Study protocol of the FIRE-8 (AIO-KRK/YMO-0519) trial: a prospective, randomized, open-label, multicenter phase II trial investigating the efficacy of trifluridine/tipiracil plus panitumumab versus trifluridine/tipiracil plus bevacizumab as first-line treatment in patients with metastatic colorectal cancer

Abstract

Background Initial systemic therapy for patients with metastatic colorectal cancer (mCRC) is usually based on two- or three-drug chemotherapy regimens with fluoropyrimidine (5-fluorouracil (5-FU) or capecitabine), oxaliplatin and/or irinotecan, combined with either anti-VEGF (bevacizumab) or, for RAS wild-type (WT) tumors, anti-EGFR antibodies (panitumumab or cetuximab). Recommendations for patients who are not eligible for intensive combination therapies are limited and include fluoropyrimidine plus bevacizumab or single agent anti-EGFR antibody treatment. The use of a monochemotherapy concept of trifluridine/ tipiracil in combination with monoclonal antibodies is not approved for first-line therapy, yet. Results from the phase II TASCO trial evaluating trifluridine/ tipiracil plus bevacicumab in first-line treatment of mCRC patients and from the phase I/II APOLLON trial investigating trifluridine/ tipiracil plus panitumumab in pre-treated mCRC patients suggest favourable activity and tolerability of these new therapeutic approaches. Methods FIRE-8 (NCT05007132) is a prospective, randomized, open-label, multicenter phase II study which aims to evaluate the efficacy of first-line treatment with trifluridine/tipiracil (35 mg/m2 body surface area (BSA), orally twice daily on days 1–5 and 8–12, q28 days) plus either the anti-EGFR antibody panitumumab (6 mg/kg body weight, intravenously on day 1 and 15, q28 days) [arm A] or (as control arm) the anti-VEGF antibody bevacizumab (5 mg/kg body weight, intravenously on day 1 and 15, q28 days) [arm B] in RAS WT mCRC patients. The primary objective is to demonstrate an improved objective response rate (ORR) according to RECIST 1.1 from 30% (control arm) to 55% with panitumumab. With a power of 80% and a two-sided significance level of 0.05, 138 evaluable patients are needed. Given an estimated drop-out rate of 10%, 153 patients will be enrolled. Discussion To the best of our knowledge, this is the first phase II trial to evaluate the efficacy of trifluridine/tipiracil plus panitumumab in first-line treatment of RAS WT mCRC patients. The administration of anti-EGFR antibodies rather than anti-VEGF antibodies in combination with trifluridine/tipiracil may result in an increased initial efficacy. Trial registration EU Clinical Trials Register (EudraCT) 2019-004223-20. Registered October 22, 2019, ClinicalTrials.govNCT05007132. Registered on August 12, 2021.

Molecular mechanisms targeting drug-resistance and metastasis in colorectal cancer: Updates and beyond

“…More recent trials showed that modern combination regimens were better substitutes for IFL; however, the efficacy of combining bevacizumab with first-line treatment of mCRC has been controversial. Several recent clinical trials demonstrated the promising efficiency of combining bevacizumab with trifluridine/tipiracil, which is usually better tolerated than capecitabine, especially in elderly patients with mCRC[ 107 - 109 ]. Notably, promising results were reported in the phase II TASCO study that assessed the effectiveness of combining bevacizumab with trifluridine/tipiracil as first-line treatment in untreated patients with unresectable mCRC[ 110 ].…”

Trifluridine/tipiracil (FTD/TPI) in metastatic colorectal cancer treatment

“…The secondary outcome measures are OS and PFS, depth of response (DpR), and early tumor shrinkage (ETS). It is planned to assess the patient's quality of life (QoL) with the EQ-5D-5L questionnaires [30].…”

Long-Term Progression-Free Survival of a Pre-Treated Patient with Metastatic Colorectal Cancer Receiving Trifluridine/Tipiracil

“…Even though it was a negative study, PFS (9.4 months in trifluridine/tipiracil arm; 95% CI [9.1–10.9] vs. 9.3 months in capecitabine arm; 95% CI [8.9–9.8]) and OS (19.74 months in trifluridine/tipiracil arm; 95% CI [18.04–22.40] vs. 18.59 months in capecitabine arm; 95% CI [16.82–21.39]) were comparable in both treatment arms, suggesting that first-line trifluridine/tipiracil plus bevacizumab is not inferior but similarly active compared to capecitabine plus bevacizumab in frail mCRC patients. Further, the German phase 2 FIRE-8 study (NCT05007132) was recently initiated and aims to compare treatment efficacy between trifluridine/tipiracil in combination with either panitumumab or bevacizumab in frail and untreated patients with RAS wild-type mCRC [ 19 ]. The study is actively recruiting patients in 40 German centers.…”