A window of opportunity study for preoperative brigatinib in resectable anaplastic lymphoma kinase (ALK)-positive non-small-cell lung cancer (NSCLC): WILDERNESS trial.

8040 Background: Although ALK inhibitors are approved for patients with ALK -positive recurrent and/or metastatic NSCLC or resected NSCLC, their role as neoadjuvant therapy in resectable NSCLC remains unclear. Here, we report the results of a window-of-opportunity study evaluating neoadjuvant brigatinib in resectable ALK -positive NSCLC, aiming to identify the molecular mechanisms underlying drug-tolerant persister cells in cancer (NCT05361564). Methods: We conducted a single-arm, open-label, phase 2 trial of neoadjuvant brigatinib in patients with resectable ALK -positive NSCLC. Patients received brigatinib at a dose of 180 mg once daily following a 7-day lead-in period at 90 mg. Radiologic objective response rate (ORR), major pathologic response (MPR) rate, disease-free survival (DFS), event-free survival (EFS), and overall survival (OS) were evaluated. Single-cell transcriptomic analyses were performed to characterize the tumor microenvironment according to the achievement of MPR. Results: All 12 enrolled patients underwent surgical resection following neoadjuvant treatment without delays or increased surgical complications. The median time interval between neoadjuvant treatment initiation and surgical resection was 45 days (range: 38-64 days). The ORR was 83.3% (10/12), and MPR (defined as ≤10% residual cancer cells in the surgical specimen) was achieved in 7 patients (58.3%). The most common adverse event was elevated creatine phosphokinase (50.0%), and one patient experienced a grade 3 adverse event (asymptomatic creatine phosphokinase elevation). Over a median follow-up period of 602 days (range: 300–826 days), three patients experienced recurrence, resulting in a 2-year EFS rate of 70.1%. Single-cell transcriptomic analysis revealed that ZNF683-positive CD8+ T cells expressing effector-related genes including Blimp-1, were significantly enriched in patients with MPR. In contrast, FOXP3-positive regulatory CD4+ T cells were enriched in patients without MPR. Conclusions: Neoadjuvant brigatinib was effective and safe in patients with resectable ALK -positive NSCLC. Single-cell transcriptomic analysis highlights the balance between effector and regulatory T cell programs as a critical determinant of pathologic response and the clearance of drug-tolerant and persister cancer cells. Clinical trial information: NCT05361564 .