Background: For patients with resectable stage III-N2b non-small cell lung cancer (NSCLC), optimal perioperative treatment strategies remain an area of active investigation. Iparomlimab and tuvonralimab (QL1706) is a novel bifunctional antibody combination targeting PD-1 and CTLA-4, designed to enhance anti-tumor immunity.

Objective: This phase II, single-arm, multicenter study aims to evaluate the efficacy and safety of neoadjuvant iparomlimab and tuvonralimab (QL1706) in combination with platinum-based chemotherapy in patients with resectable stage III-N2b NSCLC.

Study Design and Methods: A total of 28 patients will be enrolled across approximately 4 centers in China. Eligible patients (aged ≥18 years, ECOG PS 0-1) with histologically or cytologically confirmed, resectable stage III-N2b NSCLC (AJCC 9th edition) will receive three cycles of neoadjuvant therapy every three weeks. Patients with non-squamous carcinoma will receive iparomlimab and tuvonralimab (5 mg/kg) plus pemetrexed (500 mg/m²) and carboplatin (AUC 5). Patients with squamous carcinoma will receive iparomlimab and tuvonralimab (5 mg/kg) plus nab-paclitaxel (260 mg/m²) and carboplatin (AUC 5). Surgical resection will be performed within 6 weeks following completion of neoadjuvant therapy. Subsequent adjuvant treatment is at the discretion of the investigator.

Key Eligibility Criteria: Key inclusion criteria include pathologically confirmed T_anyN2b disease with mediastinal nodal status confirmed by EBUS/EUS or mediastinoscopy, and the determination by multidisciplinary team (MDT) assessment that the tumor is completely resectable (R0). Key exclusion criteria include known EGFR or ALK positive mutations, prior anti-cancer therapy for current lung cancer, active autoimmune disease, or uncontrolled hepatitis B or C.

Study Endpoints: The primary endpoint is the pathological complete response (pCR) rate. Secondary endpoints include major pathological response (MPR) rate, objective response rate (ORR), R0 resection rate, event-free survival (EFS), overall survival (OS), impact on surgical outcomes, and safety. Exploratory endpoints involve biomarker analysis including ctDNA.

Sample Size Rationale: Assuming a null hypothesis pCR rate (P0) of 8.8% (based on historical data) and an expected pCR rate (P1) of 28%, with a two-sided α of 5% and 80% power, 24 patients are required. Factoring in a 15% inoperable rate, the total sample size is 28 patients.

Statistical Analysis: The primary endpoint, pCR rate, and other binary endpoints will be summarized with frequencies, percentages, and their 95% confidence intervals calculated using the Clopper-Pearson method. Time-to-event endpoints (EFS, OS) will be analyzed using the Kaplan-Meier method. Safety data will be summarized descriptively.

Clinical Trial Information: This study is sponsored by The Second Affiliated Hospital of Air Force Medical University, PLA. The Principal Investigator is Dr. Yan Xiaolong.

As of September 20, 2024, a total of 16 clinical studies of the Iparomlimab/Tuvonralimab combination antibody had been initiated (see Investigator's Brochure for details). A total of 1,160 subjects had received treatment with the combination antibody, of whom 766 received monotherapy and 394 received combination therapy.

The safety profile of the Iparomlimab/Tuvonralimab combination antibody is consistent with its therapeutic class, with a relatively low incidence of treatment-related Grade 3 or higher toxicities. In monotherapy studies, more than half of the patients experienced treatment-emergent adverse events related to the combination antibody (77.5%), but the incidence of ≥Grade 3 events related to the combination antibody was low (25.4%). Any-grade immune-related adverse events (irAEs) were reported in 47.6% of patients; these were primarily low-grade, resolved after treatment, and considered manageable, with a ≥Grade 3 incidence of 11.9%. In studies of the combination antibody combined with chemotherapy, the AE profile was consistent with the established AE profiles of currently available immune checkpoint inhibitors and standard chemotherapy drugs. Based on the current safety information for the Iparomlimab/Tuvonralimab combination antibody, the safety profile of the investigational drug is considered generally consistent with that exhibited by currently marketed major PD-1 and CTLA-4 immune checkpoint inhibitors, with no unexpected serious safety risks observed. The investigational drug demonstrates a favorable safety and tolerability profile.

Four studies have been initiated independently in the lung cancer field, all with protocols involving combination with chemotherapy.

