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

Background

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.

Methods

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 BRAFV^600E 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 from Dec ‘17–Feb ’20; median age 67 years, 52% PS 1, 65% AJCC (7^th 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 BRAFV^600E 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.

Conclusions

The UK INTERIM study is consistent with other national studies suggesting that intermittent dosing does not improve efficacy of BRAF+MEKi.

Clinical trial identification

Protocol Number: INTERIM17; Final version and date: V4.0 01 August 2019 EudraCT Number: 2016-005228-27; ISRCTN Number: 18183156.

Editorial acknowledgement

Legal entity responsible for the study

Cambridge University Hospitals NHS Foundation Trust.

Funding

National Institute for Health and Care Research & Cancer Research UK.

Disclosure

A. Gupta: Financial Interests, Personal, Invited Speaker: Bristol Myers Squibb; Financial Interests, Personal, Writing Engagement: Novartis; Financial Interests, Personal, Advisory Board: Amgen; Financial Interests, Institutional, Local PI: Alkermes, AstraZeneca, Merck, Novartis; Financial Interests, Institutional, Coordinating PI: Bristol Myers Squibb. R.E. Board: Non-Financial Interests, Advisory Role: Melanoma Focus. M. Payne: Financial Interests, Personal, Advisory Board, clinical advisor for advisory board: BMS; Financial Interests, Personal, Invited Speaker, Invited speaker: BMS; Non-Financial Interests, Other, Received funding towards conference fess and travel for ESMO 2022: Pierre Fabre. S. Danson: Financial Interests, Institutional, Full or part-time Employment, National Specialty Lead for Early Phase Cancer: NIHR; Financial Interests, Institutional, Other, Consultancy: Oxcia, Orion; Financial Interests, Institutional, Coordinating PI, Dante lead: NIHR; Financial Interests, Institutional, Coordinating PI, Fortitude pi: Amgen; Financial Interests, Institutional, Research Grant, Ecmc lead: Cancer research UK; Non-Financial Interests, Leadership Role, Lion steering group chair: NIHR; Non-Financial Interests, Leadership Role, Concorde steering group member: Cancer Research UK. J. Carser: Financial Interests, Personal, Invited Speaker, speaker fee: Merck. C. O'Hanlon Brown: Financial Interests, Personal, Advisory Board: Gilead, Daiichi Sankyo. G.J. Burghel: Financial Interests, Personal, Invited Speaker, I was compensated for educational presentations: AstraZeneca. S. Twelves: Financial Interests, Personal, Full or part-time Employment, Partner is employee of GSK; Financial Interests, Personal, Stocks/Shares, Partner owns GSK shares. M.R. Middleton: Financial Interests, Personal and Institutional, Research Grant: Roche, AstraZeneca, Immunocore, GRAIL; Financial Interests, Institutional, Research Funding, trials fees paid to institution: Novartis, Immunocore, BMS, Pfizer, Merck/MSD, Regeneron, BioLineRx, Replimune. P.G. Corrie: Financial Interests, Personal, Advisory Board: Merck Sharp & Dohme; Financial Interests, Personal, Invited Speaker: Bristol Myers Squibb, Pierre Fabre; Financial Interests, Personal, Other, Consultancy: Microbiotica; Financial Interests, Institutional, Local PI: Bristol Myers Squibb, Novartis, Achilles, AstraZeneca, Array Pharmaceuticals, Merck Sharp & Dohme; Financial Interests, Institutional, Research Grant: Pierre Fabre. All other authors have declared no conflicts of interest.