Phase III FIRE-4 study (AIO KRK-0114): Evaluation of first-line treatment efficacy of FOLFIRI/cetuximab in patients with RAS-WT mCRC receiving the first cycle of treatment with chemotherapy only.

Abstract

100 Background: FIRE-4 (AIO KRK-0114) is performed in RAS wild-type (wt) mCRC patients. This randomized study tests the efficacy of early switch maintenance during 1st-line therapy (part 1) and re-challenge with cetuximab (part 2) in later-line treatment. In part 1, all patients received first-line induction treatment with FOLFIRI plus cetuximab (FOLFIRI/Cet). In arm A, patients were randomized to continue FOLFIRI/Cet until progression or intolerable toxicity. In arm B, patients received FOLFIRI/Cet for 8-12 cycles, after which maintenance therapy with 5-FU/FA plus bevacizumab (5-FU/Bev) was applied. The first randomization evaluates the question if an early switch from cetuximab to bevacizumab during maintenance therapy may prolong PFS. The study protocol explicitly allowed a first cycle of chemotherapy to be applied before randomization. Methods: Within this randomized, controlled, open-label phase-III study, patients received FOLFIRI (irinotecan plus 5-FU/FA) plus cetuximab every two weeks at the standard dosing schedule. In arm A, FOLFIRI plus cetuximab was continued until progression or intolerable toxicity. De- and re-escalation was allowed according to the local standard of care. In arm B, patients received 8 cycles of FOLFIRI plus cetuximab (in case of tumor response) or 12 cycles (in case of stable disease) followed by maintenance with 5-FU/FA plus bevacizumab (5mg/kg) until disease progression or intolerable toxicity. Overall survival after second randomization (part 2) is evaluated as a primary endpoint. Here, we report PFS in first-line (part 1) as a secondary study endpoint of the study. Other secondary endpoints included ORR, OS, safety, and tolerability. Results: From August 2015 to January 2021, 672 patients were randomized, and 656 patients were assigned to treatment in 120 German and 10 Austrian centers (327 arm A and 329 in arm B). Of those, 205 patients received one cycle of FOLFIRI alone before randomization. In both arms, ORR was comparable for patients receiving cetuximab from the first cycle when compared to those receiving one cycle of chemotherapy only (arm A: 58.7% vs 62.9% (p = 0.54), arm B 60.2% vs 55.6% (p = 0.48). PFS was also not influenced in both arms (arm A: 10.8mo vs. 10.6mo (p = 0.91); arm B 11.2mo vs. 11.4mo (p = 0.62)). Preliminary results suggest that also OS (event rate 38.3%) was not influenced by one cycle applied without cetuximab (arm A: 33.7 mo vs. 29.1 mo (p = 0.20); arm B: 35.6 mo vs. 28.9 mo (p = 0.13)). Conclusions: Application of one initial cycle with chemotherapy alone did not influence the efficacy of a first-line strategy of FOLFIRI plus cetuximab. If RAS mutational analysis is not timely available, a start with FOLFIRI alone adding cetuximab in cycle 2 seems to be safe with respect of overall efficacy. Clinical trial information: NCT02934529 .

Switching from FOLFIRI plus cetuximab to FOLFIRI plus bevacizumab based on early tumor shrinkage in RAS wild‐type metastatic colorectal cancer: A phase II trial (HYBRID)

“…A recent phase III trial (FIRE‐4) reported that an early switch after 8–12 cycles from FOLFIRI plus cetuximab to maintenance therapy with 5‐fluorouracil/capecitabine plus bevacizumab was not associated with superior efficacy compared to the continued cetuximab administration 16 . However, no detrimental effects were reported in patients who switched to bevacizumab.…”

“…A recent phase III trial (FIRE‐4) reported that an early switch after 8–12 cycles from FOLFIRI plus cetuximab to maintenance therapy with 5‐fluorouracil/capecitabine plus bevacizumab was not associated with superior efficacy compared to the continued cetuximab administration. 16 However, no detrimental effects were reported in patients who switched to bevacizumab. The treatment approach evaluated in FIRE‐4 was different from that in the present trial in several aspects, including the timing of the switch and the strength of backbone chemotherapy after the switch to bevacizumab.…”

Molecular screening with liquid biopsy for anti-EGFR retreatment in metastatic colorectal cancer: preliminary data from the randomized phase 2 PARERE trial

“…Numerically longer anti-EGFR-free intervals and time from the last anti-EGFR administration to firstline disease progression were observed in the group with RAS/ BRAFV600E wt ctDNA. Translational data from the randomized FIRE4 trial showed a significant correlation between the duration of the exposure to first-line anti-EGFRs and the occurrence of RAS mutations, though in the absence of any overall survival (OS) difference between the groups of patients acquiring or not RAS mutations in ctDNA (23).…”