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

Objective SMET12 is a bispecific T-cell engager targeting epidermal growth factor receptor (EGFR) and CD3. 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. Methods All advanced NSCLC patients were histologically diagnosed and tested positive for EGFR protein. This trial included three cohorts: Cohort A consisted of treatment-naïve patients, and Cohort B consisted of patients acquiring resistance to first-line immune checkpoint inhibitors-containing therapy, while Cohort C consisted of EGFR -mutated patients acquiring resistance to TKIs. All participants received triple therapy with SMET12, toripalimab and chemotherapy, and participants with complete response (CR), partial response (PR) or stable disease (SD) following 2 to 4 cycles of chemotherapy were given maintenance therapy with SMET12 plus toripalimab until progressive disease (PD) or unacceptable toxicity. Primary endpoints included safety and efficacy measures, including objective response rate (ORR), disease control rate (DCR), and progression-free survival (PFS). This trial was registered at https://clinicaltrials.gov (Trial registration number: NCT06208033). Results 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 central memory T cells (Tcm) and naïve T cells (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 regulatory T cells (Tregs), effector memory T cells (Tem) and terminally differentiated effector T cells (Tte) may correlate with poor prognosis. Conclusions 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. Clinical trial registration https://www.clinicaltrials.gov/study/ , identifier NCT06208033.