509P - FOCUS4-D: Results from a randomised, placebo controlled trial (RCT) of AZD8931 (an inhibitor of signalling by HER1, 2, and 3) in patients (pts) wit...

Date 08 October 2016
Event ESMO 2016 Congress
Session Poster Display
Topics Colon Cancer
Rectal Cancer
Presenter Richard Adams
Citation Annals of Oncology (2016) 27 (6): 149-206. 10.1093/annonc/mdw370
Authors R.A. Adams1, E. Brown2, L. Brown3, R. Butler4, S. Falk5, D. Fisher3, R. Kaplan3, P. Quirke6, S. Richman6, L. Samuel7, J. Seligmann8, M. Seymour9, K.K. Shiu10, H. Wasan10, R. Wilson11, T. Maughan12
  • 1Division Of Cancer And Genetics, Cardiff University and Velindre Cancer Centre, CF14 2TL - Cardiff/GB
  • 2Oncology, Edinburgh Cancer Centre Western General Hospital, Edinburgh/GB
  • 3Mrc Clinical Trials Unit At Ucl, Institute of Clinical Trials and Methodology-UCL, WC2B6NH - London/GB
  • 4Genetics, Cardiff and Vale University Helath Board Trust, Cardiff/GB
  • 5Oncology, University Hospitals Bristol NHS Trust Bristol Haematology and Oncology Centre, Bristol/GB
  • 6Pathology, University of Leeds-Institute of Health Sciences, Leeds/GB
  • 7Oncology, Aberdeen Royal Infirmary, Aberdeen/GB
  • 8Medical Oncology, The Leeds Teaching Hospital NHS Trust St. James University Hospital, LS9 7TF - Leeds/GB
  • 9Department Of Oncology, The Leeds Teaching Hospital NHS Trust St. James University Hospital, Leeds/GB
  • 10Oncology, University College London Hospital, London/GB
  • 11Centre For Cancer Research And Cell Biology, Queen's University Belfast, BT9 7JL - Belfast/GB
  • 12Oncology Clinical Trials Office (octo), Oxford Cancer and Haematology Centre, Churchill Hospital, Oxford/GB

Abstract

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

Disclosure

R.A. Adams: Merck Serono, Servier, Amgen, Boehringer Ingelheim consultancy fees All other authors have declared no conflicts of interest.