBI-v studies,” said Paul Nathan, PhD, of Mount Vernon Cancer Center in London, who presented the results. “We previously reported 3-year landmark analyses that showed that the progression-free survival was 23% and overall survival [was] 44% for this pooled group of patients.”

The two phase III trials, COMBI-d (NCT01584648) and COMBI-v (NCT01597908), enrolled patients with previously untreated BRAF V600–mutated unresectable or metastatic melanoma. In COMBI-d, patients received dabrafenib (150 mg twice daily) plus trametinib (2 mg once daily; n = 211) or dabrafenib plus placebo (n = 212). In COMBI-v, patients received dabrafenib (150 mg twice daily) plus trametinib (2 mg once daily; n = 352) or vemurafenib (n = 352). The primary endpoints were progression-free survival (PFS) in COMBI-d and overall survival (OS) in COMBI-v. 

Thus, in this updated 5-year analysis, the investigators sought to determine long-term survival in previously untreated patients who received the combination therapy and to confirm baseline predictive factors of long-term survival from the 3-year analysis, including lactate dehydrogenase [LDH] levels and number of organs involved.

In the pooled analysis, there were 563 patients with a median age of 55 years (range, 18–91 years; 57% male and 43% female). At baseline, 64% (363/563) had M1c disease, 19% had M1b disease (105/563), 13% had M1a disease (75/563), and 3% had M0 disease (19/563). Baseline LDH levels were normal in 65% of patients (365/563). Approximately half of patients had three or more organs involved (275/563). At the data cutoff, 62% (351/563) of patients had died, and 18% were receiving ongoing treatment. COMBI-d closed last year.

With the combination treatment, the 5-year progression-free survival (PFS) rate was 19% (95% CI, 15%–22%), and the overall survival (OS) rate was 34% (95% CI, 30%–38%). When patients were grouped based on LDH level, patients with a normal LDH level had a PFS rate of 25% and an OS rate of 45% compared with 8% and 16%, respectively, in patients with elevated LDH levels. The PFS and OS rates in patients with a normal LDH level and fewer than three organs involved were 31% and 55%, respectively.

“These are really important for patients. Long-term PFS was seen in this subset [of patients with normal LDH levels and fewer than three organs involved], but can this be improved?” asked Paul Chapman, MD, of Memorial Sloan Kettering Cancer Center, who was the discussant of the study at the meeting. “Other new ideas are needed.”

Of 561 patients who had measurable disease at baseline, 19% had complete response (109), 49% had partial response, and 23% had stable disease. The objective response rate was 68% (383; 95% CI, 64%–72%). The 5-year PFS and OS rates were 49% and 71%, respectively, in patients with complete response; 16% and 32%, respectively, in patients with partial response; and 1% and 16%, respectively, in patients with stable disease.

In total, 53% of patients (299/563) subsequently received additional anticancer therapy after dabrafenib and trametinib; of these, approximately, two-thirds received immunotherapy (196/299). The investigators reported no new safety signals, and no treatment-related deaths occurred.

Chapman concluded that the choice for a first-line therapy for patients with BRAF V600–mutated unresectable or metastatic melanoma-a BRAF/MEK inhibitor or a checkpoint inhibitor-still remains unclear.