Department of Clinical Oncology, St. Marianna University School of Medicine, Kawasaki, Japan.
Department of Clinical Oncology, Aichi Cancer Center Hospital, Nagoya, Japan.
Target Oncol. 2023 May;18(3):369-381. doi: 10.1007/s11523-023-00963-9. Epub 2023 May 6.
Trifluridine/tipiracil (FTD/TPI) improved the overall survival in patients with metastatic colorectal cancer (mCRC) who had previously received standard chemotherapies; however, the clinical outcomes remain poor.
A multicenter phase II study aimed to assess the efficacy and safety of FTD/TPI plus cetuximab rechallenge.
Patients with histologically confirmed RAS wild-type mCRC refractory to prior anti-epidermal growth factor receptor (anti-EGFR) antibody were enrolled and treated with FTD/TPI (35 mg/m twice daily on days 1-5 and 8-12) plus cetuximab (initially 400 mg/m, followed by weekly 250 mg/m) every 4 weeks. The primary endpoint was disease control rate (DCR), expecting a target DCR of 65% and null hypothesis of 45% with 90% power and 10% one-sided alpha error. Gene alterations of RAS, BRAF, EGFR, PIK3CA, ERBB2, and MET in pre-treatment circulating tumor DNA were evaluated using the Guardant360 assay.
A total of 56 patients (median age 60 years; left-sided tumors 91%; objective partial or complete response during the prior anti-EGFR therapy 61%) were enrolled. The DCR was 54% (80% confidence interval [CI] 44-63; P = 0.12), with a partial response rate of 3.6%. Median progression-free survival (PFS) was 2.4 months (95% CI 2.1-3.7). In the circulating tumor DNA analysis, patients without any alterations of the six genes (n = 20) demonstrated higher DCR (75% vs. 39%; P = 0.02) and longer PFS (median 4.7 vs. 2.1 months; P < 0.01) than those with any gene alterations (n = 33). The most common grade 3/4 hematologic adverse event was neutropenia (55%). No treatment-related deaths occurred.
FTD/TPI plus cetuximab rechallenge did not demonstrate clinically meaningful efficacy in all mCRC patients, but might be beneficial for the molecularly selected population.
曲氟尿苷/替匹嘧啶（FTD/TPI）可改善既往接受标准化疗的转移性结直肠癌（mCRC）患者的总生存期；然而，临床结局仍较差。
本多中心 II 期研究旨在评估 FTD/TPI 联合西妥昔单抗再挑战的疗效和安全性。
招募了组织学证实的 RAS 野生型 mCRC 患者，这些患者对先前的抗表皮生长因子受体（anti-EGFR）抗体治疗耐药，并接受 FTD/TPI（35 mg/m2，每日 2 次，第 1-5 天和第 8-12 天）联合西妥昔单抗（初始剂量 400 mg/m2，随后每周 250 mg/m2）治疗，每 4 周一次。主要终点为疾病控制率（DCR），预计目标 DCR 为 65%，零假设为 45%，功效为 90%，单侧 α 错误为 10%。采用 Guardant360 检测评估治疗前循环肿瘤 DNA 中 RAS、BRAF、EGFR、PIK3CA、ERBB2 和 MET 的基因改变。
共纳入 56 例患者（中位年龄 60 岁；左侧肿瘤 91%；既往抗 EGFR 治疗期间客观部分或完全缓解率 61%）。DCR 为 54%（95%CI 44-63；P=0.12），部分缓解率为 3.6%。中位无进展生存期（PFS）为 2.4 个月（95%CI 2.1-3.7）。在循环肿瘤 DNA 分析中，无 6 种基因任何改变的患者（n=20）DCR 更高（75%比 39%；P=0.02），PFS 更长（中位 4.7 比 2.1 个月；P<0.01），而有任何基因改变的患者（n=33）则较短。最常见的 3/4 级血液学不良事件是中性粒细胞减少症（55%）。无治疗相关死亡事件发生。
FTD/TPI 联合西妥昔单抗再挑战在所有 mCRC 患者中未显示出有临床意义的疗效，但可能对分子选择人群有益。
