Shitara K, et al. - In this randomized phase 2 trial, researchers tested the therapeutic sequence of regorafenib followed by cetuximab vs cetuximab followed by regorafenib as the current standard sequence for metastatic colorectal cancer patients in terms of effectiveness and safety. Sequence with regorafenib followed by cetuximab ± irinotecan (R-C arm), or the reverse sequence (cetuximab ± irinotecan followed by regorafenib [C-R arm]) was randomly administered to patients with KRAS exon 2 wild-type metastatic colorectal cancer following failure of fluoropyrimidine, oxaliplatin, and irinotecan. Efficacy was tested in 101 patients, where they mainly assessed overall survival (OS), and additionally, progression-free survival (PFS) with initial treatment (PFS1), PFS with second treatment (PFS2), safety, and quality of life. For R-C and C-R, the estimated median OS was 17.4 and 11.6 months, respectively, with a hazard ratio (HR) of 0.61 for OS. The estimated HR for PFS1 (regorafenib in R-C vs cetuximab in C-R) and PFS2 (C in R-C vs R in C-R) was 0.97 and 0.29, respectively. A longer OS was achieved with the therapeutic sequence of regorafenib followed by cetuximab vs the current standard sequence.