3687 - Patterns of Failure and Outcomes of Oligoprogression in ALK-Rearranged NSCLC Treated with ALK TKIs
Presenter(s)
H. Y. Zhang1, R. V. Mantena1, H. Walch2, E. C. Dee1, J. Willmann3, C. von Wachter1, S. Venkateswaran1, A. Drilon4, D. Jones5, M. M. Awad4, C. M. Rudin4, A. J. Schoenfeld4, J. Chaft6, D. R. Gomez7, A. J. Wu1, D. Y. Gelblum1, M. G. Kris4, N. Shaverdian1, G. Riely4, and P. Iyengar1; 1Department of Radiation Oncology, Memorial Sloan Kettering Cancer Center, New York, NY, 2Department of Epidemiology and Biostatistics, Memorial Sloan Kettering Cancer Center, New York, NY, 3Department of Radiation Oncology, University Hospital Zurich, University of Zurich, Zurich, Switzerland, 4Division of Solid Tumor Oncology, Memorial Sloan Kettering Cancer Center, New York, NY, 5Department of Surgery, Memorial Sloan Kettering Cancer Center, New York, NY, 6Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY, 7Department of Radiation Oncology, NYU Grossman School of Medicine, New York, NY
Purpose/Objective(s): Oligoprogression during ALK tyrosine kinase inhibitor (TKI) therapy is common in ALK-positive NSCLC. However, patterns of failure and the impact of radiotherapy (RT) remain incompletely defined. We characterized progression patterns across ALK fusion subtypes and evaluated outcomes associated with RT for oligoprogression.
Materials/Methods: We identified patients with ALK-positive NSCLC treated with ALK TKIs from 2010-2025 at a single institution. Fusion subtype was determined using a clinically validated targeted next-generation sequencing panel. Baseline oligometastatic disease and oligoprogression were defined by EORTC criteria (=5 lesions in =3 organs). Logistic regression evaluated factors associated with oligoprogression on first-line TKI. Among patients experiencing first oligoprogression on any TKI line, time to therapy switch and overall survival (OS), measured from first progression, were analyzed using Kaplan-Meier methods and multivariable Cox regression.
Results: A total of 187 patients were included. EML4 variant 3 (n=70, 39%) and variant 1 (n=65, 35%) were the most common. 16% had other EML4 variants, and 9% harbored non-EML4 partners. 26% of patients (n=45) had oligometastatic disease. For first-line therapy, 130 patients (69%) received a second-generation ALK TKI, 40 (21%) received crizotinib, and 15 (8%) received lorlatinib. During first-line treatment, 110 patients (59%) experienced disease progression. Among those, 56 (51%) demonstrated oligoprogression. Intrathoracic-only progression was significantly enriched among oligoprogressors compared with polyprogressors (36% vs 8%, p<0.001). In contrast, rates of intracranial involvement did not significantly differ by progression extent (30% vs 23%, p=0.5). Baseline oligometastatic disease was associated with higher odds of oligoprogression (OR 3.1, 95% CI 1.1–11.1; p=0.05), while fusion variant, metastatic timing (metachronous versus de novo), and TKI generation were not associated with progression extent.
Among patients with first oligoprogression on any ALK TKI line, RT was associated with prolonged continuation of the same TKI (median 7 vs 2 months). After adjustment, RT remained independently associated with longer post-progression TKI duration (HR 0.5, 95% CI 0.32–0.78; p=0.002). In KM analysis, RT was associated with improved overall survival from the time of first progression (median 59.8 vs 29.2 months, log-rank p=0.041)Conclusion: Oligoprogression occurs in approximately half of patients progressing on first-line ALK TKI and is enriched among those with baseline oligometastatic disease. Oligoprogressive disease was characterized predominantly by intrathoracic-only failure, a resistance pattern that may inform consolidative RT strategies. RT directed to oligoprogressive sites was associated with prolonged continuation of the same TKI, providing additional evidence for local ablative therapy in managing limited resistant disease.