Trial Confirms Clinical Activity of Trametinib Plus Dabrafenib in BRAF-V600–Mutant Melanoma

The largest known prospective study of patients treated with trametinib plus dabrafenib for unresectable advanced melanoma with BRAF-V600 mutation confirmed the combination’s clinical activity.

In patients with BRAF-V600mutant advanced melanoma, the combination of BRAF and MEK inhibitors has shown increased progression-free survival (PFS) and overall survival (OS) compared with BRAF inhibition or chemotherapy alone. Trametinib plus dabrafenib is one such combination, and a recent clinical trial in near real-world conditions confirmed the regimen’s clinical activity.

BRAF-V600 mutations occur in approximately 40% of metastatic cutaneous melanoma cases, and BRAF inhibitor monotherapy with dabrafenib or vemurafenib is known to improve PFS and OS compared with chemotherapy, but treatment resistance related to reactivation of the mitogen-activated protein kinase (MAPK) pathway is common. Adding an MEK inhibitor like trametinib mitigates that resistance by delaying MAPK pathway reactivation.

The phase 3B, single-arm, open-label, nonrandomized study assessed the safety, response to treatment, PFS, and factors associated with progression on the trametinib plus dabrafenib regimen. It also provided more insight into specific risk groups.

Patients with advanced, unresectable BRAF-V600-mutant melanoma—including those with brain metastases, Eastern Cooperative Oncology Group Performance Status (ECOG PS) 2 or lower, elevated lactate dehydrogenase (LDH), and those who had undergone previous lines of therapy for melanoma—were included in the study.

At the time of the study, trametinib was not commercially available in France as a monotherapy or in combination with dabrafenib, so the study aimed to provide access for these patients. Dabrafenib was already commercially available. Main end points were response to treatment, overall response rate (ORR), PFS, and the frequency and proportion of adverse events (AEs). Researchers also assessed the association between PFS and clinical and disease characteristics at inclusion.

Eligible patients were given 2 mg of trametinib orally once a day in combination with twice-daily 150 mg doses of dabrafenib, also orally during participation. They were evaluated every 4 weeks during the first 2 months of the study, then every 8 weeks thereafter, with data on adverse events collected up to 28 days post treatment termination.

Participants continued treatment until disease progression, a safety event warranting discontinuation, withdrawal of patient consent, or when authorization was granted for trametinib’s reimbursal in combination with dabrafenib.

Of 914 patients screened at 40 sites across France, 856 were eligible. In the overall cohort, 92% of patients had stage IV melanoma, 38% had an ECOG PS of 1 or more, 32% had brain metastases present, and 37.5% had elevated LDH at inclusion.

Over the course of the study, 59.1% of cohort withdrew prematurely, while the remainder of patients transitioned to marketed product. Disease progression (63.2%), AEs (18.8%), and death (5.3%) were the main reasons patients discontinued treatment. Overall, 93.9% of patients experienced AEs or severe AEs.

The median follow-up was 5.63 months, with a range of 0.03 to 20.53 months and 21.1% of patients reaching 48 weeks of follow-up. Median PFS was 8.02 months (95% CI, 7.33-8.77).

Lower PFS was seen in patients with ECOG PS of at least 1, elevated LDH, 3 or more metastatic sites, or brain metastases. Conversely, those with less than 3 metastatic sites, ECOG of 0, and no BM had the highest chance of PFS at 6 months (83%; 95 CI, 76-87) and 12 months (56%; 95% CI, 47-64). The overall response rate (ORR) was 50.2%, and complete response occurred in 15.3% of patients.

The authors conclude, “The results not only confirm the clinical activity of trametinib plus dabrafenib, but also provide realistic figures of ORR and PFS in a real-world setting, and provide clinicians with practical tools to predict the PFS when treated by trametinib plus dabrafenib.”

Reference

Saiag P, Robert C, Grob J, et al. Efficacy, safety and factors associated with disease progression in patients with unresectable (stage III) or distant metastatic (stage IV) BRAF-V600-mutant melanoma: an open label, non-randomized, phase IIIb study of trametinib in combination with dabrafenib. Eur J Cancer. 2021;154:57-65 doi:10.1016/j.ejca.2021.05.031