Pembrolizumab for the treatment of programmed death-ligand 1-positive advanced carcinoid or pancreatic neuroendocrine tumors: Results from the KEYNOTE-028 study
Pembrolizumab for the treatment of programmed death-ligand 1-positive advanced carcinoid or pancreatic neuroendocrine tumors: Results from the KEYNOTE-028 study
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DOI：
10.1002/cncr.32883
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发表时间：
2020-04-22
期刊：
影响因子：
6.2
通讯作者：
Piha-Paul, Sarina A.
中科院分区：
文献类型：
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作者：
Mehnert, Janice M.;Bergsland, Emily;Piha-Paul, Sarina A.
背景：尽管高分化神经内分泌肿瘤(NETs)的病程较长，治疗方法多样，但患者的病情发展是不可避免的。程序性死亡配体1(PD-L1)与肿瘤的净进展和预后有关。这项多队列，第1阶段Keynote-028研究(ClinicalTrials.gov标识符NCT02054806)评估了抗程序性细胞死亡蛋白1免疫疗法培溴珠单抗在高分化或中分化NETs患者中的活性和安全性。方法将PD-L1阳性、局部晚期或转移性类癌或高分化或中分化胰脏网络(PNETs)患者分成不同的队列，接受培溴利珠单抗治疗，每2周10 mg/kg，最长持续2年。客观应答率是主要终点(根据研究人员综述的实体瘤1.1版的反应评估标准)。安全性是次要目标。结果分别有170名和106名患者可评估样本，在类癌和pNET队列筛查中，PD-L1阳性肿瘤分别占21%和25%；在这些患者中，分别有25名和16名患者符合条件并接受了治疗。中位随访时间分别为20个月(2~35个月)和21个月(5~32个月)。客观有效率分别为12.0%(95%CI，2.5%~31.2%)和6.3%(95%CI，0.2%~30.2%)，类癌队列中出现3例部分缓解，pNET队列中出现1例部分缓解。类癌队列的中位反应持续时间为9.2个月(范围为6.9-11.1个月)，而pNET队列中没有达到。没有出现完整的响应。与治疗相关的不良事件分别发生在68%和69%的患者中，最常见的是腹泻(类癌队列中有7名患者，pNET队列中有4名患者)和疲劳(每个队列中有6名患者)。甲状腺功能减退是最常见的免疫调节不良事件(类癌队列中5例，pNET队列中2例)。结论培溴利珠单抗在部分NET患者中显示出抗肿瘤活性，且耐受性良好。
Background Despite a protracted disease course and multiple available therapies, patients with well-differentiated neuroendocrine tumors (NETs) inevitably experience disease progression. Programmed death-ligand 1 (PD-L1) has been associated with NET progression and prognosis. The multicohort, phase 1 KEYNOTE-028 study (ClinicalTrials.gov identifier NCT02054806) evaluated the activity and safety of the anti-programmed cell death protein 1 immunotherapy pembrolizumab in patients with well-differentiated or moderately-differentiated NETs.Methods Patients with PD-L1-positive, locally advanced or metastatic carcinoid or well-differentiated or moderately-differentiated pancreatic NETs (pNETs) were enrolled into separate cohorts and received pembrolizumab at a dose of 10 mg/kg every 2 weeks for up to 2 years. The objective response rate was the primary endpoint (as per Response Evaluation Criteria in Solid Tumors version 1.1, by investigator review). Safety was a secondary endpoint.Results Of 170 and 106 patients, respectively, who had evaluable samples among those screened for the carcinoid and pNET cohorts, 21% and 25%, respectively, had PD-L1-positive tumors; of these, 25 and 16 patients, respectively, were eligible and treated. The median follow-up was 20 months (range, 2-35 months) and 21 months (range, 5-32 months), respectively. The objective response rate was 12.0% (95% CI, 2.5%-31.2%) and 6.3% (95% CI, 0.2%-30.2%), respectively; 3 partial responses occurred among the carcinoid cohort and 1 among the pNET cohort. The median duration of response in the carcinoid cohort was 9.2 months (range, 6.9-11.1 months), and was not reached in the pNET cohort. No complete responses occurred. Treatment-related adverse events occurred in 68% and 69% of patients, respectively, most often diarrhea (7 patients in the carcinoid cohort and 4 patients in the pNET cohort) and fatigue (6 patients in each cohort). Hypothyroidism was the most common immune-mediated adverse event (5 patients in the carcinoid cohort and 2 patients in the pNET cohort).Conclusions Pembrolizumab demonstrated antitumor activity in a subset of patients with NETs and was well-tolerated.