Induction alectinib or crizotinib for stage III NSCLC harboring ALK fusion: A study with 4-year follow-up

Despite increased response and long-term benefit of anaplastic lymphoma kinase (ALK)-tyrosine kinase inhibitors (TKIs) in advanced non-small cell lung cancer (NSCLC) harboring ALK -fusion, the role of induction ALK-TKIs in locally advanced NSCLC remained poorly investigated. This study aimed to demonstrate the short-term and long-term efficacy of ALK-targeted induction therapy in stage III lung cancer.

We consecutively collected data of patients from Guangdong Lung Cancer Institute since 2016, and those who were pathologically confirmed stages IIIA-IIIB NSCLC treated with induction ALK-TKIs initially were eligible for subsequent analysis. Patients' clinicopathological features as well as therapeutic management were fully reviewed. Analysis of longitudinal single-cell RNA sequencing from patients treated with alectinib were performed. Fisher's exact test was used to compare two categorical variable and Kaplan-Meier was applied for survival curve with estimation for median and 95% confidence interval (CI) value if available.

Forty stage III NSCLC patients treated with either alectinib or crizotinib were enrolled. Among those who had surgery, all patients had R0 resection without postoperative radiotherapy. Only two patients suffered grade 2 postoperative complications in terms of Clavien-Dindo score. Induction alectinib showed numerically superior pathological response compared with crizotinib with both major pathological response (MPR) (11/17, 64.7% vs. 6/13, 46.2%, P = 0.46) and complete pathological response (pCR) (6/17, 35% vs. 2/13, 15%, P = 0.41). Patients who received induction alectinib had significantly longer PFS (not reached [NR] vs. 17.9 months, P <0.001) and numerically improved overall survival (NR vs. NR, P = 0.092) compared with crizotinib. Brain metastasis remained the most common recurrent pattern after induction ALK-TKIs. Longitudinal single-cell RNA sequencing revealed increased tumor stemness and induced a more suppressive immune microenvironment in the residual tumor while highly inflamed microenvironment along with low infiltrating regulatory T cell and exhausted T cell was observed in resected specimens which achieved pCR.

Induction ALK-TKIs provided a clinically efficient and well-tolerated therapeutic strategy in locally advanced ALK-positive NSCLC.