Efficacy and Safety of SMET12 in Combination with Toripalimab and Chemotherapy in Advanced Non-Small-Cell Lung Cancer Patients tested positive for EGFR Protein Who Are Treatment-Naïve or Harbor Acquired Resistance to Standard Therapy: A Phase 2, Multi-Cohort Clinical Trial

Jinghui Lin¹Shanshan Chen¹meifang li¹Lihong Weng¹Xu Haipeng¹Qiang Wang¹Jing Zhang¹Dong Lin¹Haipo Wang¹Qinying Liu¹Zhiyong He^2*

• ¹Clinical Oncology School of Fujian Medical University, Fuzhou, China
• ²School of Oncology Clinical Medicine, Fujian Medical University, Fujian Provincial Cancer Hospital, Fujian, China

This phase 2 clinical trial aimed to investigate the efficacy and safety of SMET12 plus toripalimab and chemotherapy among advanced non-small-cell lung cancer (NSCLC) patients tested positive for EGFR protein, including treatment-naïve patients, patients with resistance to first-line immune checkpoint inhibitors-containing therapy and EGFR-mutated patients with resistance to first-line EGFR tyrosine kinase inhibitors (TKIs), and to examine the associations of lymphocyte numbers and differentiation patterns with therapeutic efficacy among advanced NSCLC patients. A total of 32 patients were included in the trial until January 21, 2025. The ORR, DCR and median PFS were 83.3%, 100% and 8.3 (95% CI: 3.8, 12.8) months in Cohort A, 22.2%, 55.6% and 4.2 (95% CI: 3.6, 4.8) months in Cohort B, and 41.7%, 100% and 7.2 (95% CI: 5.0, 9.4) months in Cohort C. The most common treatment-related adverse events (20% incidence and higher) included cytokine release syndrome (53.13%), leukopenia (43.75%), elevated alanine aminotransferase (43.75%), neutropenia (37.5%), constipation (31.25%) and elevated aspartate aminotransferase (28.13%). Grade 3-4 adverse events included neutropenia (15.63%), Lung infections (15.63%), anemia (6.25%), immune-related hepatitis (6.25%), immune-related pneumonia (6.25%), leukopenia (3.13%), and hypertriglyceridemia (3.13%). No grade 5 adverse events were observed. At baseline among the three cohorts, Cohort A presented the lowest Treg, PD-1⁺ and LAG-3⁺T cell proportions; Cohort B had the highest Treg and LAG-3⁺T cell proportions, and Cohort C had the highest PD-1⁺T cell proportion. High numbers of peripheral blood T lymphocytes and CD69+ T cells, and higher proportions of Tcm and Tn may be predictive of a higher response to the triple therapy, and an increase in the positive rate of PD-1 and LAG3 expression on T cell surface and proportions of Tregs, Tem and Tte may correlate with poor prognosis. Our data demonstrate that triple therapy consisting of SMET12, toripalimab, and chemotherapy exhibited manageable safety in patients with advanced non-small cell lung cancer (NSCLC) expressing EGFR protein, while demonstrating promising efficacy in EGFR-mutant patients with acquired resistance to EGFR-TKIs. The functional phenotype and differentiation pattern of peripheral blood T lymphocytes exert a critical impact on the therapeutic response to this triple therapy.