目的:家族性腺瘤性息肉病(FAP)患者发生十二指肠腺瘤和肿瘤的风险明显增加。舒林酸和厄洛替尼联合使用先前被证明可以减少十二指肠息肉负担,但与相对较高的不良事件(AE)发生率相关。
目的:评估厄洛替尼干预的每周一次给药方案是否能改善AE状况,虽然仍然提供关于减少息肉负担的功效,FAP参与者。
方法:单臂试验,46名FAP参与者,2017年10月至2019年9月在八个学术癌症中心进行。
方法:参与者自行口服350mg埃罗替尼,每周一次,持续6个月。
方法:在基线和6个月时通过食管胃十二指肠镜检查评估十二指肠近端十二指肠息肉负担(息肉直径之和)。平均百分比变化定义为感兴趣的主要疗效结果。评估2-3级AE的发生率作为共同主要结果。次要结果包括十二指肠息肉总数的变化,以及下胃肠道(GI)息肉负担和计数的变化(对于通过可选的下内镜检查检查的参与者)。
结果:46名参与者(平均年龄,44.1年(范围,18-68);妇女,22名(48%));42名参与者完成了6个月的干预,并纳入了符合方案分析。每周厄洛替尼干预6个月后,十二指肠息肉负担显着降低。平均百分比变化为-29.6%(95%CI,-39.6%至-19.7%;p<0.0001)。在基线时由患有晚期十二指肠息肉病(Spigelman3)的参与者定义的亚组分析中观察到类似的结果(平均值,-27%;95%CI,-38.7%至-15.2%;p<0.0001)。干预后Spigelman阶段在12%的参与者中被降级。干预6个月后,下GI息肉数量也减少(中位数,-30.8%;IQR,-47.4%至0.0%;p=0.0256)。71.7%的受试者报告2级或3级不良事件,只有两个经历3级毒性,至少可能与干预有关。
结论:在这种单臂中,FAP参与者的多中心试验,厄洛替尼每周一次可显著降低十二指肠息肉负担,适度减少胃肠道息肉负担,经过6个月的干预。尽管所有参与者中仍有近四分之三报告了AE,这些事件通常级别较低,且耐受性良好.这些发现支持进一步研究厄洛替尼作为一种有效的药物,FAP相关GI息肉可接受的癌症预防剂。
背景:NCT02961374。
Patients with familial adenomatous
polyposis (FAP) are at markedly increased risk for duodenal adenomas and cancer. Combination sulindac and erlotinib was previously shown to reduce duodenal polyp burden but was associated with a relatively high adverse event (AE) rate.
To evaluate if a once weekly dosing schedule for erlotinib intervention improves the AE profile, while still providing efficacy with respect to reduced polyp burden, in participants with FAP.
Single-arm
trial, enrolling 46 participants with FAP, conducted from October 2017 to September 2019 in eight academic cancer centres.
Participants self-administered 350 mg of erlotinib by mouth, one time per week for 6 months.
Duodenal polyp burden (sum of polyp diameters) was assessed in the proximal duodenum by esophagogastroduodenoscopy performed at baseline and 6 months, with mean per cent change defined as the primary efficacy outcome of interest. Rate of grade 2-3 AEs was evaluated as a co-primary outcome. Secondary outcomes included changes in total duodenal polyp count, along with changes in lower gastrointestinal (GI) polyp burden and count (for participants examined by optional lower endoscopy).
Forty-six participants (mean age, 44.1 years (range, 18-68); women, 22 (48%)) were enrolled; 42 participants completed 6 months of intervention and were included in the per-protocol analysis. Duodenal polyp burden was significantly reduced after 6 months of weekly erlotinib intervention, with a mean per cent change of -29.6% (95% CI, -39.6% to -19.7%; p<0.0001). Similar results were observed in subgroup analyses defined by participants with advanced duodenal
polyposis (Spigelman 3) at baseline (mean, -27%; 95% CI, -38.7% to -15.2%; p<0.0001). Post-intervention Spigelman stage was downstaged in 12% of the participants. Lower GI polyp number was also decreased after 6 months of intervention (median, -30.8%; IQR, -47.4% to 0.0%; p=0.0256). Grade 2 or 3 AEs were reported in 71.7% of subjects, with only two experiencing grade 3 toxicity at least possibly related to intervention.
In this single-arm, multi-centre
trial of participants with FAP, erlotinib one time per week resulted in markedly lower duodenal polyp burden, and modestly reduced lower GI polyp burden, after 6 months of intervention. While AEs were still reported by nearly three-quarters of all participants, these events were generally lower grade and well-tolerated. These findings support further investigation of erlotinib as an effective, acceptable cancer preventive agent for FAP-associated GI
polyposis.
NCT02961374.