OBJECTIVES KRAS mutations, which occur in approximately 25% of lung adenocarcinoma cases, represent a major unmet clinical need in thoracic oncology. Preclinical studies have demonstrated that KRAS mutant NSCLC cell lines and xenografts with additional alterations in either TP53 or CDKN2A (INK4A/ARF) loci are sensitive to focal adhesion kinase (FAK) inhibition. Defactinib (VS-6063) is a selective oral inhibitor of FAK. MATERIALS AND METHODS Patients with previously treated advanced KRAS mutant NSCLC were prospectively assigned to one of four molecularly defined cohorts based on the presence or absence of TP53 or CDKN2A alterations and received treatment with defactinib 400 mg orally BID until disease progression or intolerable toxicity. The primary endpoint was progression-free survival (PFS) at 12 weeks. RESULTS Fifty-five patients were enrolled. Mean age was 62 years; 51% were female. The median number of prior lines of therapy was 4 (range 1-8). Fifteen (28%) patients met the 12-week PFS endpoint, with one patient achieving a partial response. Median PFS was 45 days. Clinical efficacy did not correlate with TP53 or CDKN2A status. The most common adverse events were fatigue, gastrointestinal, and increased bilirubin, and were generally grade 1 or 2 in severity. CONCLUSION In heavily pretreated patients with KRAS mutant NSCLC, defactinib monotherapy demonstrated modest clinical activity. Efficacy was not associated with TP53 and CDKN2A status. Defactinib was generally well tolerated.

中文翻译：

---

粘着斑激酶抑制剂 defactinib (VS-6063) 用于既往治疗的晚期 KRAS 突变非小细胞肺癌的 2 期研究。


目标 KRAS 突变发生在大约 25% 的肺腺癌病例中，代表了胸部肿瘤学中未满足的主要临床需求。临床前研究表明，TP53 或 CDKN2A (INK4A/ARF) 位点发生额外改变的 KRAS 突变 NSCLC 细胞系和异种移植物对粘着斑激酶 (FAK) 抑制敏感。 Defactinib (VS-6063) 是一种选择性口服 FAK 抑制剂。材料和方法 先前接受过治疗的晚期 KRAS 突变 NSCLC 患者根据是否存在 TP53 或 CDKN2A 改变被前瞻性地分配到四个分子定义的队列之一，并接受 defactinib 400 mg 口服 BID 治疗，直至疾病进展或出现不可耐受的毒性。主要终点是 12 周时的无进展生存期 (PFS)。结果 纳入了 55 名患者。平均年龄为 62 岁； 51%是女性。既往治疗线数中位数为 4 线（范围 1-8）。 15 名 (28%) 患者达到了 12 周 PFS 终点，其中一名患者实现了部分缓解。中位 PFS 为 45 天。临床疗效与 TP53 或 CDKN2A 状态无关。最常见的不良事件是疲劳、胃肠道和胆红素升高，严重程度一般为 1 级或 2 级。结论 在接受过多次治疗的 KRAS 突变 NSCLC 患者中，德法替尼单药疗法表现出适度的临床活性。疗效与 TP53 和 CDKN2A 状态无关。德法替尼总体耐受性良好。