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.

Inclusion criteria

Participants must meet all of the following criteria to be eligible for the study:

• Voluntary participation and provision of signed written informed consent.
• Age ≥ 18 years.
• Life expectancy ≥ 3 months.
• Histologically or cytologically confirmed diagnosis of Stage IIIB-IV lung cancer that is not amenable to curative surgery or radiotherapy.
• Tumor demonstrates loss of BRG1 protein (encoded by the SMARCA4 gene) as confirmed by immunohistochemistry (IHC).
• No prior systemic anti-cancer therapy for advanced disease.
• Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1.
• Willingness to provide archived or fresh tumor tissue samples from primary or metastatic lesions. If unavailable, enrollment may be permitted following investigator assessment.
• At least one measurable lesion as defined by RECIST v1.1.
• Adequate organ function within the screening period, as evidenced by:

10.1 Absolute neutrophil count (ANC) ≥ 1.5 × 10^9/L 10.2 Platelet count ≥ 100 × 10^9/L 10.3 Hemoglobin ≥ 90 g/L (without transfusion within 14 days) 10.4 Serum creatinine ≤ 1 × ULN OR Creatinine clearance > 50 mL/min (calculated by Cockcroft-Gault formula) 10.5 AST and ALT ≤ 2.5 × ULN (≤ 5 × ULN for patients with liver metastases) 10.6 Total bilirubin ≤ 1.5 × ULN (except for participants with Gilbert's syndrome) 10.7 TSH, FT3, and FT4 within normal limits (±10%)

Exclusion criteria

Participants meeting any of the following criteria will be excluded from the study:

• Pathological diagnosis containing a small cell component.
• Symptomatic brain metastases.
• Leptomeningeal metastases.
• Recurrence within 6 months after completing prior adjuvant therapy (if applicable).
• Active, known, or suspected autoimmune disease (with specific exceptions, e.g., vitiligo, type I diabetes, hypothyroidism managed with hormone replacement only).
• Active tuberculosis (TB) infection or history of active TB within the past year.
• Comorbidities requiring immunosuppressive medications, including systemic corticosteroids at immunosuppressive doses.
• Pregnancy or lactation in female participants.
• Symptomatic interstitial lung disease that could interfere with the detection or management of suspected drug-related pulmonary toxicity.
• Known HIV infection, active Hepatitis B (HBsAg positive with HBV-DNA > 10^3 copies/mL), or active Hepatitis C (HCV antibody positive with detectable HCV-RNA).
• Significant history of neurological or psychiatric disorders.
• Treatment with any investigational drug within 4 weeks prior to the first dose of study treatment.
• Use of Chinese herbal medicines with anti-tumor activity within 2 weeks prior to study treatment initiation.
• History of another active malignancy within the past 2 years (with specific exceptions for certain early-stage cancers).
• Significant cardiovascular or cerebrovascular disease history.
• Uncontrolled thrombotic events within 6 months prior to screening.
• Administration of a live vaccine within 28 days prior to the first study dose.
• Major surgery or significant trauma within 4 weeks prior to the first study dose.
• Conditions that may impair oral drug absorption.
• Uncontrolled active infection requiring systemic therapy.
• Known hypersensitivity to any of the study drug components.
• Any other condition that, in the investigator's judgment, would make the participant unsuitable for participation in the study.