Phase II study of cetuximab rechallenge in patients with ras wild-type metastatic colorectal cancer: E-rechallenge trial

Background: Several previous reports indicated that cetuximab (Cmab) rechallenge may be efficacious in patients for whom Cmab was previously effective. On the other hand, some reports did not support this. Considering the plasticity of sensitive clone, we assumed that an anti-EGFR antibody-free interval (aEFI) and efficacy may be correlated. This current study investigates the efficacy and safety of Cmab rechallenge as a salvage chemotherapy. Methods: The E-Rechallenge tiral is a multicenter phase II study in mCRC patients who have become refractory to fluoropyrimidines, L-OHP, CPT-11, Cmab and bevacizumab, and in whom previous treatment with Cmab was effective in any earlier line (achieving CR, PR, or SD that persisted for ≥6 months). The other main eligibility criteria are; RAS wild-type, measurable disease, aEFI ≥16 weeks between the last dose of Cmab during previous treatment and the start of Cmab rechallenge. Protocol treatment is the combination of weekly Cmab with biweekly CPT-11. The primary endpoint is response rate (RR). Secondary endpoints are progression free survival (PFS), overall survival (OS), association between the aEFI and efficacy, and safety. Using a single-stage binominal design, 45 patients were required; a RR of ≥ 20% was considered promising, and a RR of ≤ 5% unacceptable (one-sided α = 2.5%, β = 10%). Additional research of ctDNA was conducted optionally. Results: Between Dec 2014 and Oct 2017, 33 patients were enrolled. Patients’ characteristics were as follows; mean age 64.4, male/female 84.8%/15.2%, primary location right/left 12.1%/87.9% and the efficacy in previous Cmab, CR/PR/SD ≥6 months 3%/78.8%/18.2%, respectively. The primary endpoint; the rates of PR/SD/PD (95%CI) were PR 15.6% (5.3-32.7%)/SD 40.6% (23.6-57.6%)/ PD 43.8% (26.4-62.3%). Secondary endpoint; median PFS and OS (95%CI) were 88 days (62-113days) and 262 days (195-307days). There were no statistical significant difference of PFS stratified by median aEFI. New signals of adverse events were not identified. Conclusions: Cmab rechallenge showed some activity in the salvage setting, in patients for whom Cmab was previously effective. The additional research of ctDNA may contribute to identify patients with benefit from Cmab rechallenge. Clinical trial identification: UMIN 000016439. Legal entity responsible for the study: Comprehensive Support Project for Oncological Research. Funding: Merck Serono. Disclosure: E. Shinozaki, H. Satake: Honoraria: Merck Serono. All other authors have declared no conflicts of interest.