Efficacy of regorafenib according to extended RAS evaluation: A multicenter retrospective analysis

Regorafenib has been shown to improve survival in later lines of treatment of metastatic colorectal cancer patients, irrespective of RAS status. This study aimed to retrospectively assess the efficacy of regorafenib in relation to extended RAS evaluation in a multi-center real-world setting.

Nine Institution from Central-Southern Italy were involved in the study. Main inclusion criteria were: availability of extended RAS evaluation, availability of data concerning time to progression (TTP) and overall survival (OS). Primary endpoint was OS, independently from line (>2), in relation to different RAS mutations.

Data of 866 regorafenib and/or TAS102-treated patients were collected. RAS extended evaluation was available for 584. In the present study 324 have been enrolled. Patients were divided in six groups: WT (RAS wild-type), 156 pts; Codon 12 (KRAS codon 12 mutation), 82 pts; Codon 13 (KRAS codon 13 mutation), 23 pts; Rare (KRAS codon 61 and 146 mutation or NRAS mutations), 25 pts; G12C (KRAS G12c mutation), 7 pts; G12D (KRAS G12D mutation), 26 pts. Baseline characteristics were well-balanced between groups. No significant differences in OS between groups were observed (p 0.6), with a trend of better survival in favor of mutated patients (median OS=12 m, 8 m and 7 m for G12D, codon 13 and codon 12 when compared to 6 m of WT). No significant differences between groups were observed in terms of TTP (p 0.7). A trend toward a better TTP in mutated patients (median TTP 4.5 in G12C and 3.9 in Rare) in comparison with WT patients (median TTP 3.0 m) was confirmed. Considering those patients who received TAS in addition to regorafenib (either before or after, 163 patients), an overall OS advantage was observed (p 0.0002) suggesting a favorable prognostic factors enriched population. According to RAS extended evaluation, patients treated with both TAS and regorafenib displayed significant different survival (p 0.05), with a better performance for WT (OS 10 m), Codon 12 (OS 12 m) and G12D (OS 14 m). In particular OS of regorafenib in WT patients was significant longer in those receiving even TAS (before or after, 78 pts vs 85 pts, p 0.0003). Differently, in G12D, G12C, Rare, Codon 12 and Codon 13 groups no significant differences were observed in OS of regorafenib between patients receiving only regorafenib or both drugs.

Our data demonstrate that RAS mutations do not affect outcome in regorafenib-treated patients, although a trend toward a better efficacy in RAS mutated patients has been observed. Patients receiving TAS102 in addition to regorafenib (before or after) show a better Regorafenib-related survival, probably because of a less aggressive disease; the benefit of the combination is significantly higher in WT patients and not significant in RAS mutated subgroups. These data, even bearing in mind that less than 50% of patients will receive both drugs, might advise regorafenib anticipation (compared to TAS 102) in RAS mutated patients.

The authors.

Has not received any funding.

All authors have declared no conflicts of interest.