Pathological response and tumor immune microenvironment remodeling of neoadjuvant ALK-TKIs in NSCLC with ALK.

Abstract

e20574 Background: Anaplastic lymphoma kinase–tyrosine kinase inhibitor (ALK-TKI; ALKi) has shown potent antitumor activity in metastatic non–small-cell lung cancer (NSCLC) with ALK rearrangement (ALK+). However, its efficacy in neoadjuvant settings for patients with ALK+ resectable NSCLC has been poorly explored. Given this, the present study aimed to examine the clinical activity and tumor immune microenvironment (TIME) remodeling of neoadjuvant ALKi therapy. Methods: In this retrospective study, ALK+ NSCLC patients treated with neoadjuvant ALKi therapy at three hospitals in China were enrolled between February 2018 and April 2022.Data on clinical features, radiographic responses, and pathological responses were collected and evaluated. Multiplex immunofluorescence was performed on pre-treatment biopsy specimens and surgically resected specimens to investigate the impact of ALKi on TIME. Two panels (Panel 1: CD8, PD1, GB, CK, 4′,6-diamidino-2-phenylindole [DAPI]; Panel 2: CD4, FOXP3, CD68, CD163, CK, DAPI) were used to identify multiple immune cell types. Results: A total of 12 patients with stage IIA to IIIB NSCLC who received neoadjuvant ALKi therapy and R0 resection were enrolled; the median age was 54.0 years, and 66.7% (8/12) were female. The median duration of neoadjuvant ALKi was 5.5 months. The objective response rate was 91.7% (11/12). All patients successfully underwent R0 resection. The major pathological response (MPR) rate was 75.0% (9/12), with 58.3% (7/12) achieving a pathological complete response (pCR). After neoadjuvant ALKi therapy, we observed asignificant increase in immune infiltration of total CD8+ (histochemistry score: median, 10.51 vs 24.01, P= 0.028; density: median, 128.38 vs 694.09 cells/mm2, P= 0.028; percentage: median, 3.53% vs 15.92%, P= 0.028) and total CD4+ (density: median, 275.56 vs 651.82 cells/mm2, P= 0.028; percentage: median, 5.98% vs 10.46%, P= 0.028). Similar results were found for CD4+FOXP3+, CD8+PD1+, CD8+PD1-, CD8+GB+, and CD8+GB-. However,macrophages, including CD68+CD163- M1 and CD68+CD163+ M2 macrophages, showed little change after neoadjuvant ALKi therapy. When comparing TIME between neoadjuvant ALKi and PD1 inhibitors in resected specimens from patients with pCR, neoadjuvant ALKi therapy presented higher levels of CD8+PD1+ but lower levels of CD8+GB+. Conclusions: Neoadjuvant ALKi therapy achieved an encouraging MPR rate of 75% and enhanced immune infiltration, suggesting its safety and feasibility for ALK+ resectable NSCLC. This study advances our understanding of TIME remodeling by neoadjuvant ALKi therapy and merits further investigation in the neoadjuvant setting for patients with ALK+ resectable NSCLC.