Phase 1b study to assess the safety of neoadjuvant trifluridine/tipiracil with concurrent radiation in resectable stage II/III rectal cancer: Initial results of the FIERCE study.

3602 Background: Total neoadjuvant therapy (TNT) with chemo-radiation (CRT) followed by doublet chemotherapy for rectal cancer can yield clinical complete response (CR) to allow successful surgery or organ-sparing. Trifluridine exhibited cytotoxic effect of ionizing radiation superior to fluorouracil in colonogenic survival assay (dose modification factor: 2.7). The FIERCE trial (NCT04104139) sought to determine the maximum tolerated dose (MTD) of trifluridine/tipiracil (FTD-TPI) with concurrent CRT during TNT with future goals of improving CR. Methods: MRI-staged participants (pts) with stage II (T3-4N0M0) or stage III (TxN+M0) resectable rectal adenocarcinoma, underwent CRT with FTD-TPI for 6 weeks followed by either FOLFOX or CAPOX for 4 months. Cohorts of 3 pts were examined at three dose levels (DLs) until a total of 18 pts were reached per Bayesian Optimal Interval design. FTD-TPI was taken orally BID for five days/week on weeks 1, 3, and 5 at the assigned dose (DL1 = 25mg/m2; DL2 = 30 mg/m2; DL3 = 35 mg/m2) with concurrent pelvic radiation of 25-28 fractions. Dose limiting toxicity (DLT) was defined by sustained hematologic, gastrointestinal, and serious adverse events related to FTD-TPI. Primary endpoint was the proportion of DLT from CRT at MTD. Results: Among 22 screened patients (3 ineligible and 1 removed for non-compliance in week 1), 18 pts were evaluable. Median age was 52 years (range 37-73), female sex was 4 (22%), and 16 (89%) were ECOG 0. All pts had proficient mismatch repair. All 18 pts were staged as cT3, with 8 (44%) N0 (stage II), 7 (39%) N1, and 3 (17%) N2. All 18 pts completed CRT in their assigned DL (6 DL1, 3 DL2, 9 DL3) followed by chemotherapy (16 FOLFOX; 2 CAPOX) with the 18th pt scheduled to finish treatment in February 2025. One pt was switched to irinotecan due to intolerable oxaliplatin-related neuropathy. During CRT, grade 3 neutropenia without fevers (4/18, 22%) led to 1/6 DLT in DL1 and 1/9 DLT in DL3, which were mitigated by dose interruptions (2/18 missed last week of FTD-TPI). No grade 4 adverse events were observed during CRT. At data cutoff, 10 (56%) pts entered into watch-and-wait surveillance, 6 (33%) pts had surgery, and 2 (11%) pts await final assessment. Conclusions: FTD-TPI at DL3, the MTD of 35 mg/m2 on days 1-5, 15-19, and 29-33, is the recommended phase 2 dose for CRT in TNT for locally-advanced rectal cancer. Short-course filgrastim, or day 29-33 adjustment to DL2, may be needed in last 2 weeks of CRT to prevent dose interruptions. A dose expansion study is being explored as the next step. Clinical trial information: NCT04104139 .