克唑替尼联合帕博利珠单抗治疗未经治的伴有 ALK 重排的晚期非小细胞肺癌的 Ib 期研究。
Phase Ib Study of Crizotinib plus Pembrolizumab in Patients with Previously Untreated Advanced Non-Small Cell Lung Cancer with ALK Translocation.
机构信息
Moores Cancer Center, University of California at San Diego Health-La Jolla, La Jolla, California, USA.
Emory Winship Cancer Institute, Atlanta, Georgia, USA.
出版信息
Oncologist. 2020 Jul;25(7):562-e1012. doi: 10.1634/theoncologist.2020-0034. Epub 2020 Feb 12.
LESSONS LEARNED
This study evaluating first-line crizotinib plus pembrolizumab in patients with anaplastic lymphoma kinase (ALK)-positive advanced non-small cell lung cancer (NSCLC) was terminated early because increased availability of second-generation ALK inhibitors resulted in difficulty identifying and accruing eligible patients. In the small number of patients enrolled, elevated transaminases were the most common treatment-related toxicity. No other relevant toxicities were observed. Although no definitive conclusions could be drawn because of the small number of patients studied, the higher frequency of severe transaminase increases noted in this sample should be of concern if ALK inhibitor and PD-L1/PD-1 inhibitor combinations are tested in future studies.
BACKGROUND
Previous research suggests single-agent crizotinib is efficacious for the treatment of anaplastic lymphoma kinase (ALK)-rearranged advanced non-small cell lung cancer (NSCLC).
METHODS
This study evaluated the safety and preliminary antitumor activity of crizotinib plus pembrolizumab as first-line therapy in patients with ALK-rearranged NSCLC. Patients were initially treated at dose level 0 (DL0) with crizotinib 250 mg twice daily and pembrolizumab 200 mg every 3 weeks (cycle duration was 3 weeks). If a dose-limiting toxicity occurred, subsequent patients were enrolled at a lower dose level (dose level -1 [DL-1]: 3 weeks of crizotinib monotherapy 250 mg twice daily, followed by crizotinib 250 mg twice daily with the addition of pembrolizumab 200 mg every 3 weeks). The primary endpoint was dose-limiting toxicity. Antitumor activity was assessed.
RESULTS
Nine patients were enrolled: two at DL0, then seven at DL-1. Dose-limiting toxicities occurred in four patients (grade 3 increases in alanine aminotransferase [ALT] and aspartate aminotransferase [AST] and grade 3 fatigue at DL0; grade 3 increase in ALT and grade 3 increases in both ALT and AST at DL-1).
CONCLUSION
The maximum tolerated dose was not determined because slow accrual resulted in early study termination.
经验教训
本研究评估了一线克唑替尼联合帕博利珠单抗治疗间变性淋巴瘤激酶（ALK）阳性晚期非小细胞肺癌（NSCLC）患者，因第二代 ALK 抑制剂的广泛应用导致难以识别和招募合格患者，该研究提前终止。在入组的少数患者中，最常见的治疗相关毒性是转氨酶升高。未观察到其他相关毒性。由于研究患者数量较少，因此无法得出明确结论，但如果在未来的研究中测试 ALK 抑制剂和 PD-L1/PD-1 抑制剂联合用药，本研究样本中观察到的严重转氨酶升高频率较高应引起关注。
背景
先前的研究表明，单药克唑替尼对治疗间变性淋巴瘤激酶（ALK）重排的晚期非小细胞肺癌（NSCLC）有效。
方法
本研究评估了克唑替尼联合帕博利珠单抗作为 ALK 重排 NSCLC 一线治疗的安全性和初步抗肿瘤活性。患者最初在剂量水平 0（DL0）接受克唑替尼 250 mg 每日两次和帕博利珠单抗 200 mg 每 3 周（周期持续时间为 3 周）治疗。如果发生剂量限制性毒性，则随后的患者入组较低剂量水平（剂量水平-1[DL-1]：克唑替尼单药治疗 250 mg 每日两次，持续 3 周，随后加用克唑替尼 250 mg 每日两次和帕博利珠单抗 200 mg 每 3 周）。主要终点是剂量限制性毒性。评估抗肿瘤活性。
结果
共入组 9 例患者：2 例在 DL0，7 例在 DL-1。4 例患者发生剂量限制性毒性（DL0 时丙氨酸氨基转移酶[ALT]和天冬氨酸氨基转移酶[AST]升高 3 级和疲劳 3 级；DL-1 时 ALT 升高 3 级，ALT 和 AST 均升高 3 级）。
结论
由于入组速度较慢导致研究提前终止，因此未确定最大耐受剂量。
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