The multi-kinase inhibitor regorafenib is approved for the treatment of metastatic colorectal cancer (mCRC) that is refractory to all other standard treatments. Thus, patients with RAS-wild-type mCRC are typically treated with regorafenib only after receiving anti-EGFR antibodies, such as cetuximab. Now, data from the phase II REVERCE trial suggest that the reverse sequence is preferable.

In REVERCE, patients with KRAS-wild-type mCRC who had treatment failure with fluoropyrimidines, irinotecan and oxaliplatin, most of whom (96–98%) were also refractory to bevacizumab, were randomly assigned to receive regorafenib followed by cetuximab ± irinotecan upon disease progression (R–C; n = 51) or the opposite sequence (C–R; n = 50). Overall survival (OS) was superior in the R–C arm (17.4 months versus 11.6 months; HR 0.61; P = 0.0293), with no difference in quality of life between the arms. Interestingly, the OS benefit seemed to be driven mostly by greater activity of cetuximab than regorafenib as the second treatment: first progression-free survival (PFS1) was 2.4 months in the R–C arm versus 4.2 months in the C–R arm (HR 0.97; P = 0.91), whereas PFS2 was 5.2 months versus 1.8 months (HR 0.29; P < 0.0001). Notably, the disease-control rate (DCR) was lower when regorafenib was used second rather than first (31% versus 46%). By contrast, the DCR with cetuximab was similar irrespective of sequencing (77% versus 78%).

“Circulating biomarker analyses revealed that, after the first treatment, more patients who had received cetuximab versus regorafenib had new alterations in RAS, BRAF, EGFR, ERBB2 (HER2) and/or MET (12 versus 3),” states lead author Kohei Shitara. “Earlier occurrence of these acquired or selected oncogenic alterations might partially explain the worse outcomes when cetuximab is used before regorafenib,” he opines. Indeed, these treatment-emergent alterations correlated with shorter OS (HR 2.02; P = 0.027).

“This trial included a small number of patients and thus the results are hypothesis-generating: a phase III study is needed to confirm our findings,” Shitara concludes.