Guangdong Lung Cancer Institute, Guangdong Provincial Key Laboratory of Translational Medicine in Lung Cancer, Guangdong General Hospital and Guangdong Academy of Medical Sciences, Guangzhou, People's Republic of China; School of Medicine, South China University of Technology, Guangzhou, People's Republic of China.
Department of Thoracic Surgery II, Key Laboratory of Carcinogenesis and Translational Research, Ministry of Education, Peking University Cancer Hospital and Institute, Beijing, People's Republic of China.
J Thorac Oncol. 2019 Apr;14(4):726-731. doi: 10.1016/j.jtho.2018.10.161. Epub 2018 Nov 5.
Locally advanced NSCLC is one of the most heterogeneous conditions, with multidimensional treatments involved. Neoadjuvant therapy had been commonly considered an optimal management strategy for patients with operable locally advanced. However, as targeted therapy has been widely applied in advanced NSCLC, neoadjuvant targeted therapy has remained poorly explored in locally advanced disease.
We have described 11 ALK receptor tyrosine kinase gene (ALK)-positive patients with pathologically confirmed N2 NSCLC who were treated with neoadjuvant crizotinib. All the patients were treatment naive and received crizotinib at a starting dose of 250 mg twice daily. Patient 3 was provided with dynamic monitoring before and after neoadjuvant therapy through next-generation sequencing of plasma and tissue. In case 4, next-generation sequencing of preoperative tissue was performed.
Of the 11 patients, 10 had a partial response and one was stable disease after neoadjuvant crizotinib, with one suffering from grade 4 hepatic damage. Of the 11 patients, 10 (91.0%) received an R0 resection and 2 patients achieved a pathological complete response to neoadjuvant crizotinib. Six patients had disease recurrence, with five of them receiving crizotinib as first-line treatment and achieving a long duration of response. Dynamic monitoring of both plasma and tissue simultaneously indicated a decrease in sensitive ALK signaling in patient 3 and a partial response (approximately 50% of partial response), and no ALK-dependent resistance variants were captured.
Neoadjuvant crizotinib may be feasible and well tolerated in locally advanced disease for complete resection. Crizotinib therapy before surgery may provide thorough elimination of circulating molecular residual disease and not influence the reuse of first-line crizotinib, but ongoing prospective trials are warranted to prove its efficacy in the neoadjuvant setting.
局部晚期非小细胞肺癌（NSCLC）是一种异质性最强的疾病之一，涉及多维治疗。新辅助治疗通常被认为是可手术局部晚期患者的最佳治疗策略。然而，随着靶向治疗在晚期 NSCLC 中的广泛应用，局部晚期疾病中的新辅助靶向治疗仍未得到充分探索。
我们描述了 11 例经病理证实为 N2 局部晚期 NSCLC 的 ALK 受体酪氨酸激酶（ALK）阳性患者，他们接受了新辅助克唑替尼治疗。所有患者均为初治患者，起始剂量为 250 mg，每日两次。患者 3 在新辅助治疗前后通过血浆和组织的下一代测序进行了动态监测。在病例 4 中，进行了术前组织的下一代测序。
11 例患者中，10 例患者在新辅助克唑替尼治疗后部分缓解，1 例疾病稳定，1 例患者发生 4 级肝损伤。11 例患者中有 10 例（91.0%）接受了 R0 切除，2 例患者对新辅助克唑替尼达到了病理完全缓解。6 例患者疾病复发，其中 5 例患者接受克唑替尼作为一线治疗，获得了长期缓解。同时对血浆和组织进行的动态监测表明，患者 3 中敏感的 ALK 信号降低，出现部分缓解（约 50%的部分缓解），并且未捕获到依赖 ALK 的耐药变异。
新辅助克唑替尼治疗局部晚期疾病可完全切除，具有可行性和良好的耐受性。手术前的克唑替尼治疗可能会彻底消除循环分子残留疾病，并且不会影响一线克唑替尼的再利用，但需要进行前瞻性试验来证明其在新辅助治疗中的疗效。
