Abstract 430P
Background
FOCUS4 was the first molecularly stratified trial in metastatic colorectal cancer (mCRC) and 1 of the first umbrella trial designs launched globally. After 10 years of trial delivery we report our molecular results and learning from all stakeholders.
Methods
FOCUS4 (phase II/III) tested safety and efficacy of targeted therapies in mCRC. It used adaptive statistical methodology to decide if sub-trials should close early and new therapies were added as protocol amendments. Patients with newly diagnosed mCRC were registered and central laboratory testing stratified tumours into molecular subtypes (MSI, BRAF, PIK3CA, TP53 and RAS). After 16 weeks therapy, those with stable/responding disease were eligible for randomisation into a molecularly stratified sub-trial (FOCUS4-B, C or D) or non-stratified FOCUS4-N. The primary outcome was progression-free-survival (PFS) comparing intervention with active monitoring/placebo. On trial completion we sent a detailed questionnaire to key study team members and recruiting sites via an online portal.
Results
From Jan 2014 - Oct 2020, 1434 patients were registered (88 sites). Mutations were found in 1291/1382 samples: BRAF 10%; PIK3CA 14%; RAS 58%; TP53 69%; RAS+TP53 32%; BRAF-PIK3CA-RAS wildtype 26%. 908/1315 (69%) patients completing 16 weeks therapy were eligible for randomisation and 361 allocated into a sub-trial. We activated 3 molecularly targeted sub-trials: FOCUS4-D evaluated AZD8931 in BRAF-PIK3CA-RAS wildtype subgroup (negative trial); FOCUS4-B evaluated aspirin in the PIK3CA mutant subgroup (unable to recruit) and FOCUS4-C evaluated adavosertib in the RAS+TP53 dual mutant subgroup (positive trial; see separate abstract). FOCUS4-N evaluated capecitabine versus a treatment break (positive trial; see separate abstract).
Conclusions
Adaptive stratified medicine trials have many advantages & challenges. Our stakeholder feedback helped inform how such trial designs can succeed in answering multiple questions efficiently, providing resources are adequate. Robust biomarker analysis, correct positioning in the disease pathway, strong partnerships between participating organisations and nimble regulatory control are key to successful delivery of such complex studies.
Clinical trial identification
ISRCTN - ISRCTN90061546.
Editorial acknowledgement
Legal entity responsible for the study
UCL.
Funding
CRUK, MRC, AstraZeneca.
Disclosure
All authors have declared no conflicts of interest.