Patients with RAS-wild-type metastatic colorectal cancer did not experience a benefit in terms of response rate or survival when cetuximab was added to the first cycle of chemotherapy.
Patients with RAS-wild-type metastatic colorectal cancer (mCRC) did not experience a benefit in terms of response rate or survival when cetuximab (Erbitux) was added to the first cycle of chemotherapy, according to findings from the phase 3 FIRE-4 (AIO KRK-0114; NCT02934529) presented during the 2023 Gastrointestinal Cancers Symposium.1
All patients (n = 657) were allowed to receive an initial cycle of chemotherapy before radiation. First-line treatment for all patients in the study consisted of irinotecan, fluorouracil (5-FU), and folinic acid (leucovorin; FOLFIRI) plus cetuximab. Patients were then randomized to 2 arms: arm A received the doublet until progression or intolerable toxicity and arm B received 8 cycles of FOLFIRI plus cetuximab if there was a tumor response or 12 cycles for stable disease (SD) followed by maintenance with 5-FU/FA plus bevacizumab (Avastin) at a dose of 5 mg/kg until disease progression or intolerable toxicity. FOLFIRI plus cetuximab was given at the standard dosing schedule every 2 weeks.
In the total safety set, patients in arm A (n = 327) experienced a complete response (CR) rate of 2.4% and those in arm B (n = 330) experienced a CR rate of 4.8%. The overall response rates (ORRs) were 62.1% vs 59.4%, respectively (OR, 1.12; 95% CI, 0.82-1.53). SD rates in the cetuximab combination compared with the switch maintenance arm were 15.9% vs 17.0%, respectively. Progressive disease (PD) rates were 4.9% vs 6.4%, respectively, and 17.1% vs 17.3% of patients were not evaluable (NE), respectively. The disease control rate (DCR) was 78.0% in arm A compared with 76.4% in arm B (OR, 1.10; 95% CI, 0.76-1.58).
“The omission of cetuximab in the first cycle of chemotherapy did not affect ORR or PFS within a first-line strategy of FOLFIRI plus cetuximab,” the study authors wrote. “If RAS mutational analysis is not timely available, a start of adding cetuximab in cycle 2 seems to be safe with respect of efficacy.”
Arm A and arm B were subsequently stratified by those who received one previous FOLFIRI cycle prior randomization (n = 205), and in patients who had not received a previous FORFIRI cycle prior to randomization (n = 452).
In the cohort of patients who received a FOLFIRI cycle prior to randomization, no patients in arm A (n = 97) experienced a CR vs 3.7% of patients in arm B (n = 108). The ORRs were 67.0% vs 57.4%, respectively (OR, 1.41; 95% CI, 0.74-2.71). In the cetuximab combination arm compared with the switch maintenance arm, SD rates were 12.4% vs 15.7%, respectively. PD rates were 4.1% vs 10.2%, respectively and 16.5% vs 16.7%, respectively, of patients were NE. Arm A experienced a DCR of 79.4% vs 73.1% in arm B (OR, 0.97; 95% CI, 0.62-1.51).
Additionally,patients who had not received prior cycles of FOLFIRI before randomization treated with the cetuximab combination (n = 230) achieved a CR rate of 3.5% compared with 5.4% in the switch maintenance arm (n = 222). The ORRs were 60.0% vs 60.4%, respectively (OR, > 0.99; 95% CI, 0.62-1.51). In arm A compared with arm B, SD rates were 17.4% vs 17.6%, respectively, PD rates were 5.2% vs 4.5%, respectively, and 17.4% vs 17.6% of patients were not evaluable, respectively. The DCR in the cetuximab combination arm was 77.4% compared with 77.9% in the switch maintenance arm (OR, 0.97; 95% CI, 0.62-1.51).
Overall, patients who received a previous cycle of FOLFIRI achieved a median PFS of 11.0 months (range, 9.7-12.3) vs 11.2 months among patients who did not (range, 10.3-12.3; p = 0.64). The median OS was 28.1 months (range, 24.8-31.4) vs 33.4 months (range, 30.0-36.4), respectively (P = 0.01).
For patients in arm A who received the prior cycle of therapy, median PFS was 10.6 months (range, 9.0-12.2; P = 0.91) and median OS was 28.5 months (range, 22.4-34.7; P = 0.22) compared with those in arm A who did receive a cycle of prior therapy, median PFS was 10.9 months (range, 9.1-12.6) and median OS was 33.4 months (range, 29.3-37.5). Patients in arm B who received the prior cycle of therapy had a median PFS of 11.4 months (range, 9.3-13.6; P = 0.62) and median OS of 28.5 months (range, 22.3-33.8; P = 0.019) while those who did not receive the prior cycle had a median PFS of 11.2 months (range, 10.2-12.2) and median OS of 32.1 months (range, 28.2-37.2).
When examining the first cycle of FOLFIRI with cetuximab, arm A had a median PFS of 10.6 months (range, 9.0-12.2; P = 0.55) and median OS of 28.5 months (range, 22.3-33.8; P = 0.97) compared with a median PFS of 11.4 months (range, 9.3-13.6) and median OS of 28.1 months (range, 22.4-34.7) in arm B. Comparatively, patients who started with FOLFIRI plus cetuximab in arm A experienced a median PFS of 10.9 months (range, 9.1-12.6; P = 0.57) and a median OS of 33.4 months (range, 29.3-37.5; P = 0.33) while those in arm B experienced median figures of 11.2 months (range, 10.2-12.2) and 32.7 months (range, 28.2-37.2), respectively.
Overall, patients primarily had left sided tumors in arm A (82.6%) and arm B (80.0%) with 15.4% and 16.1% being right-sided, respectively. Patients had more than 1 metastatic site at rates of 59.0% in arm A and 56.7% in arm B, with the liver being a metastatic site for 79.2% and 82.1% of patients, respectively. Previous treatments in arm A and arm B included primary removed (61.2% vs 58.2%), adjuvant chemotherapy (17.7% vs 18.5%), and adjuvant/neoadjuvant chemotherapy (21.4% vs 21.5%). The median age of patients was 65 years (range, 31-85) in the cetuximab combination group and 64 years (range, 31-84) in the switch maintenance group.
The primary end point was OS after second randomization. Secondary end points included PFS after first line treatment, ORR, OS, safety, and tolerability. The study was conducted between August 2015 to January 2021.
Stintzing S, von Weikersthal LF, Fuchs M, et al. 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. J Clin Oncol. 2023;41(supp 4):100. doi:10.1200/JCO.2023.41.3_suppl.100