Efficacacy of trifluridine/tipiracil according to extended RAS evaluation: A multicenter retrospective analysis

Trifluridine/tipiracil (TAS102) 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 TAS102 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 361 have been enrolled. Patients were divided in six groups: WT (RAS wild-type), 154 pts; Codon 12 (KRAS codon 12 mutation), 81 pts; Codon 13 (KRAS codon 13 mutation), 37 pts; Rare (KRAS codon 61 and 146 mutation or NRAS mutations), 33 pts; G12C (KRAS G12c mutation), 12 pts; G12D (KRAS G12D mutation), 44 pts. Baseline characteristics were well-balanced between groups. No significant differences in OS between groups were observed (p 0.09), with a trend of better survival in favor of WT patients (median OS 9 m when compared to 7 m of overall population). No significant differences between groups were observed in terms of TTP (p 0.8). Accordingly, a trend toward a better TTP in WT patients (median TTP 4.0) in comparison with G12C and Rare patients (median TTP 3.0 m) was confirmed. Considering those patients who received regorafenib in addition to TAS102 (either before or after, 164 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 no significant different in survival (p 0.4). When considering each group separately, OS of TAS 102 was significant longer in patients receiving even regorafenib in WT (13 vs 7 m, p 0.002), but also in G12D (10 vs 5 m, p 0.002) Rare (9 vs 4 m, p 0.02) and Codon 12 (9 vs 5 m, p 0.002) groups.

Our data demonstrate that RAS mutations do not affect outcome in TAS102-treated patients, although a trend toward a better efficacy in WT patients has been observed. Patients receiving regorafenib in addition to TAS102 (before or after) show a better TAS-related survival, probably because of a less aggressive disease; the benefit of the combination is higher in WT patients but even present in mutated ones subgroups (Codon 12 and rare RAS mutations). 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.