PEARL: A Multicenter Phase 2 Study of Lorlatinib in Patients with ALK-Rearranged NSCLC and Central Nervous System Disease.

Background: Patients with ALK-rearranged non-small cell lung cancer (ALK+ NSCLC) with symptomatic brain (BM) and leptomeningeal (LM) metastases are underrepresented in clinical trials due to poor performance status. Additionally, the need for improved and validated assessment criteria for evaluating central nervous system (CNS) response remains critical. Lorlatinib has demonstrated systemic activity in patients with ALK+ NSCLC. This ongoing phase II study aims to evaluate the efficacy and safety of lorlatinib in ALK+ NSCLC patients with progressive CNS metastases.

Patients And Methods: This study is a multicenter, open-label, single-arm, prospective trial. Fifty eligible subjects will be divided into 2 cohorts: BM (progressive or new brain parenchymal; n = 30) and LM (positive cerebrospinal fluid cytology and/or MRI ± brain parenchymal metastasis; n = 20). Key inclusion criteria include ALK status confirmed using FDA-approved tests, at least 1 CNS lesion, with or without CNS-related symptoms, and an ECOG performance status of 0-2 for the BM cohort and 0-3 for the LM cohort. Primary endpoint is intracranial objective response rate based on the modified version of response evaluation criteria in solid tumors v1.1 for BM and modified RANO-LM criteria for LM. Key secondary endpoints include intracranial progression-free survival, overall progression-free survival, objective response rate, overall survival, safety and quality of life. Biomarker analysis of paired pretreatment tumor, blood and optional cerebrospinal fluid will be performed as preplanned exploratory analyses.

Conclusions: The PEARL study (CTONG2303) will evaluate efficacy of lorlatinib in CNS metastases in ALK+ NSCLC using refined CNS response evaluation criteria, with biomarker analyses providing insights into response and resistance mechanisms.