背景:在未接受轉移性疾病治療的 BRAF v600e 突變轉移性結直腸癌(mCRC)患者中，與 FOLFOXIRI 聯合西妥昔單抗或貝伐珠單抗進行了比較。

Background: FIRE-4.5 (AIO KRK-0116) compared FOLFOXIRI plus either cetuximab or bevacizumab in BRAF V600E-mutant metastatic colorectal cancer (mCRC) patients not treated for metastatic disease before.

方法:在這個 1:2 隨機、對照、開放標簽的 II 期研究中，患者按以下計劃每 2 周接受 FOLFOXIRI治療:伊立替康 150mg/m2 (30-90min，第 1 天)，葉酸 400mg/m2 (120min，第 1 天)，ox ali 鉑 85mg/m2 (120min，第 1 天)，隨後 5-氟尿嘧啶 3000mg /m2, 48h。FOLFOXIRI 聯合貝伐單抗(A 組)，劑量為 5mg/kg 體重，每 2 周或西妥昔單抗(B 組)，負載劑量 400mg/m2，隨後每周劑量 250mg/m2。FOLFOXIRI 在推薦維持治療前應用最多 12 個周期。根據 RECIST 1.1 標準，主要終點是 B 組在總體緩解率(ORR)方麵的優勢(ons)。次要終點包括 PFS、OS 和耐受性。

Methods: Within this 1:2 randomized, controlled, open-label phase-II study, patients received FOLFOXIRI every two weeks at the following schedule: irinotecan 150mg/m² (30-90min, day 1), folinic acid 400mg/m² (120min, day 1), oxaliplatin 85mg/m² (120 min, day 1), followed by 5-fluorouracil 3,000 mg/m², 48h. FOLFOXIRI was combined with either bevacizumab (arm A) at a dose of 5mg/kg body weight, every 2 weeks or cetuximab (arm B) at a loading dose of 400mg/m² and subsequent weekly doses of 250mg/m². FOLFOXIRI was applied for a maximum of 12 cycles before maintenance treatment was recommended. Primary endpoint was superiority of Arm B with respect to overall response rate (ORR) according to RECIST 1.1 criterions. Secondary endpoints included PFS, OS, and tolerability.

結果:從 2016 年 11 月到 2020 年 12 月，108 例患者隨機分布在 90 個德國和 10 個法國(A 組 35 例，B 組 73 例)。沒有觀察到新的或未知的毒性。主要終點的 ORR 分別為 66.7%和 52.0% (p =0.23)。A 組的中位無進展生存期(8.3 個月 vs 5.9 個月;Log rank p =0.03;1.8)。雖然 OS 數據仍然不成熟，但中位 OS 時間在分析時具有可比性。左側原發腫瘤患者與貝伐單抗或西妥昔單抗有可比性結果，其中作為那些右側原發腫瘤患者顯示出貝伐單抗聯合治療效果更好的趨勢。最新的研究結果將在年度會議上公布。

Results: From November 2016 to December 2020 108 patients were randomized in 90 German and 10 French centers (35 arm A and 73 in arm B). No new or unexpected toxicities were observed. Primary endpoint was not met with an ORR of 66.7% and 52.0% (p =0.23) in the respective arms. Median PFS was significantly longer in arm A vs arm B (8.3 months vs 5.9 months; logrank p = 0.03; HR 1.8). While OS data is still immature, median OS time are comparable at the time of analysis. Patients with left-sided primary tumors had comparable results with either bevacizumab or cetuximab, whereas those with right-sided primary tumors showed a trend towards better efficacy of the bevacizumab combination. Updated results will be presented at the annual meeting.

結論:FIRE-4.5 是首個研究 FOLFOXIRI 聯合靶向治療 BRAF v600e 突變型 mCRC 一線療效的前瞻性隨機研究。FOLFOXIRI 聯合貝伐單抗或西妥昔單抗具有相當的療效，但根據原發性腫瘤的偏側性，支持 mCRC BRAF v600e 突變亞群的異質性。

Conclusions: FIRE-4.5 is the first prospective and randomized study investigating efficacy of FOLFOXIRI combined with targeted therapy in the first-line treatment of BRAF V600E-mutant mCRC. FOLFOXIRI plus either bevacizumab or cetuximab have comparable efficacy with differential effects according to primary tumor sidedness supporting the heterogeneity of BRAF V600E-mutant subpopulation of mCRC.