Dana-Farber Cancer Institute, Boston, MA.
Brigham and Women's Hospital, Boston, MA.
JCO Precis Oncol. 2024 Apr;8:e2300644. doi: 10.1200/PO.23.00644.
is the most commonly mutated driver oncogene in non-small cell lung cancer (NSCLC). Sotorasib and adagrasib, KRAS inhibitors, have been granted accelerated US approval; however, hepatotoxicity is a common side effect with higher rates in patients treated with sotorasib proximal to checkpoint inhibitor (CPI) therapy. The aim of this study was to assess the feasibility and safety of adagrasib after discontinuation of sotorasib because of treatment-related grade 3 hepatotoxicity through real-world and clinical cases.
Medical records from five patients treated in real-world settings were retrospectively reviewed. Patients had locally advanced or metastatic -mutated NSCLC and received adagrasib after sotorasib in the absence of extracranial disease progression. Additional data were collected for 12 patients with -mutated NSCLC enrolled in a phase Ib cohort of the KRYSTAL-1 study and previously treated with sotorasib. The end points associated with both drugs included timing and severity of hepatotoxicity, best overall response, and duration of therapy.
All patients were treated with CPIs followed by sotorasib (initiated 0-64 days after CPI). All five real-world patients experienced hepatotoxicity with sotorasib that led to treatment discontinuation, whereas none experienced treatment-related hepatotoxicity with subsequent adagrasib treatment. Three patients from KRYSTAL-1 transitioned from sotorasib to adagrasib because of hepatotoxicity; one experienced grade 3 ALT elevation on adagrasib that resolved with therapy interruption and dose reduction.
Adagrasib may have a distinct hepatotoxicity profile from sotorasib and is more easily combined with CPIs either sequentially or concurrently. These differences may be used to inform clinical decisions regarding an initial KRAS inhibitor for patients who recently discontinued a CPI or experience hepatotoxicity on sotorasib.
是最常见的非小细胞肺癌（NSCLC）驱动基因突变致癌基因。KRAS 抑制剂索托拉西布和阿达格拉西布已获得美国加速批准；然而，肝毒性是一种常见的副作用，在接受索托拉西布治疗的患者中，其发生率高于接受检查点抑制剂（CPI）治疗的患者。本研究旨在通过真实世界和临床病例评估因治疗相关 3 级肝毒性而停用索托拉西布后接受阿达格拉西布的可行性和安全性。
回顾性分析了五名在真实环境中接受治疗的患者的病历。这些患者患有局部晚期或转移性 -突变 NSCLC，在无颅外疾病进展的情况下接受索托拉西布治疗后接受了阿达格拉西布治疗。还为先前接受过索托拉西布治疗的 12 名 -突变 NSCLC 患者的 KRYSTAL-1 研究的 I 期队列中的患者收集了额外的数据。与两种药物相关的终点包括肝毒性的发生时间和严重程度、最佳总体反应和治疗持续时间。
所有患者均接受了 CPI 治疗，然后接受了索托拉西布治疗（在 CPI 后 0-64 天开始）。所有五名真实世界患者在接受索托拉西布治疗后均发生了肝毒性，导致治疗停止，而随后接受阿达格拉西布治疗时则没有发生与治疗相关的肝毒性。KRYSTAL-1 中有三名患者因肝毒性从索托拉西布转为阿达格拉西布；一名患者在接受阿达格拉西布治疗时出现 3 级 ALT 升高，经中断治疗和剂量减少后缓解。
阿达格拉西布与索托拉西布的肝毒性谱可能不同，并且更容易与 CPI 序贯或同时联合使用。这些差异可用于为最近停止使用 CPI 或在索托拉西布治疗期间发生肝毒性的患者提供有关初始 KRAS 抑制剂的临床决策。
