A randomised phase 2 study of intermittent versus continuous dosing of dabrafenib plus trametinib in patients with BRAF V600 mutant advanced melanoma (INTERIM).

Background: BRAF+MEK inhibitors extend life expectancy of patients with BRAF ^V600 mutant advanced melanoma. Acquired resistance limits duration of benefit, but preclinical and case studies suggest intermittent dosing could overcome this limitation. INTERIM was a phase 2 trial evaluating an intermittent dosing regimen.
Methods: Patients with BRAF ^V600 mutant advanced melanoma due to start dabrafenib+trametinib were randomised to receive either continuous (CONT), or intermittent (INT; dabrafenib d1-21, trametinib d1-14 every 28 days) dosing. A composite primary endpoint included progression-free survival (PFS) and quality of life (QoL). Secondary endpoints included response rate (ORR), overall survival (OS) and adverse events (AEs). Mutant BRAF ^V600E ctDNA was measured by droplet digital PCR (ddPCR), using mutant allele frequency of > 1 % as the detection threshold.
Results: 79 patients (39 INT, 40 CONT) were recruited; median age 67 years, 65 % AJCC (7th ed) stage IV M1c, 29 % had brain metastases. With 19 months median follow-up, INT was inferior in all efficacy measures: median PFS 8.5 vs 10.7mo (HR 1.39, 95 %CI 0.79-2.45, p = 0.255); median OS 18.1mo vs not reached (HR 1.69, 95 %CI 0.87-3.28, p = 0.121), ORR 57 % vs 77 %. INT patients experienced fewer treatment-related AEs (76 % vs 88 %), but more grade > 3 AEs (53 % vs 42 %). QoL favoured CONT. Detection of BRAF ^V600E ctDNA prior to treatment correlated with worse OS (HR 2.55, 95 %CI 1.25-5.21, p = 0.01) in both arms. A change to undetected during treatment did not significantly predict better OS.
Conclusion: INTERIM findings are consistent with other recent clinical trials reporting that intermittent dosing does not improve efficacy of BRAF+MEK inhibitors.
Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.
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