Clinicogenomic characteristics associated with non-durable response to first-line immunotherapy among advanced lung squamous cell carcinoma with PD-L1 ≥ 50%.

e20614 Background: While immune checkpoint inhibitors (ICIs) are a cornerstone of therapy in advanced lung squamous cell carcinoma (LSqCC) with PD-L1≥50%, clinical outcomes are variable and additional biomarkers to predict response to ICIs are poorly defined. We compared clinical and genomic characteristics of individuals with durable response (DR) and non-durable response (NDR) to ICIs. Methods: We conducted a retrospective analysis of individuals with advanced LSqCC and PD-L1 TPS ≥50% treated with frontline ICI-based therapy at Indiana University Health System from January 1, 2018 - June 30, 2025. Demographics, clinical features associated with poor response to ICIs, and next-generation sequencing data were collected using electronic medical records. Response was assessed using standardized real-world criteria. Median progression-free survival (PFS) and overall survival (OS) were calculated using the Kaplan-Meier method. DR and NDR were defined as a PFS ≥ and <6 months, respectively. Variables were compared using Wilcoxon/χ²/Fisher’s exact tests. Results: We identified 646 individuals with LSqCC of whom 41 were eligible for analysis. 19 (46%) had a NDR with a mean age of 68 (vs. 66 for DR; p=0.44). 63% were male (vs. 59%; p=0.79), 79% were white (vs. 73%; p> 0.99), and 95% were current/former smokers (vs. 96%; p>0.99). Individuals with NDR had lower baseline hemoglobins but were otherwise similar to those with DR, Table. ICI monotherapy was more common among those with NDR (74% vs. 26%), while chemo-ICI was more frequently used in those with DR (73% vs. 26%, p< 0.01). As expected, response rates (21% vs. 86%; p <0.01), PFS (2.9 vs. 10.8 mo; p< 0.01), and OS (9.4 vs. 19.6 mo; p=0.03) were significantly lower among those with NDR. KRAS alterations were more frequent among those with DR (24% vs. 5%; p =0.19), while CDKN2A and CDKN2B alterations were significantly more common among those with NDR (63% vs. 19% and 21% vs. 0%, p < 0.01). Conclusions: In our cohort, 46% of advanced LSqCC with PD-L1≥50% had a NDR to frontline ICIs. While clinical factors were comparable, chemo-ICI use was more common among DR, suggesting the addition of chemotherapy to ICIs may result in improved outcomes even with PD-L1≥50% LSqCC. The presence of CDKN2A/B alterations among those with NDR suggests a potential association with poor ICI response that warrants further investigation and highlights the role of genomic profiling to identify biomarkers beyond PD-L1 for treatment selection in LSqCC. Variable NDR n=19 (46.3%) DR n=22 (53.7%) P Stage IV 8 (42.1) 11 (50.0) 0.475 Metastasis Brain/Bone/Liver 7 (36.8) 10 (45.5) 0.922 BMI≥25 14 (73.7) 15 (68.2) 0.848 ECOG ≥2 2 (10.5) 3 (13.6) >0.999 Immunosuppression 1 (5.3) 5 (22.7) 0.184 Hb – mean (range) 11.3 (7.3 – 16.7) 12.5 (9.7 – 15.8) 0.047 ANC/ALC ratio ≥3 11 (57.9) 14 (63.6) 0.893 PD-L1 ≥90% 7 (36.8) 11 (50.0) 0.621