Background: The epidermal growth factor receptor (EGFR) is overactive in many tumors. This phase I trial evaluated the safety and preliminary efficacy of afatinib plus capecitabine in refractory pancreatic ductal adenocarcinoma (PDA), biliary tract cancers (BTC), and other solid tumors. Patients and Methods: The phase Ia study had a 3 + 3 design with capecitabine 1000 mg/m2twice daily on days 1–14 and afatinib 20 mg, 30 mg, or 40 mg daily in 21-day cycles. In phase Ib, 15 patients, each with PDA and BTC, were treated at maximum tolerated dose (MTD). Results: A total of 41 patients were enrolled. No dose-limiting toxicities were observed, and the MTD was 40 mg afatinib plus capecitabine. Among 36 response-evaluable patients, one had a partial response (3%), and eight (22%) had stable disease. Median progression-free survival (PFS) was 1.9 months (95% CI 1.0, 2.0) for PDA and 1.9 months (95% CI 1.6, 3.4) for BTC. Median overall survival (OS) was 3.2 months (95% CI 2.0, 5.8) for PDA, and 4.6 months (95% CI 1.9, 6.1) for BTC. Median OS was 5.8 months (95% CI 2.0, 9.6) forKRASWTPDA, and 5.0 months (95% CI 1.6, 6.1) forKRASWTBTC, vs. 3.9 months (95% CI 1.9, 5.8) forKRASMUTPDA and 3.1 months (95% CI 1.0, 22.8) forKRASMUTBTC, respectively. Conclusions: Afatinib plus capecitabine is tolerable but does not have clinically meaningful efficacy in refractory PDA/BTC. Future studies should test novel anti-EGFR/HER2 therapies inKRASWTcancers further selected with a comprehensive molecular profile.
背景：表皮生长因子受体（EGFR）在许多肿瘤中过度活跃。本项I期临床试验评估了阿法替尼联合卡培他滨在难治性胰腺导管腺癌（PDA）、胆道癌（BTC）及其他实体瘤中的安全性和初步疗效。患者与方法：Ia期研究采用3+3设计，卡培他滨剂量为1000 mg/m²每日两次（第1-14天），阿法替尼每日剂量分别为20 mg、30 mg或40 mg，以21天为一个周期。在Ib期研究中，15例PDA患者和15例BTC患者在最大耐受剂量（MTD）下接受治疗。结果：共纳入41例患者。未观察到剂量限制性毒性，MTD确定为阿法替尼40 mg联合卡培他滨。在36例可评估疗效的患者中，1例（3%）达到部分缓解，8例（22%）疾病稳定。PDA患者的中位无进展生存期（PFS）为1.9个月（95% CI 1.0, 2.0），BTC患者为1.9个月（95% CI 1.6, 3.4）。PDA患者的中位总生存期（OS）为3.2个月（95% CI 2.0, 5.8），BTC患者为4.6个月（95% CI 1.9, 6.1）。KRAS野生型PDA患者的中位OS为5.8个月（95% CI 2.0, 9.6），KRAS野生型BTC患者为5.0个月（95% CI 1.6, 6.1）；而KRAS突变型PDA患者为3.9个月（95% CI 1.9, 5.8），KRAS突变型BTC患者为3.1个月（95% CI 1.0, 22.8）。结论：阿法替尼联合卡培他滨耐受性良好，但在难治性PDA/BTC中未显示出具有临床意义的疗效。未来研究应在通过全面分子谱进一步筛选的KRAS野生型癌症中，探索新型抗EGFR/HER2疗法。
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