Background: FOCUS4 is a phase II/III trial programme testing targeted agents in pts with aCRC in molecularly stratified cohorts. Her 1,2,3 signal inhibition has been hypothesized as a mechanism for tumour control in aCRC potentially sensitive to EGFR inhibition which might delay emergence of resistance in pts responding to standard therapy.
Methods: The FOCUS4-D molecular cohort includes pts whose tumour biomarker assessment confirms wt status for BRAF, PIK3CA, KRAS & NRAS. Following 16 weeks of first-line therapy, patients with stable or responding tumours were randomised to receive either oral AZD8931 or matching lacebo. Patients were followed for progression-free-survival (PFS) as the primary outcome according to RECIST v1.1 criteria. Secondary outcomes included toxicity. Pre-planned interim analyses were agreed using Multi-Arm Multi-Stage (MAMS) trial design methodology triggered by occurrence of PFS events in the placebo arm. Cox regression was used to estimate PFS hazard ratios of AZD8931 relative to placebo adjusted for minimisation factors.
Results: Across 18 UK sites, 32 patients were randomised (16 into each arm) between 01/2014 and 03/2016. Patients were balanced for baseline characteristics. At the first pre-planned interim analysis, the Independent Data Monitoring Committee recommended closure of FOCUS4-D on grounds of lack of activity. At this analysis, 26 patients had experienced a PFS event (11 in the placebo arm). Analyses by both Intention-to-treat (HR = 1.31 [95% CI 0.56-3.08], p = 0.54) and per-protocol (HR = 1.42 [95% CI 0.58-3.50], p = 0.49) did not indicate any benefit for PFS. Toxicity was minimal with the most frequent relating to skin rash; graded at ≥3 in 2 patients (13%).
Conclusions: Despite minimal toxicity, there was no evidence to suggest any efficacy of single agent Her 1,2,3 inhibition in aCRC patients whose tumour is wt for BRAF, PIK3CA, KRAS and NRAS after induction therapy in the first-line setting.
Clinical trial identification: ISRCTN90061546 EUDRACT #: 2012-005111-12
Legal entity responsible for the study: MRC CTU at University College London
Funding: CRUK and MRC
CORE (COnnecting REpositories)
CORE (COnnecting REpositories)