背景:在 RAS 野生型轉移性結直腸癌(mCRC)患者中，三聯療法、FOLFOXIRI、聯合貝伐單抗(bev)或帕尼單抗(panitumumab)在早期腫瘤收縮(ETS)和反應深度(DpR)方麵優於雙聯療法。在 TRIBE 試驗(N EnglJ Med 2014)或 VOLFI 試驗(J Clin Oncol 2019)中分別進行。對於西妥昔單抗(cet)與 bev 聯合三組治療方案進行直接比較的研究較少。因此，我們研究了 bev 與 cet 聯合 FOLFOXIRI 治療既往未經治療的 RAS 野生型腫瘤 mCRC 患者的有效性和安全性。
Background: Triplet regimens, FOLFOXIRI, combined with bevacizumab (bev) or panitumumab have been shown to be superior in terms of early tumor shrinkage (ETS) and depth of response (DpR) compared to doublet combinations in patients with RAS wild-type metastatic colorectal cancer (mCRC), in the TRIBE trial (N Engl J Med 2014) or the VOLFI trial (J Clin Oncol 2019), respectively. There have been few studies which directly compared cetuximab (cet) with bev when combined with triplet regimen. Therefore, we investigated the efficacy and safety of bev vs. cet in combination with FOLFOXIRI in previously untreated mCRC patients with RAS wild-type tumors.
方法：該試驗是一項隨機 II 期試驗，以 360 例 RAS 野生型 mCRC 患者為主要終點，評價改良(m) FOLFOXIRI(伊立替康 150mg/m2，奧沙利鉑 85mg/m2, 5-FU 2400mg/m2)聯合 cet / bev 作為一線治療 DpR 的整個療程。試驗的目的是為了表明 cet 組的中位數 DpR 比 bev 組高 12.5% 以上，在 0.05 的顯著性水平下冪為 85%。中的次要終點包括第 8 周的 ETS 率、總緩解率(ORR)、無進展生存期(PFS)、總生存期(OS)、二次切除率和毒性。
Methods: This trial was a randomized phase II trial to evaluate modified (m)-FOLFOXIRI (irinotecan 150mg/m2, oxaliplatin 85mg/m2, 5-FU 2400mg/m2) plus cet vs. bev as first-line treatment in terms of DpR during the entire course as the primary endpoint in 360 patients with RAS wild-type mCRC. The aim of the trial was to show that median DpR of cet arm was more than 12.5% higher than bev arm, with a power of 85% at a significance level of 0.05. Secondary endpoints included ETS rate at week 8, overall response rate (ORR), progression-free survival (PFS), overall survival (OS), secondary resection rate, and toxicity.
結果：2015 年 7 月至 2019 年 6 月期間，共有 359 名患者入組。對於完整的分析集（中位年齡65 歲，男性 64％，PS0 / 1：91％/ 9％，左/右原發性：83％/ 17％），分別將 173 例和 175例患者隨機分配到 cet 和 bev 組。在 2020 年 9 月的截止日期，cet 組的平均周期數為 10（範圍 1-51），bev 組的平均周期數為 12（範圍 1-51）。 ASCO GI 專題討論會 2021（《臨床研究雜誌》 39,2021，增刊 3；摘要 86）。達到主要終點（p = 0.001）； CET 組為 57.4％（-15.0〜100），BEV 組為 46.0％（-0.6〜100）。至於主要腫瘤方麵，左側的中位 DpR 分別為 60.3％對 46.1％（p = .0007）和右側的 50.0％對 41.2％（p = .46）。次要終點的 ETS 發生率和 ORR 分別為 77.8％和 69.1％，而 bev 組分別為 74.6％和 71.7％，無統計學意義。盡管存活數據不成熟，但兩組的 PFS 和 OS 分別為 12.7 個月（95％CI 11.5-14.0）和 37.6 個月（95％CI 30.8 至 43.0）。
Results: A total of 359 patients were enrolled between July 2015 and June 2019. For the full analysis set (median age 65y, 64% male, PS0/1: 91%/9%, left/right primary: 83%/17%), 173 and 175 patients were randomly assigned to the cet and bev arms, respectively. On the cutoff date of September 2020, the median number of cycles administered was 10 (range, 1-51) for the cet arm and 12 (range, 1-51) for the bev arm. Safety data was already reported at the ASCO GI symposium 2021 (J Clin Oncol 39, 2021 suppl 3; abstr 86). The primary endpoint was met (p =.001); 57.4%（-15.0̃100）for the cet arm versus 46.0% （-0.6̃100）for the bev arm. As for primary tumor sidedness, median DpR were 60.3% versus 46.1% (p =.0007) in the left-side and 50.0% versus 41.2% (p =.46) in the right-side. The ETS rate and ORR as the secondary endpoints were 77.8% and 69.1% in the cet arm versus 74.6% and 71.7% in the bev arm, respectively, with no statistical significance. Although the survival data were immature, PFS and OS of both arms were 12.7 months (95%CI 11.5-14.0) and 37.6 months (95%CI 30.8 to 43.0), respectively.
結論:作為 RAS 野生型 mCRC 一線治療的主要終點，mFOLFOXIRI + cet 被證明明顯優於 mFOLFOXIRI + bev。
Conclusion: The mFOLFOXIRI plus cet has been shown to be significantly superior to the mFOLFOXIRI plus bev in terms of DpR as the primary endpoint in first-line treatment for RAS wild-type mCRC.
