Dabrafenib/Trametinib Combo Provides Lasting Control for BRAF V600-Mutant Metastatic Melanoma

Five years out, one-third of patients with unresectable or metastatic BRAF V600-mutant melanoma remained alive following treatment with dual targeted therapy with dabrafenib (Tafinlar) plus trametinib (Mekinist), and 1 in 5 remained alive without progression, according to an analysis COMBI-d and COMBI-v trials reported at the 2019 ASCO Annual Meeting.¹

Pooled data from 2 randomized trials of the BRAF inhibitor and MEK-targeted trametinib (Mekinist) showed a 5-year overall survival (OS) of 34% among 563 evaluable patients. Additionally, 19% of the patients were living without disease progression at 5 years.

Patients who achieved complete responses had the best odds of attaining long-term benefit, said Paul Nathan, MBBS, PhD, FRCP, in the Department of Medical Oncology, Mount Vernon Cancer Centre.

“This is the largest data set and longest follow-up in previously untreated patients with BRAF V600-mutant unresectable or metastatic melanoma treated with BRAF and MEK inhibitors,” he said. “Lower baseline tumor burden and less-aggressive tumor biology were associated with prolonged progression-free survival (PFS) and overall survival. These results suggest that first-line treatment with dabrafenib plus trametinib provides long-term survival benefit in a sizeable cohort of patients.”

Nathan presented long-term follow-up results from the international randomized COMBI-d² and COMBI-v³ trials. Investigators in both studies enrolled adult patients with unresectable or metastatic melanoma that harbored BRAF V600E/K mutations. Eligibility criteria limited enrollment to patients with no prior systemic therapy and no prior exposure to a BRAF inhibitor or MEK inhibitor.

COMBI-d involved 423 patients randomized to dabrafenib plus trametinib (N = 211) or to dabrafenib plus placebo (n = 212). In COMBO-v, 704 patients were randomized to dabrafenib plus trametinib (N = 352) or to single-agent vemurafenib (Zelboraf; n = 352). The original report of pooled data showed a 3-year PFS probability of 23% and a 3-year OS of 44%.⁴

Nathan said the updated analysis had a two-fold objective: determine long-term survival in the patients randomized to dabrafenib/trametinib in the 2 trials combined and to confirm baseline predictors of long-term survival. At the data cutoff dates of December 2018 for COMBI-d and October 2018 for COMBI-v, 62% of patients in the 2 studies had died, 7% remained on treatment, and 11% remained in follow-up.

The median age was 55, and men accounted for 57% of those treated with dabrafenib/trametinib. Only 3% of patients had nonmetastatic disease; two-thirds had M1c metastatic disease. One-third of the patients had elevated LDH, including 11% who had elevations two times the upper limit of normal (ULN). Half of the patients had ≥3 metastatic sites, and the median sum of lesion diameters was 57 mm.

The updated analysis showed a 4-year PFS rate of 21%, declining slightly to 19% at 5 years. Baseline LDH and number of involved organ sites both had favorable associations with PFS. Among patients with LDH at or below the ULN and <3 metastatic sites, the 4-year PFS rate was 33%, declining to 31% at 5 years.

An OS analysis revealed a 4-year survival rate of 37% and a 5-year OS rate of 34%. Patients with prognostically favorable baseline LDH and fewer metastatic sites had a 4-year OS of 58% and 5-year OS of 55%.

The dabrafenib/trametinib combination achieved objective responses in 68% of patients, including complete responses (CRs) in 19%. Patients with CRs had a 4-year PFS rate of 52% and a 5-year PFS of 49%. PFS declined sharply for patients who had less than CR: 17% and 16% at 4 and 5 years, respectively, with partial response (PR) and then to 5% and 1% for patients who had stable disease (SD) as best response.

Response status had a similar association with OS, declining from 76% at 4 years among complete responders to 35% and 18% for patients who had PR or SD. The 5-year OS rate was 71% after CR, 32% after PR, and 16% with SD.

References

1. Nathan P, Robert C, Grob JJ, et al. Five-year analysis of dabrafenib plus trametinib in patients with BRAF V600-mutant unresectable or metastatic melanoma. J Clin Oncol. 2019;37 (suppl; abstr 9507).
2. Long GV, Stroyakovskiy D, Gogas H, et al. Combined BRAF and MEK Inhibition versus BRAF inhibition alone in melanoma. N Eng J Med. 2014; 371:1877-1888 doi: 10.1056/NEJMoa1406037.
3. Robert C, Karaszewska B, Schachter J, et al. Improved overall survival in melanoma with combined dabrafenib and trametinib. N Engl J Med. 2015;372:30-39. doi: 10.1056/NEJMoa1412690.
4. Schadendorf D, Long GV, Strojakovski D, et al. Three-year pooled analysis of factors associated with clinical outcomes across dabrafenib and trametinib combination therapy phase 3 randomised trials. Eur J Cancer. 2017;82:45-55.

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