Effects of upfront dual immunotherapy on overall survival in patients with metastatic non-small cell lung cancer with no targetable mutations or PD-L1 expression.

e20588 Background: Upfront treatment decision for patients with metastatic Non-Small Cell Lung Cancer (NSCLC) with no targetable mutations and no Programmed Death Ligand 1 (PD-L1) expression remains controversial. Although FDA approved, the combination of conventional chemotherapy and PD-1/L-1 antibody has shown mixed results as multiple sub-groups analyses of clinical trials failed to show a benefit in PD-L1 negative tumors. Conversely, a combination of 2 checkpoint inhibitors, ipilimumab and nivolumab (ipi+nivo), is not Food and Drug Administration approved for these tumors but is an option in the NCCN guidelines. To our knowledge, this is the first large-scale study to address survival outcomes between upfront chemotherapy-immunotherapy (ChemoIO) vs dual immunotherapy alone in metastatic NSCLC. Methods: A retrospective cohort study using TriNetX Research Network, a federated platform of HIPAA-compliant patient records from 159 healthcare organizations (HCO) from the Global Collaborative Network was carried out. Patients with NSCLC and no targetable mutation defined as HER2, MET variant, EGFR, ALK, RET, EGFR, BRAF, ROS1, NTRK1/2/3 and no PDL1 were identified. Outcomes were compared of first-line ipi+nivo vs ChemoIO (pembrolizumab plus cisplatin, carboplatin, paclitaxel, pemetrexed or a combination of these). Cohorts were balanced for age and sex. Overall survival (OS) was assessed via Kaplan-Meier analysis. Results: Between May 2020 and December 2025, 739 patients received ChemoIO and 173 ipi+nivo across 26/24 HCO. After balancing, cohorts totaled 172 each. Patients diagnosed with NSCLC with no targetable mutation and no PDL1 expression who received first line treatment with dual immunotherapy had superior OS than those who were treated with ChemoIO p = 0.0001. The survival probability at 6-, 12- and 24- months for ipi+nivo vs ChemoIO was noted to be 88% vs 74%, 81% vs 66%, and 68% vs 51%, respectively. In comparison to ChemoIO, patients with ipi+nivo had more hospitalizations but similar incidence of emergency department visits. There was a tendency for longer time to second line of therapy for ipi+nivo, which was not yet statistically significant. Conclusions: Patients with metastatic NSCLC with no targetable mutations and no PDL1 expression who received dual immunotherapy in the first line setting had superior survival than those treated with ChemoIO. Our results show a very significant survival difference in favor of combination immunotherapy, indicating that further investigation of the best initial therapy for these patients is urgently needed. Dual immunotherapy was associated with higher rates of healthcare utilization, perhaps suggesting a need for proactive recognition of possible side effects and implementation of standardized protocols to assist with their management.