A Phase II Study of QL1706 and Platinum-Based Chemotherapy in Patients With SMARCA4-Deficient, Locally Advanced or Metastatic Non-Small Cell Lung Cancer.

SMARCA4-deficient non-small cell lung cancer (NSCLC) represents a highly aggressive molecular subtype, accounting for approximately 5-10% of all NSCLC cases. The majority of patients (over 80%) present with distant metastases at diagnosis, and prognosis is exceptionally poor, with median overall survival (mOS) historically ranging from 4 to 7 months. Currently, no standardized treatment exists for this subset, and therapeutic efficacy remains limited. Immune checkpoint inhibitors (ICIs) combined with platinum-based chemotherapy have become a cornerstone of treatment for advanced NSCLC without driver mutations. However, the benefit of this approach in SMARCA4-deficient NSCLC is uncertain and appears heterogeneous. A large retrospective analysis (n=707) indicated that SMARCA4-mutant tumors derived significantly less benefit from first-line chemoimmunotherapy compared to wild-type tumors, showing inferior objective response rate (ORR) and progression-free survival (PFS). Conversely, other retrospective data suggest a potential survival advantage with ICI-chemotherapy over chemotherapy alone. This discrepancy may be influenced by BRG1 protein expression loss, a key molecular feature with prognostic implications, highlighting the complexity of this disease and the need for prospective validation. QL1706 (iparomlimab and tuvonralimab) is a novel bifunctional MabPair antibody that concurrently targets PD-1 and CTLA-4 at a fixed 2:1 ratio. This design aims to enhance synergistic immune activation while potentially mitigating toxicity associated with conventional CTLA-4 inhibition. Approved in 2024, QL1706 has demonstrated promising efficacy and a manageable safety profile in multiple solid tumors, including NSCLC. In the DUBHE-L-201 trial, QL1706 combined with chemotherapy demonstrated encouraging activity. To date, there are no prospective clinical data on the use of QL1706 combined with chemotherapy in SMARCA4-deficient NSCLC. This phase II, single-arm, open-label trial is proposed to evaluate the efficacy and safety of QL1706 plus platinum-based chemotherapy as a first-line treatment for patients with locally advanced or metastatic SMARCA4-deficient NSCLC. The study aims to address a significant unmet need and explore a potentially effective therapeutic strategy for this challenging patient population.