A Phase 2 Multi-institutional Study of Nivolumab for Patients With Advanced Refractory Biliary Tract Cancer
A Phase 2 Multi-institutional Study of Nivolumab for Patients With Advanced Refractory Biliary Tract Cancer
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DOI：
10.1001/jamaoncol.2020.0930
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发表时间：
2020-06-01
期刊：
影响因子：
28.4
通讯作者：
Kim, Dae Won
中科院分区：
文献类型：
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作者：
Kim, Richard D.;Chung, Vincent;Kim, Dae Won
这项多中心ii期研究评估了nivolumab在晚期难治性胆道癌患者中的抗癌活性。nivolumab在晚期难治性胆道癌患者中的临床活性是什么？在54例晚期难治性胆道癌患者的多中心ii期研究中，经研究者评估，10例患者达到客观缓解，疾病控制率为59%。通过盲法中心独立放射学检查，5例患者客观缓解，疾病控制率为50%。意味着进一步探索纳武单抗用于晚期难治性胆道癌患者是必要的。目前，对于胆道癌（BTC）还没有确定的二线全身治疗方法。临床前数据表明，BTC肿瘤微环境中存在肿瘤浸润性CD8 T细胞和表达程序性细胞死亡1配体1的肿瘤细胞，这支持了在BTC中使用程序性细胞死亡1蛋白阻断免疫疗法的基本原理。目的评价纳武单抗在晚期难治性BTC患者中的抗癌活性。在这项单组、多中心的nivolumab 2期研究中，在2016年10月5日至2018年12月26日期间入组了54例组织学证实的BTC患者，这些患者在接受至少1线但不超过3线全身治疗时疾病进展。在意向治疗基础上进行分析。Nivolumab, 240 mg，每2周静脉滴注一次，持续16周，然后每4周静脉滴注480 mg，直到疾病进展或不可接受的毒性作用发生。主要结局和测量主要终点是研究者评估的客观缓解率，次要终点是无进展生存期、总生存期和不良事件发生率。结果共入组54例患者（男性27例，女性27例，中位年龄65岁[范围28-86岁]），46例患者（男性22例，女性24例，中位年龄65岁[范围28-86岁]）接受放射影像学检查客观反应。研究者评估的客观缓解率为22%（46例中的10例），包括1例未证实的部分缓解，疾病控制率为59%（46例中的27例）。中央独立审查发现客观缓解率为11%（46例中的5例），包括1例未证实的部分缓解，疾病控制率为50%（46例中的23例）。所有对治疗有反应的患者（以下简称应答者）都有错配修复蛋白精通的肿瘤。研究者评估的应答中位持续时间未达到，中位随访时间为12.4个月。在意向治疗人群中，中位无进展生存期为3.68个月（95% CI, 2.30-5.69个月），中位总生存期为14.24个月（95% CI， 5.98个月至未达到）。程序性细胞死亡1配体1在肿瘤中的表达与延长无进展生存期相关（风险比，0.23;95% CI, 0.10-0.51; P < 0.001）。最常见的与治疗相关的3级或4级毒性作用是低钠血症（54例中3例[6%]）和碱性磷酸酶升高（54例中2例[4%]）。该研究发现，nivolumab耐受性良好，在难治性BTC患者中表现出中等疗效和持久反应。需要进一步的研究来验证这些发现，并评估生物标志物，以改善患者的治疗选择。
This multicenter phase 2 study evaluates the anticancer activity of nivolumab in patients with advanced refractory biliary tract cancer.Question What is the clinical activity of nivolumab in patients with advanced refractory biliary tract cancer? Findings In this multicenter phase 2 study of 54 patients with advanced refractory biliary tract cancer, 10 patients achieved an objective response with a disease control rate of 59% by investigator assessment. Five patients experienced an objective response with a disease control rate of 50% by blinded central independent radiologic review. Meaning Further exploration of nivolumab is warranted for patients with advanced refractory biliary tract cancer.IMPORTANCE Currently, there is no established second-line systemic treatment for biliary tract cancer (BTC). Preclinical data have demonstrated that the presence of tumor-infiltrating CD8 T cells and programmed cell death 1 ligand 1-expressing tumor cells in the tumor microenvironment of BTC supports the rationale of using programmed cell death 1 protein blockade immunotherapy in BTC.OBJECTIVE To evaluate anticancer activity of nivolumab in patients with advanced refractory BTC.DESIGN, SETTING, AND PARTICIPANTS In this single-group, multicenter phase 2 study of nivolumab, 54 patients with histologically confirmed BTC whose disease progressed while undergoing treatment with at least 1 line but no more than 3 lines of systemic therapy were enrolled between October 5, 2016, and December 26, 2018. Analysis was performed on an intention-to-treat basis.INTERVENTIONS Nivolumab, 240 mg, was delivered intravenously every 2 weeks for 16 weeks, and then 480 mg was delivered intravenously every 4 weeks until disease progression or unacceptable toxic effects occurred.MAIN OUTCOMES AND MEASURES The primary end point was investigator-assessed objective response rate, and the secondary end points were progression-free survival, overall survival, and incidence of adverse events.RESULTS A total of 54 patients (27 men and 27 women; median age, 65 years [range, 28-86 years]) enrolled, and 46 (22 men and 24 women; median age, 65 years [range, 28-86 years]) were examined for objective response with radiologic imaging. The investigator-assessed objective response rate was 22% (10 of 46), including 1 unconfirmed partial response, with a disease control rate of 59% (27 of 46). Central independent review found an objective response rate of 11% (5 of 46), including 1 unconfirmed partial response, with a disease control rate of 50% (23 of 46). All patients who responded to treated (hereafter referred to as responders) had mismatch repair protein-proficient tumors. The median duration of investigator-assessed response was not reached, with a median follow-up of 12.4 months. Among the intention-to-treat population, median progression-free survival was 3.68 months (95% CI, 2.30-5.69 months) and median overall survival was 14.24 months (95% CI, 5.98 months to not reached). Programmed cell death 1 ligand 1 expression in tumors was associated with prolonged progression-free survival (hazard ratio, 0.23; 95% CI, 0.10-0.51; P < .001). The most common treatment-related grade 3 or 4 toxic effects were hyponatremia (3 of 54 [6%]) and increased alkaline phosphatase (2 of 54 [4%]).CONCLUSIONS AND RELEVANCE This study found that nivolumab was well tolerated and showed modest efficacy with durable response in patients with refractory BTC. Further studies are warranted to verify the findings and evaluate biomarkers for improved treatment selection for patients.