Intermittent chemotherapy (CT) plus continuous or intermittent cetuximab (C) in the first-line treatment of advanced colorectal cancer (aCRC): Results of the two-arm phase II randomized MRC COIN-B trial

Background: COIN‐B is a trial of intermittent chemotherapy (ICT) plus intermittent cetuximab (C) vs ICT plus continuous C in the first‐line treatment of aCRC. It complements the COIN trial by investigating how C might safely and effectively be added to an ICT strategy. Methods: Patients (pts) had measurable aCRC; no prior CT for metastases; WHO PS 0‐2 and good organ function. Randomisation was: Arm D ‐ continuous OxFU + weekly C for 12 wks then a planned break from all therapy; Arm E ‐ OxFU + weekly C for 12 wks then weekly C. Upon RECIST progression on either arm, OxFU (or FU) plus C was restarted and continued until progression on maximal tolerated therapy. Prospective KRAS testing was introduced in May 2008. Primary outcome measure is Failure‐Free Survival (FFS) at 10 months (mo) in KRAS‐wt pts who had not progressed, died or failed the treatment strategy within 3 mo of randomisation. The trial was powered to differentiate between a desired 10‐mo FFS rate of 50% and a minimum of 35%, in 136 pts (168 allowing for drop‐outs). Secondary outcome measures included safety, overall survival (OS) and toxicity. Results: 169 KRAS‐wt pts were randomised 07/07 to 06/10, 77 arm D / 92 arm E. Median age 64 years (IQR 55‐70); 92% PS 0‐1. In Arms D and E respectively, 65 (84%) and 67 (73%) pts were eligible for the primary analysis; 10‐mo FFS rates were 48% vs 54% (one‐sided 95% confidence limit 37% and 43% respectively). Median FFS was 12.0 vs 13.7 mo respectively (IQR 6.1‐20.3 and 8.6‐23.2). Median OS was 20.1 vs 18.4 mo. First CFI length was 3.7 mo vs 5.1 mo (IQR 2.5‐6.2 and 2.5‐8.9). In pre‐planned exploratory analysis, median time to progression/death after chemo break was 3.1 mo (IQR 2.1‐8.1) in Arm D and 6.0 mo (IQR 2.9‐10.9) in Arm E. Toxicity was similar and only 1 arm D pt had G 3 hypersensitivity following C reintroduction. Analyses by BRAF & NRAS (tested retrospectively) will be presented. Conclusions: C was safely incorporated in 2 ICT strategies. Continuous C as maintenance was associated with a longer CFI and longer time to progression/death. This encouraging strategy of incorporating biological maintenance therapy needs validation in phase III trials.