1111P A randomised phase II study of intermittent versus continuous dosing of targeted therapy in patients with BRAFV600 mutant advanced melanoma (INTERIM)

BRAF+MEK inhibitors extend life expectancy of BRAF V600 mutant advanced melanoma patients; acquired resistance limits duration of benefit. Preclinical and case studies suggested that intermittent dosing could enable patients to remain on treatment longer, delay onset of disease progression and offer improved quality of life (QoL). INTERIM was a UK randomised multicentre phase II trial testing an intermittent dosing regimen. Patients with BRAFV600 mutant advanced melanoma with ECOG PS 0-1 due to start dabrafenib+trametinib were randomised to receive dabrafenib (150mg bid) and trametinib (2mg od) either continuously (CONT) or intermittently (INT; dabrafenib d1-22+trametinib d1–15) on a 28 day cycle. Prior immunotherapy and brain involvement was allowed. Patient recruitment, treatment compliance, QoL and progression-free survival (PFS) were evaluated for the primary endpoint. Secondary endpoints included response rate (ORR), overall survival (OS) and toxicity. The prognostic and predictive value of mutant BRAFV600E ctDNA was measured by droplet digital PCR (ddPCR), using mutant allele frequency of >1% as the detection threshold. 79 patients (39 INT, 40 CONT) were recruited from Dec ‘17–Feb ’20; median age 67 years, 52% PS 1, 65% AJCC (7th ed) M1c, 29% had brain metastases and 46% had LDH > ULN. With median follow-up of 19 months, 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 18.1 mo 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 a higher proportion of grade >3 AEs (53% vs 42%). QoL at 6 months favoured CONT. 66 patients had baseline plasma collected for ctDNA analysis and 27 (41%) of these had detectable BRAFV600E ctDNA. Detection prior to treatment correlated with worse OS (HR 2.55, 95%CI 1.25-5.21, p=0.01) and higher disease burden (LDH>ULN; p<0.001). A change to undetected during treatment did not significantly predict better OS. The UK INTERIM study is consistent with other national studies suggesting that intermittent dosing does not improve efficacy of BRAF+MEKi.