Oncologic Outcomes in Metastatic Colorectal Cancer with Regorafenib with FOLFIRI as a Third- or Fourth-Line Setting

Abstract

BACKGROUND: To evaluate the efficacy and toxicities of regorafenib plus irinotecan, dose-escalated on the basis of uridine diphosphate glucuronosyltransferase 1A1 (UGT1A1) genotyping, in previously heavily treated metastatic colorectal cancer (mCRC) and the prognostic values of EGFR expression, KRAS mutations, and tumor sidedness. METHODS: Forty-one patients with mCRC with disease progression after treatment with fluoropyrimidines, oxaliplatin, irinotecan, anti-VEGF, and anti-EGFR MoAbs were subjected to UGT1A1 genotyping and received regorafenib combined with FOLFIRI with dose-escalated irinotecan. RESULTS: The median follow-up period was 10.0 months (1.3-23.5 months). The overall disease control rate was 58.5%, whereas the median progression-free survival (PFS) and overall survival (OS) were 6.0 months and 12.0 months, respectively. KRAS mutations were significantly associated with positive EGFR expression (P = .026). KRAS mutations significantly correlated with a shorter OS than KRAS wild-type (6.0 vs. 14.4 months, P = .014) but had no significant association with PFS. Positive EGFR expression had an inverse correlation with PFS (2.5 vs. 14.0 months, P = .039) and OS (9.6 vs. 19.7 months, P = .044). Moreover, left-sided tumors associated with superior PFS (2.0 vs. 7.0 months, P < .0001) and OS (4.0 vs. 13.0 months, P < .0001), and tumor sidedness was an independent prognostic factor by the multivariate analysis. CONCLUSION: Regorafenib and FOLFIRI concomitant therapy with dose-escalated irinotecan seemed to be potentially practicable with satisfactory oncological results. KRAS mutations and EGFR expression might be predictors of poor oncological outcomes; however, left-sided mCRCs would be more beneficial for concomitant regorafenib and FOLFIRI therapy.

Epidermal growth factor receptor mRNA expression: A potential molecular escape mechanism from regorafenib

“…Preclinical studies have previously indicated that BRAF inhibition causes feedback activation of EGFR signaling and increased EGFR expression, allowing for ongoing tumor cell proliferation . In previous studies, tumor tissue EGFR expression has been shown to be a negative prognostic marker . Our data further support these findings, suggesting that regorafenib therapy could increase EGFR expression and signaling to an extent that leads to molecular escape and treatment resistance.…”

Regorafenib plus FOLFIRI with irinotecan dose escalated according to uridine diphosphate glucuronosyltransferase 1A1 genotyping in previous treated metastatic colorectal cancer patients: study protocol for a randomized controlled trial

“…In our preliminary, retrospective and observational study, which 41 mCRC patients treated with regorafenib plus irinotecan dose escalated FOLFIRI as a third-or fourth-line setting were analyzed, median PFS was 6.0 months, median OS was 12.0 months and DCR was 58.5% [13]. Compared to CORRECT and CONCUR studies, the oncological outcomes were satisfactory and treatment-related adverse events were acceptable.…”

Regorafenib plus FOLFIRI with irinotecan dose escalated according to uridine diphosphate glucuronosyltransferase 1A1genotyping in previous treated metastatic colorectal cancer patients:study protocol for a randomized controlled trial

“…In our preliminary, retrospective and observational study, in which 41 patients with mCRC were treated with regorafenib plus irinotecan dose-escalated FOLFIRI as a third- or fourth-line setting, median PFS was 6.0 months, median OS was 12.0 months and DCR was 58.5% [13]. Compared to the CORRECT and CONCUR studies, the oncological outcomes were satisfactory and treatment-related AEs were acceptable.…”