Inhibition of EGFR, HER2, and HER3 signalling in patients with colorectal cancer wild-type for BRAF, PIK3CA, KRAS, and NRAS (FOCUS4-D): a phase 2–3 randomised trial

Journal article

Background: There has been a significant change in trials methodology for solid tumours, in response to our greater understanding of cancer biology. FOCUS4 is a phase II/III trial programme testing targeted agents in patients with advanced colorectal cancer (CRC) in molecularly stratified cohorts. Here we present the first results testing the hypothesis that combined Her 1,2,3 signal inhibition, using the tyrosine kinase inhibitor AZD8931, will control growth of ‘all wildtype’ tumours.

Methods: FOCUS4-D includes patients with newly diagnosed advanced or metastatic colorectal cancer whose tumour is BRAF, PIK3CA, KRAS & NRAS wildtype. Following 16 weeks of first-line therapy, patients with stable or responding tumours were randomised to oral AZD8931 (40mg bd) or placebo. Randomisation was done using minimisation with a random element of 20%, with minimisation factors were of randomising hospital site, site of primary tumour, WHO performance status, 16-week CT scan result, number of metastatic sites, and first-line chemotherapy regimen. The primary outcome was progression-free-survival (PFS) according to RECIST v1.1 criteria, pre-specified to be analysed by intention-to-treat. Pre-planned interim analyses were agreed using MAMS trial design methodology triggered by occurrence of PFS events in the placebo group. This trial is registered, number ISRCTN 90061546.

Results: 32 patients were randomised between 01/2014 and 03/2016. Patients were balanced for baseline characteristics. At the first pre-planned interim analysis, the IDMC recommended closure of FOCUS4-D on grounds of lack of activity. At final analysis, 31 patients had experienced a PFS event (16 in the placebo group). Adjusted analyses by both Intention-to-treat (HR=1.10 [95%CI 0.51-2.38], p=0.81) and per-protocol (HR=1.15 [95% CI 0.51-2.62], p=0.73) indicated no benefit for PFS. The most common grade 3 or worse adverse events were skin rash (three [20%] of 15 patients with available data in the AZD8931 group vs none of 16 patients in the placebo group) and diarrhoea (one [7%] vs one [6%]).

Conclusions: The MAMS trial design for FOCUS4 has demonstrated efficiency and effectiveness in trial outcome delivery, informing the decision to proceed or stop clinical evaluation of a targeted therapy within a molecularly defined cohort of patients. The overarching FOCUS4 trial is now poised to open a replacement arm in the all wild type cohort.

Authors: Adams, R; Brown, E; Brown, L; Butler, R; Falk, S

• Publication status: Published
• Peer review status: Peer reviewed
• Publisher: Elsevier
• Journal: Lancet Gastroenterology and Hepatology
• Volume: 3
• Issue: 3
• Pages: 162-171
• Publication date: 2017-01-01
• Acceptance date: 2017-11-09
• DOI: 10.1016/S2468-1253(17)30394-1
• EISSN: 2468-1253