261 - Clinical and Genomic Landscape of Recurrence After Concurrent Chemoradiotherapy and Adjuvant Immunotherapy in Unresectable NSCLC
Presenter(s)
K. Olabode1, K. Shin2, L. Martinka1, Simran1,3, J. Gray4, S. Puri4, A. N. Saltos4, T. Tanvetyanon4, B. Creelan4, A. Chiappori4, C. Lu4, M. Shafique4, K. A. Ahmed5, K. Yamoah1, P. C. Rodriguez6, S. K. Jabbour7, S. A. Rosenberg1, T. J. Dilling1, and J. Kim6,8; 1Department of Radiation Oncology, H. Lee Moffitt Cancer Center and Research Institute, Tampa, FL, 2Division of Radiation Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, 3Department of Radiation Oncology, All India Institute of Medical Sciences (AIIMS), New Delhi, India, 4Department of Thoracic Oncology, H. Lee Moffitt Cancer Center and Research Institute, Tampa, FL, 5H. Lee Moffitt Cancer Center and Research Institute, Department of Radiation Oncology, Tampa, FL, 6Department of Immunology, H. Lee Moffitt Cancer Center and Research Institute, Tampa, FL, 7Department of Radiation Oncology, Rutgers Cancer Institute, New Brunswick, NJ, 8Department of Radiation Oncology, Moffitt Cancer Center, Tampa, FL
Purpose/Objective(s):
Despite the PACIFIC paradigm of concurrent chemoradiation (CHRT) followed by consolidative immunotherapy (IO), recurrence remains a major cause of mortality in unresectable stage II–III non-small cell lung cancer (NSCLC). Here, we aim to integrate comprehensive genomic profiling with clinical variables to identify recurrence-associated clinical and molecular signatures and uncover biologically relevant pathways that may inform risk stratification and therapeutic optimization.Materials/Methods:
We retrospectively analyzed 114 patients with Stage II–III unresectable NSCLC treated with definitive CHRT followed by adjuvant IO between 2017 and 2025. All patients underwent next-generation sequencing using a 252-gene panel. Overall survival was stratified by recurrence status using Kaplan–Meier analysis and log-rank test. Clinical and genomic predictors of recurrence were analyzed using univariable and multivariable Firth penalized logistic regression and Cox proportional hazards models. Functional enrichment of recurrence-associated genetic alterations was assessed using a heatmap and DAVID (Database for Annotation, Visualization, and Integrated Discovery) analysis.Results:
The median age was 68 years (range, 39-87). The median follow-up was 45.3 months (4.5-85.4). 54.4% were female, while 46.5% (n=53) were former smokers and 29.8% (n=34) were current smokers. Stage III disease was present in 102 patients (89.5%). Adenocarcinoma was the most common histology (n=62; 54.4%), followed by squamous cell carcinoma (n=24; 21.2%). The median radiation dose was 60Gy (60-70). The most common chemotherapy regimen was weekly Carboplatin/Paclitaxel (n=85; 74.6%). 67 patients (58.8%) experienced disease recurrence, including locoregional (n=21) and distant (n=58) recurrences; 12 had both. Patients with recurrence had significantly inferior median OS compared with those without recurrence (31.8 months [25.3-55.5] vs. not reached [53.9-NA], p = 0.02). Univariable Firth regression identified clinical stage, chemotherapy regimen, and several genomic alterations, including TP53, STK11, EGFR, and DNA damage response–related genes, as associated with recurrence risk. The heatmap showed that 68 genes were exclusively mutated in the patients with distant recurrence. These genes were enriched for PI3K-Akt, T-cell receptor, ErbB, FoxO, MAPK, PD-L1, and Ras signaling pathways in DAVID analysis.Conclusion:
Recurrence after concurrent CHRT and adjuvant IO is prevalent and associated with significantly worse OS in unresectable NSCLC. Distinct clinical features and genomic alterations characterize recurrent disease, highlighting potential biological mechanisms of radioresistance and opportunities for biomarker-driven surveillance and radiosensitization strategies in the post-PACIFIC setting.