2539 - Prognostic Impact of Comprehensive Genomic Profiling Stratified by STK11 Status in NSCLC Treated with the PACIFIC Regimen
Presenter(s)
L. Martinka1, K. Shin2, K. Olabode1, Simran3,4, J. Gray5, S. Puri5, A. N. Saltos5, T. Tanvetyanon5, B. Creelan5, A. Chiappori5, C. Lu5, M. Shafique5, K. A. Ahmed6, K. Yamoah1, P. C. Rodriguez7, S. A. Rosenberg1, S. K. Jabbour8, T. J. Dilling1, and J. Kim7,9; 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, 4Moffitt Cancer Center, Tampa, FL, 5Department of Thoracic Oncology, H. Lee Moffitt Cancer Center and Research Institute, Tampa, FL, 6H. Lee Moffitt Cancer Center and Research Institute, Department of Radiation Oncology, Tampa, FL, 7Department of Immunology, H. Lee Moffitt Cancer Center and Research Institute, Tampa, FL, 8Department of Radiation Oncology, Rutgers Cancer Institute, New Brunswick, NJ, 9Department of Radiation Oncology, Moffitt Cancer Center, Tampa, FL
Purpose/Objective(s):
STK11 (Serine/Threonine Kinase 11) is among the most frequently mutated genes in non-small cell lung cancer (NSCLC). Emerging evidence suggests STK11 alterations may influence response to systemic therapies. However, the clinical and genomic landscape stratified by STK11 status in patients treated with definitive chemoradiation and consolidation durvalumab per the PACIFIC regimen remains incompletely characterized. We hypothesized that STK11 mutations are associated with inferior clinical outcomes and distinct genomic features in this setting. Therefore, we investigated the landscape of STK11 mutations in unresectable locally advanced NSCLC (LA-NSCLC) and their significance for treatment response.Materials/Methods:
Patients with histologically confirmed unresectable stage II-III NSCLC treated with the PACIFIC regimen from 2015 to 2024 were retrospectively identified. Of 263 patients treated, 114 had next-generation sequencing (NGS) performed using a 252-gene panel. Patients were stratified by STK11 mutation status. Clinical outcomes of interest included overall survival (OS) and progression-free survival (PFS). PFS and OS were estimated using the Kaplan–Meier method. Heatmaps identified genomic alterations exclusive to STK11-mutant and wild-type subgroups, and gene ontology and pathway enrichment analyses were performed through DAVID (Database for Annotation, Visualization, and Integrated Discovery).Results:
Of the 114 patients included, 98 had STK11 wild-type (WT) tumors and 16 had STK11-mutant (MUT) tumors. The median follow-up was 45.3 months (range: 0.87 – 93.33). The median age was 68 years (39-87). 54.5% were female, while 46.5% (n=52) 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; 21.1%). Median radiation dose was 60 Gy (60-70). The most common chemotherapy regimen was weekly paclitaxel-carboplatin (n=85; 74.6%). The median PFS for STK11 WT and STK11 MUT cohorts was 24.2 months (95% CI: 19.3-28.8) and 12.3 months (95% CI: 7.4-NA), respectively (p = 0.003). The median OS for STK11 WT and STK11 MUT cohorts was 53.9 months (95% CI 34.3-NA) and 27.3 months (95% CI 20.9-NA), respectively (p = 0.23). Heatmap analysis showed that 16 genes were exclusively mutated in the STK11 MUT cohort. These genes were enriched in the MAP Kinase pathway, the ERK1/2 pathway, and T-cell proliferation/differentiation in DAVID analysis.Conclusion:
STK11 mutation was associated with inferior PFS and a trend toward worse OS in patients with unresectable LA-NSCLC treated with the PACIFIC regimen. The distinct co-mutation profile observed in STK11-mutant tumors suggests biologically driven resistance and supports further evaluation of STK11 as a risk-stratifying biomarker.