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

A Phase II Clinical Trial of Iparomlimab and Tuvonralimab in Combination With Platinum-based Chemotherapy in Patients With SMARCA4-Deficient, Locally Advanced or Metastatic Non-Small Cell Lung Cancer.

This single-arm, open-label, Phase II study assesses first-line QL1706 (iparomlimab and tuvonralimab, an anti-PD-1/CTLA-4 bispecific antibody) combined with platinum-based chemotherapy to treat patients with treatment-naïve, locally advanced or metastatic, SMARCA4-deficient non-small cell lung cancer (NSCLC).

The main questions it aims to answer are:Evaluate the efficacy and safety of this combination regimen in this specific patient population. Explore correlations between tumor molecular characteristics, the immune microenvironment, and treatment efficacy or toxicity.

Participants must:

Have histologically or cytologically confirmed, treatment-naïve, locally advanced or metastatic non-small cell lung cancer (NSCLC) with SMARCA4 deficiency. Be willing to provide archived or fresh tumor tissue samples. If unavailable, enrollment may proceed per investigator assessment. Have at least one measurable lesion per RECIST v1.1.

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:

1. Voluntary participation and provision of signed written informed consent.
2. Age ≥ 18 years.
3. Life expectancy ≥ 3 months.
4. Histologically or cytologically confirmed diagnosis of Stage IIIB-IV lung cancer that is not amenable to curative surgery or radiotherapy.
5. Tumor demonstrates loss of BRG1 protein (encoded by the SMARCA4 gene) as confirmed by immunohistochemistry (IHC).
6. No prior systemic anti-cancer therapy for advanced disease.
7. Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1.
8. Willingness to provide archived or fresh tumor tissue samples from primary or metastatic lesions. If unavailable, enrollment may be permitted following investigator assessment.
9. At least one measurable lesion as defined by RECIST v1.1.
10. 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:

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