From the Divisions of Medical Oncology, Hematology, and Surgical Oncology, Princess Margaret Hospital, Toronto; National Cancer Institute of Canada Clinical Trials Group, Kingston; Algoma District Cancer Program, Sault Ste Marie, Ontario; Cross Cancer Institute, Edmonton, Alberta, Canada; the Australasian Gastrointestinal Tumor Group, Sydney, Australia; Norton Healthcare Pavilion, Louisville, KY; UCLA Medical Center, Los Angeles, CA; M. D. Anderson Cancer Centre, Houston, TX; OSI Pharmaceuticals, Boulder, CO; Sourasky Medical Centre, Tel Aviv, Israel; Great Poland Centre for Oncology, Poznan, Poland; Confidence Medical Centre, San Isidro, Argentina; and the National University Hospital, Singapore, Singapore.
J Clin Oncol. 2023 Oct 20;41(30):4714-4720. doi: 10.1200/JCO.22.02770.
Patients with advanced pancreatic cancer have a poor prognosis and there have been no improvements in survival since the introduction of gemcitabine in 1996. Pancreatic tumors often overexpress human epidermal growth factor receptor type 1 (HER1/EGFR) and this is associated with a worse prognosis. We studied the effects of adding the HER1/EGFR-targeted agent erlotinib to gemcitabine in patients with unresectable, locally advanced, or metastatic pancreatic cancer.
Patients were randomly assigned 1:1 to receive standard gemcitabine plus erlotinib (100 or 150 mg/d orally) or gemcitabine plus placebo in a double-blind, international phase III trial. The primary end point was overall survival.
A total of 569 patients were randomly assigned. Overall survival based on an intent-to-treat analysis was significantly prolonged on the erlotinib/gemcitabine arm with a hazard ratio (HR) of 0.82 (95% CI, 0.69 to 0.99; = .038, adjusted for stratification factors; median 6.24 months 5.91 months). One-year survival was also greater with erlotinib plus gemcitabine (23% 17%; = .023). Progression-free survival was significantly longer with erlotinib plus gemcitabine with an estimated HR of 0.77 (95% CI, 0.64 to 0.92; = .004). Objective response rates were not significantly different between the arms, although more patients on erlotinib had disease stabilization. There was a higher incidence of some adverse events with erlotinib plus gemcitabine, but most were grade 1 or 2.
To our knowledge, this randomized phase III trial is the first to demonstrate statistically significantly improved survival in advanced pancreatic cancer by adding any agent to gemcitabine. The recommended dose of erlotinib with gemcitabine for this indication is 100 mg/d.
自 1996 年吉西他滨问世以来，晚期胰腺癌患者的预后仍然很差，且生存状况无明显改善。胰腺肿瘤常过度表达人表皮生长因子受体 1（HER1/EGFR），且与预后不良相关。我们研究了表皮生长因子受体 1（HER1/EGFR）靶向药物厄洛替尼联合吉西他滨在不可切除的局部晚期或转移性胰腺癌患者中的疗效。
患者被随机 1:1 分配接受标准吉西他滨联合厄洛替尼（100 或 150 mg/d 口服）或吉西他滨联合安慰剂治疗，进行了一项双盲、国际 III 期临床试验。主要终点是总生存期。
共随机分配了 569 例患者。基于意向治疗分析，厄洛替尼联合吉西他滨组的总生存期显著延长，风险比（HR）为 0.82（95%CI，0.69 至 0.99；P=0.038，调整了分层因素；中位 6.24 个月 5.91 个月）。厄洛替尼联合吉西他滨组的 1 年生存率也更高（23% 17%；P=0.023）。无进展生存期也显著延长，厄洛替尼联合吉西他滨组的估计 HR 为 0.77（95%CI，0.64 至 0.92；P=0.004）。尽管厄洛替尼组有更多的患者疾病稳定，但客观缓解率在两组之间无显著差异。厄洛替尼联合吉西他滨组的一些不良反应发生率较高，但大多数为 1 级或 2 级。
据我们所知，这是第一项证明在晚期胰腺癌中通过联合任何药物（吉西他滨）治疗可显著改善生存的随机 III 期临床试验。该适应证下吉西他滨联合厄洛替尼的推荐剂量为 100 mg/d。
