Phase Ib Study to Assess the Safety of Neoadjuvant Trifluridine/Tipiracil With Concurrent Radiation in Resectable Stage II/III Rectal Cancer: The FIERCE Study

Abstract

Background

Trifluridine has demonstrated superior radio-sensitizing ability in vitro, and trifluridine/tipiracil (FTD/TPI) confers clinical benefit in metastatic colorectal cancer. The FIERCE trial (NCT04104139) sought to assess the safety of FTD/TPI as total neoadjuvant therapy (TNT) for rectal cancer.

Methods

Patients with stage II/III rectal adenocarcinoma at a single institution underwent chemo-radiation with FTD/TPI followed by oxaliplatin-based chemotherapy for 4 months. FTD/TPI was examined in cohorts of 3 patients at 3 dose levels (25 mg/m², 30 mg/m², and 35 mg/m²) until 18 were reached per Bayesian Optimal Interval design (BOIN). FTD/TPI was taken orally twice-daily for 5 days/week on weeks 1, 3, and 5 of radiation. Dose-limiting toxicity (DLT) was defined by relevant adverse events related to FTD/TPI. The primary endpoint was the proportion of DLT during chemo-radiation.

Results

Eighteen of 22 screened patients were evaluable after completing TNT. All patients had proficient mismatch repair and staged as cT3, of which 8 (44%) were node-negative and 10 (56%) were node-positive. Grade 3 neutropenia was observed in 4 (22%) patients during chemo-radiation, with 1 DLT occurring at 25 mg/m² and 1 at 35 mg/m². Using isotonic estimate of observed toxicity probability, the maximum tolerated dose of FTD/TPI was 35 mg/m² (PO, BID). At data cutoff, 10 (56%) patients entered into watch-and-wait surveillance, with 9 (50%) achieving clinical complete response.

Conclusion

FTD/TPI at 35 mg/m² on days 1 to 5, 15 to 19, and 29 to 33, is safe and feasible with concurrent radiation as TNT for rectal cancer and should be further studied to evaluate promising efficacy signal including organ preservation.