Abstract C061: Real-World Outcomes of Immune Checkpoint Inhibitors and Emerging Immunotherapies in Molecularly Characterized NSCLC Treated in a Phase 1 Clinical Trial Unit

Abstract BACKGROUND Non-small cell lung cancer (NSCLC) constitutes approximately 80% of all lung cancer cases. Immune checkpoint inhibitors (ICIs) targeting PD-1/PD-L1 have significantly improved outcomes in advanced NSCLC, yet a substantial proportion of patients still fail to respond3. Understanding resistance mechanisms and identifying predictive biomarkers is crucial for optimizing treatment selection and developing effective strategies. Novel immunotherapies targeting alternative immune pathways, including T cell co-stimulation, immune evasion inhibition, cellular therapy, cytokines, and NK activation, are currently under investigation. METHODS We retrospectively analyzed stage IV NSCLC patients who underwent next-generation sequencing (NGS) via liquid or tissue biopsy at Fundación Jiménez Díaz Hospital from January 2011 to June 2024. Patients were treated with ICIs as a standard of care or enrolled in clinical trials involving novel immunotherapies. Efficacy was assessed per iRECIST, and toxicity per CTCAE v5.0. Imaging was performed at protocol-defined intervals. Statistical analysis was conducted in R (version 4.4.1) using the 'tableone' package for descriptive statistics. Categorical variables were compared using frequency distributions, and continuous variables were summarized with means, standard deviations, and medians (95% CI), utilizing bootstrapping for median confidence intervals. RESULTS A total of 124 patients were included. 62.9% were male, and 63.9% were former smokers. The median pack-year index was 32. ICIs were administered to 60.2%, while 31.7% received novel immunotherapies. Among ICI-treated patients, overall responses were observed in 51.4% patients (6.8% complete response (CR); 44.6% partial response (PR); 33.8% had stable disease (SD), and 14.9% progressive disease (PD). In clinical trials, no CR were observed; 18.9% patients had PR, 33.2% SD and 37.8% PD. EGFR mutations were associated with worse outcomes in patients treated with ICIs (n: 11) (90.9% SD < 6 months or PD) compared to EGFR wild-type patients (n: 113) (57.5% SD < 6 months or PD); p = 0.0487. No difference was observed with novel immunotherapies according to EGFR status (p = 0.6038). MET-altered tumors showed poorer response to ICIs (n: 6) (83.3% SD < 6 months or PD) compared to MET wild-type patients (n: 118) (59.32% SD < 6 months or PD) however, this difference did not reach statistical significance. Significantly better outcomes were observed in association with novel immunotherapies in MET-altered tumors (50% SD < 6 months or PD) compared to MET wild-type (9.2% SD < 6 months or PD); p = 0.0152. CONCLUSIONS EGFR mutations are linked to detrimental prognosis in patients treated with ICIs, likely due to a less immunogenic tumor microenvironment. MET alterations showed mixed results with better outcomes for novel immunotherapies. Due to the limited number of patients, these findings should be confirmed in larger cohorts of patients. Our study highlights the importance of comprehensive molecular profiling to guide NSCLC immunotherapy strategies. Citation Format: Paula Rodríguez-Hernáez, Igor López, Manuel Pedregal, Bernard Doger, Victor Moreno, Alberto Ocana, Ester García-Lorenzo. Real-World Outcomes of Immune Checkpoint Inhibitors and Emerging Immunotherapies in Molecularly Characterized NSCLC Treated in a Phase 1 Clinical Trial Unit [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference on Molecular Targets and Cancer Therapeutics; 2025 Oct 22-26; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2025;24(10 Suppl):Abstract nr C061.