Aim: This study aimed to evaluate the real-world efficacy and safety of lorlatinib in patients with anaplastic lymphoma kinase (ALK)-rearranged metastatic non-small cell lung cancer (NSCLC) after the failure of at least one prior ALK tyrosine kinase inhibitor (TKI). Methods: The dataset included 82 subjects with metastatic NSCLC, who received lorlatinib upon compassionate use program or routine treatment between January 2017 and May 2025. All patients involved in this study responded to a prior ALK inhibitor for at least 4 months and switched to the above drug due to disease progression. Results: The overall objective response rate (ORR) was 64.6%, with the disease control rate (DCR) of 96.3%. Among 65 patients with brain metastases, the intracranial ORR and DCR were 66.2% and 96.9%, respectively. After a median follow-up of 82.7 months, the median progression-free survival (PFS) was 66.7 months (95% CI, 40.5–75.0 months), while the median overall survival (OS) was not reached (NR) (95% CI, NR–NR). Patients who had benefited from prior ALK TKI for more than 12 months achieved significantly longer PFS (NR vs. 34.0 months; p = 0.013) and OS (NR vs. 39.4 months; p = 0.002). Multivariate analysis showed that prior response to ALK TKI of less than 12 months was an independent negative predictor of survival (PFS: p = 0.039, OS: p = 0.027). Treatment-related adverse events (AEs) were reported in 75.6% of patients, with 8.1% experiencing grade 3 or higher toxicity; no treatment-related AEs led to permanent discontinuation of lorlatinib. Conclusions: This real-world dataset demonstrates an unusually pronounced benefit from lorlatinib in selected patients who progressed on early-generation TKIs, especially in long-term responders to prior therapy. However, the observed outcomes should be interpreted within the context of patient selection. The enrichment for prior responders limits the generalizability to unselected post-TKI populations, including those with primary resistance.
Orlov et al. (Thu,) studied this question.