Clinical outcomes and Guardant360 circulating tumor DNA profiling in ALK-positive non-small cell lung cancer treated with lorlatinib after alectinib

Background Lorlatinib is a third-generation ALK tyrosine kinase inhibitor with activity against ALK-positive non-small cell lung cancer (NSCLC), including tumors previously treated with second-generation ALK inhibitors. However, molecular features observed by plasma circulating tumor DNA (ctDNA) profiling in patients receiving lorlatinib after alectinib remain incompletely characterized. We evaluated clinical outcomes and Guardant360 ctDNA findings in patients with ALK-positive NSCLC treated with lorlatinib after alectinib. Methods Patients with ALK-positive NSCLC scheduled to receive lorlatinib after prior alectinib were prospectively enrolled in a multicenter study. Clinical outcomes, including response, progression-free survival (PFS), overall survival (OS), treatment discontinuation, and adverse events, were collected. Plasma ctDNA was analyzed using Guardant360 at lorlatinib initiation and, when available, at disease progression. Lorlatinib outcomes were descriptively summarized according to baseline ctDNA findings. Results Twenty-eight patients were included. The median age at alectinib initiation was 61.5 years, and all patients had adenocarcinoma. The median PFS with prior alectinib was 25.3 months. At lorlatinib initiation, brain and bone metastases were each present in 46.4% of patients. Lorlatinib achieved a partial response in 35.7% and stable disease in 17.9% of patients. Median PFS and OS with lorlatinib were 4.8 months and 26.6 months, respectively. At lorlatinib initiation, Guardant360 detected ALK rearrangements in 13 patients (46.4%), including EML4-ALK in 11 patients (39.3% of the total cohort), and TP53 alterations in 9 patients (32.1%). Patients with TP53 alterations or detectable ALK fusion in baseline ctDNA numerically showed shorter PFS than those without these findings. At lorlatinib progression, heterogeneous genomic changes were observed, including persistent ALK rearrangements, bypass pathway alterations, and a candidate ANK2-ALK fusion. Conclusion Lorlatinib demonstrated clinical activity after alectinib, although outcomes were heterogeneous. Guardant360 ctDNA profiling provided a descriptive view of molecular heterogeneity before lorlatinib and at disease progression. A candidate ANK2-ALK fusion detected at progression may represent a previously unreported ALK fusion partner, but additional validation was not feasible because of limited specimen availability and the patient’s complete response to subsequent pemetrexed. These findings support further evaluation of longitudinal ctDNA profiling in ALK-positive NSCLC.