Phase II Clinical Trial of Trametinib and Low-Dose Dabrafenib in Advanced, Previously Treated BRAFV600/NRASQ61 Wild-Type Melanoma (TraMel-WT)

Patients with BRAFV600/NRASQ61 wild-type melanoma who progress after immune
checkpoint inhibitors (ICIs) have a poor prognosis. MEK inhibition has
shown activity in this patient population but is associated with treatmentlimiting
skin toxicity. Combining a BRAF inhibitor with a MEK inhibitor is
associated with less skin toxicity.
METHODS This phase II trial investigated trametinib (2 mg once daily) in patients with
advanced BRAFV600/NRASQ61 wild-type, ICI-refractory melanoma. In case of
treatment-limiting skin toxicity, low-dose dabrafenib (50 mg twice daily) was
added to trametinib. After a trial amendment, both drugs were combined upfront.
The confirmed objective response rate (cORR) served as the primary end
point.
RESULTS Twenty-four patients were included (50% male; median age 57 years; 92%
Eastern Cooperative Oncology Group Performance Status 0-2; 75% stage IVM1c/
stage IV-M1d; median number of prior therapies: two [range, 1-5]). Three
patients were enrolled before and 21 patients after the amendment, respectively.
Seven confirmed and one unconfirmed partial responses (PRs) were observed
(cORR, 29.2%). The median duration of response was 16.6 weeks (95% CI, 5.5 to
27.7). Stable disease (SD) was the best response in an additional five patients.
Among the responding patients, genetic alterations causing mitogen-activated
protein kinase (MAPK) pathway activation were documented in six patients. The
disease control rate in patients with MAPK pathway–activating alterations was
64.3% (five confirmed PR, one unconfirmed PR, and three SD). The median
progression-free survival was 13.3 weeks (95% CI, 3.5 to 23.1), and the median
overall survival was 54.3 weeks (95% CI, 37.9 to 70.6). Adding low-dose dabrafenib
to trametinib effectively mitigated or prevented treatment-limiting
trametinib-related skin toxicity.
CONCLUSION The combination of trametinib plus low-dose dabrafenib demonstrated
encouraging efficacy and effective mitigation of skin toxicity in patients with
advanced, ICI-pretreated BRAFV600/NRASQ61 wild-type melanoma patients.
MAPK pathway–activating alterations hold promise as a predictive
biomarker.