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Clinical Trial
. 2024 Jan:196:113455.
doi: 10.1016/j.ejca.2023.113455. Epub 2023 Nov 24.

A randomised phase 2 study of intermittent versus continuous dosing of dabrafenib plus trametinib in patients with BRAFV600 mutant advanced melanoma (INTERIM)

Alimu Dayimu  1 , Avinash Gupta  2 , Rubeta N Matin  3 , Jenny Nobes  4 , Ruth Board  5 , Miranda Payne  6 , Ankit Rao  7 , Alberto Fusi  8 , Sarah Danson  9 , Bryony Eccles  10 , Judith Carser  11 , Ciara O'Hanlon Brown  12 , Neil Steven  13 , Madhumita Bhattacharyya  14 , Ewan Brown  15 , Michael Gonzalez  16 , Martin Highley  17 , Lisa Pickering  18 , Satish Kumar  19 , Ashita Waterston  20 , George Burghel  21 , Leigh Demain  21 , Eleanor Baker  21 , Jerome Wulff  22 , Wendi Qian  23 , Sophie Twelves  22 , Mark Middleton  24 , Pippa Corrie  25
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Free article
Clinical Trial

A randomised phase 2 study of intermittent versus continuous dosing of dabrafenib plus trametinib in patients with BRAFV600 mutant advanced melanoma (INTERIM)

Alimu Dayimu et al. Eur J Cancer. 2024 Jan.
Free article

Abstract

Background: BRAF+MEK inhibitors extend life expectancy of patients with BRAFV600 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 BRAFV600 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 BRAFV600E 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 BRAFV600E 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.

Keywords: BRAF; Circulating tumour DNA; Continuous dosing; Dabrafenib; Intermittent dosing; Metastatic melanoma; Scheduling; Trametinib.

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Conflict of interest statement

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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