Dirozalkib in patients with advanced ALK-positive non-small cell lung cancer (NSCLC): Results from a phase 2 study

Background: Dirozalkib is a novel, highly selective inhibitor of anaplastic lymphoma kinase (ALK). The phase 2 study (NCT05482087) in Chinese patients (pts) with advanced ALK-positive NSCLC was designed to evaluate the efficacy and tolerability of dirozalkib in pts with different ALK inhibitor therapy history. Methods: This study enrolled pts with advanced ALK-positive NSCLC into three cohorts (Cohort A, B, C) based on prior ALK inhibitor therapy. Cohort A enrolled pts with ALK inhibitor-naïve, Cohort B included pts previously treated with only crizotinib, and Cohort C included pts previously treated with other ALK inhibitors ± crizotinib. All pts received dirozalkib 500 mg orally once daily. The primary endpoint was objective response rate (ORR) per RECIST version 1.1. Secondary endpoints included progression-free survival (PFS), disease control rate (DCR), duration of response (DoR), intracranial objective response rate (IC-ORR), overall survival (OS) and safety etc. Exploratory objective was to characterize resistance mechanisms and molecular correlations between the antitumor efficacy of dirozalkib and ALK mutations. Results: At data cutoff (Mar. 27, 2024), the ORR for Cohorts A (n=31), B (n=33), and C (n=49) was 71.0%, 33.3% and 22.4%, respectively, with a DCR of 83.9%, 87.9%, and 65.3%, and a median PFS of 11.07 months (mo), 9.26 mo, and 4.63 mo, respectively. OS data in all cohorts remained immature at the time of analysis. Among pts with measurable brain metastases at baseline across the three cohorts, the IC-ORR was 59.1%. Analysis of paired baseline and end-of-treatment (EOT) circulating tumor DNA (ctDNA) samples from 50 pts demonstrated that: in Cohort A (n=8), no new ALK resistance mutations emerged following dirozalkib treatment. In Cohort B (n=11), baseline ALK resistance mutations were detected in 7 pts, and dirozalkib treatment led to the mutant ctDNA clearance at EOT or tumor response in 6 pts with some common crizotinib resistance mutations (e.g., F1174L, G1296A, L1196M, C1156Y, I1171T). In Cohort C (n=31), 5 pts had baseline ALK resistance mutations, including 2 with the G1202R mutation. In one patient, dirozalkib treatment resulted in the clearance of the G1202R mutant ctDNA at EOT, with a corresponding best overall response (BOR) of stable disease (SD). The most common treatment-related adverse events (TRAEs) were gastrointestinal disorders and transaminase elevations. Grade ≥3 TRAEs mainly included diarrhea (13.3%), hypertriglyceridemia (3.5%), gamma-glutamyltransferase increased (3.5%), hypokalemia (2.7%), anaemia (2.7%), and QT interval prolongation (2.7%). No new safety signal was observed. Conclusions: Both ctDNA testing results and clinical data demonstrated the promising efficacy of dirozalkib in patients with advanced ALK-positive NSCLC.