Phase II Study of Cetuximab Rechallenge in Patients with RAS Wild-Type metastatic Colorectal Cancer: E-Rechallenge Trial

Abstract

Introduction: Several reports indicated that cetuximab (Cmab) rechallenge may be efficacious in patients for whom Cmab was previously effective. This current study investigates prospectively the efficacy and safety of Cmab rechallenge as a salvage chemotherapy and clinical utility of liquid biopsy. Methods: The E-Rechallenge tiral (UMIN 000016439) is a multicenter phase II singlearm study in mCRC patients, who have become refractory to fluoropyrimidines, oxaliplatin, 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). Protocol treatment is a single arm of 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 anti-EGFR antibody free interval (aEFI) and efficacy, and safety. Additional research of ctDNA was conducted optionally. Baseline plasma samples were analyzed for KRAS, NRAS, BRAF, PIK3CA and EGFR S492R mutations using digital PCR. Results: Between Dec 2014 and Oct 2017, 33 patients were enrolled. Tumor response were PR 15.6%/SD 40.6%/PD 43.8%. Median PFS and OS were 2.9 months and 8.6 months. A statistical significant association between aEFI and PFS was not found by the Log-rank test. Twenty-four of 33 patients participated in the ctDNA research. In the liquid biopsy cohort, tumor response were PR 12.5%/SD 50.0%/PD 37.5%. At least one mutation was detected in 75% of patients at the baseline. In wild type of these genes the PR and DCR increased to 50% and 83.3%, and median PFS was significantly prolonged compared with those in any mutations (7.0 vs 2.9 months). Conclusion: Cmab rechallenge showed moderate activity in patients for whom Cmab was previously effective. Analyzing ctDNA of EGFR signaling pathway should contribute to enrich the patients with benefit from Cmab rechallenge.