To investigate the impact of distinct clinical progression patterns on progression-free survival (PFS) in patients with anaplastic lymphoma kinase (ALK) fusion gene-positive non-small cell lung cancer (NSCLC) following treatment with first-generation, first-line and sequential second-line second-generation ALK tyrosine kinase inhibitors (ALK-TKIs), to analyze whether baseline patient characteristics can predict progression patterns, and to evaluate survival differences among various treatment strategies after second-generation ALK-TKI resistance.

A retrospective analysis was conducted on ALK-positive advanced NSCLC patients who experienced disease progression after ALK-TKI therapy between January 1, 2017, and September 30, 2025, across four centers (Eastern Theater Command General Hospital, Hunan Cancer Hospital, Shanxi Bethune Hospital, and Nanjing Chest Hospital). Patients were divided into first-generation ALK-TKI resistance cohort and second-generation ALK-TKI resistance cohort based on the targeted agent and treatment line at the time of drug resistance. The second-generation ALK-TKI resistance cohort included two subgroups: patients progressed after first-line second-generation ALK-TKI treatment, and patients progressed after sequential second-generation ALK-TKI treatment (second-line) following first-generation ALK-TKI. Progression patterns (oligoprogression vs. systemic progression; primary site progression vs. distant site progression) were assessed according to RECIST 1.1 criteria. Kaplan-Meier method was used for PFS analysis, and Firth regression was applied to identify predictive factors for systemic progression after second-generation ALK-TKI resistance.

The first- and second-generation TKI resistance cohorts included 53 and 56 patients, respectively. The median PFS for patients with oligoprogression after second-generation TKI resistance (17.7 months; 95%CI: 12.5~22.8 months) was significantly longer than for those with systemic progression (9.0 months; 95%CI: 4.5~13.5 months, P<0.001). Subgroup analysis showed that patients with oligoprogression had significantly better PFS than those with systemic progression, regardless of first-line or sequential second-line second-generation TKI treatment (all P<0.05). Patients presenting with oligometastatic disease before second-generation TKI treatment were less likely to develop systemic progression (OR=0.18, 95%CI: 0.03~0.87, P=0.033). After second-generation TKI resistance, no significant difference in PFS was observed among patients who continued the original drug, switched to another second-generation TKI, or initiated a third-generation TKI (P=0.979).

After second generation ALK-TKI resistance, oligoprogression pattern is associated with longer PFS regardless of treatment line, and pre-treatment metastatic status may serve as an independent predictor for the progression pattern. No significant difference in efficacy was found among different subsequent TKI strategies following second-generation TKI resistance, and this result is only an exploratory analysis, which needs to be further verified by prospective studies