BACKGROUND The current standard initial therapy for advanced ALK-positive non-small cell lung cancer (NSCLC) is a second-generation ALK tyrosine kinase inhibitor (TKI) such as alectinib. The optimal next-line therapy after failure of a second-generation ALK TKI remains to be established; however, standard options include the third generation ALK TKI lorlatinib or platinum/pemetrexed-based chemotherapy. The efficacy of platinum/pemetrexed-based chemotherapy has not been evaluated in patients refractory to second-generation TKIs. METHODS This was a retrospective study performed at three institutions. Patients were eligible if they had advanced ALK-positive NSCLC refractory to ≥1 second-generation ALK TKI(s) and had received platinum/pemetrexed-based chemotherapy. RESULTS Among 58 patients eligible for this study, 37 had scans evaluable for response with measurable disease at baseline. The confirmed objective response rate to platinum/pemetrexed-based chemotherapy was 29.7% (11/37; 95% CI, 15.9% to 47.0%), with median duration of response of 6.4 months (95% CI, 1.6 months to not reached). The median progression-free survival (PFS) for the entire cohort was 4.3 months (95% CI, 2.9 to 5.8 months). PFS was longer in patients who received platinum/pemetrexed in combination with an ALK TKI, compared to those who received platinum/pemetrexed alone (6.8 months vs 3.2 months, respectively; HR 0.33, p=0.025). CONCLUSIONS Platinum/pemetrexed-based chemotherapy shows modest efficacy in ALK-positive NSCLC after failure of second-generation ALK TKIs. The activity may be higher if administered with an ALK TKI, suggesting a potential role for continued ALK inhibition.

中文翻译：

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铂类/培美曲塞联合化疗治疗二代 ALK 抑制剂难治性 ALK 阳性非小细胞肺癌的疗效

背景 目前晚期 ALK 阳性非小细胞肺癌 (NSCLC) 的标准初始治疗是第二代 ALK 酪氨酸激酶抑制剂 (TKI)，如艾乐替尼。第二代 ALK TKI 失败后的最佳下线治疗仍有待确定；然而，标准选项包括第三代 ALK TKI 劳拉替尼或基于铂/培美曲塞的化疗。尚未在第二代 TKI 难治性患者中评估基于铂/培美曲塞的化疗的疗效。方法 这是一项在三个机构进行的回顾性研究。如果患者患有对≥1 种第二代 ALK TKI 难治的晚期 ALK 阳性 NSCLC，并且接受过基于铂类/培美曲塞的化疗，则符合条件。结果 在符合本研究条件的 58 名患者中，37 人的扫描可评估基线时可测量疾病的反应。对基于铂类/培美曲塞的化疗的确认客观缓解率为 29.7%（11/37；95% CI，15.9% 至 47.0%），中位缓解持续时间为 6.4 个月（95% CI，1.6 个月至未达到） . 整个队列的中位无进展生存期 (PFS) 为 4.3 个月（95% CI，2.9 至 5.8 个月）。与单独接受铂/培美曲塞治疗的患者相比，接受铂/培美曲塞联合 ALK TKI 治疗的患者的 PFS 更长（分别为 6.8 个月和 3.2 个月；HR 0.33，p=0.025）。结论 以铂类/培美曲塞为基础的化疗在第二代 ALK TKI 失败后的 ALK 阳性 NSCLC 中显示出中等疗效。如果与 ALK TKI 一起给药，活性可能更高，这表明持续抑制 ALK 的潜在作用。