The DUBHE-L-201/QL1706-201 study is a single-arm, non-randomized, open-label, single-center Phase II clinical study evaluating the safety and efficacy of the Iparomlimab/Tuvonralimab combination antibody combined with chemotherapy ± bevacizumab as first-line treatment for advanced non-small cell lung cancer. The study was divided into five cohorts. Cohorts 1-4 focused on first-line treatment for stage IIIB-IV NSCLC without EGFR/ALK alterations: Cohort 1 enrolled 17 patients with squamous carcinoma, treated with the combination antibody combined with paclitaxel and carboplatin Q3W for 2 cycles, followed by maintenance with the combination antibody; Cohort 2 enrolled 11 patients with squamous carcinoma, treated with the combination antibody combined with paclitaxel and carboplatin Q3W for 4 cycles, followed by maintenance with the combination antibody; Cohort 3 enrolled 12 patients with non-squamous carcinoma, treated with the combination antibody combined with pemetrexed and carboplatin Q3W for 2 cycles, followed by maintenance with the combination antibody; Cohort 4 enrolled 20 patients with non-squamous carcinoma, treated with the combination antibody combined with pemetrexed, carboplatin, and bevacizumab Q3W for 4 cycles, followed by maintenance with the combination antibody, pemetrexed, and bevacizumab. Cohort 5 enrolled 31 patients with non-squamous carcinoma harboring EGFR-sensitive mutations who had progressed on EGFR-TKI therapy, treated with the combination antibody combined with pemetrexed, carboplatin, and bevacizumab Q3W for 4 cycles, followed by maintenance with the combination antibody, pemetrexed, and bevacizumab. The incidence of TRAEs leading to discontinuation was 8.3% in first-line cohorts 1-4 and 3.2% in the EGFR-TKI resistant cohort 5. In first-line treatment, the ORR was 45.0%, median PFS was 6.8 months, the incidence of ≥Grade 3 TRAEs was 31.7%, TRSAE incidence was 25.0%, the incidence of TRAEs leading to dose interruption was 63.3%, the incidence leading to study discontinuation was 8.3%, and no TRAEs led to death. In the EGFR-TKI resistant cohort 5, the ORR was 54.8%, median PFS was 8.5 months, and median OS was 26.5 months.

The DUBHE-L-209/QL1706-209 study is a single-arm, multicenter Phase II clinical study of the Iparomlimab/Tuvonralimab combination antibody combined with carboplatin and etoposide as first-line treatment for extensive-stage small cell lung cancer (ES-SCLC), designed to evaluate safety, tolerability, efficacy, PK characteristics, and immunogenicity. The study enrolled a total of 40 patients with untreated ES-SCLC. During the intensive treatment phase, patients received the combination antibody combined with carboplatin and etoposide Q3W for 4-6 cycles, followed by maintenance with the combination antibody alone. The incidence of ≥Grade 3 TEAEs was 90%, SAE incidence was 50%, irAE incidence was 15%, TEAEs leading to death occurred in 5%, and no TRAEs led to discontinuation or death. The ORR was 89.7%, and median PFS was 5.7 months.

The DUBHE-L-303/QL1706-303 study (NCT05690945 / CTR20223309) is a randomized, double-blind, active-controlled, multicenter Phase III clinical study designed to evaluate the efficacy and safety of the Iparomlimab/Tuvonralimab combination antibody combined with chemotherapy versus tislelizumab combined with chemotherapy in patients with PD-L1 negative, driver gene-negative locally advanced or metastatic NSCLC. The study plans to enroll 650 subjects, randomized 1:1 into two groups. The study includes a screening period (≤28 days from ICF signing to first dose), a treatment period (subjects receive study treatment until end of treatment), and a follow-up period (including safety follow-up and survival follow-up). Subjects will receive the following regimens until disease progression, intolerable toxicity, withdrawal of consent, non-compliance, investigator decision to withdraw, or other protocol-specified reasons (Iparomlimab/Tuvonralimab combination antibody/tislelizumab treatment for a maximum of 2 years [35 cycles]). Experimental Group: Iparomlimab/Tuvonralimab combination antibody + pemetrexed + carboplatin (non-squamous), or Iparomlimab/Tuvonralimab combination antibody + paclitaxel + carboplatin (squamous), for 4 cycles, then enter maintenance phase, continuing with Iparomlimab/Tuvonralimab combination antibody + pemetrexed (non-squamous) or Iparomlimab/Tuvonralimab combination antibody alone (squamous). Control Group: Tislelizumab + pemetrexed + carboplatin (non-squamous), or tislelizumab + paclitaxel + carboplatin (squamous), for 4 cycles, then enter maintenance phase, continuing with tislelizumab + pemetrexed (non-squamous) or tislelizumab alone (squamous).

The DUBHE-L-304/QL1706-304 study (NCT05487391/CTR20222281) is a randomized, double-blind, placebo-controlled, multicenter Phase III clinical study evaluating the safety and efficacy of the Iparomlimab/Tuvonralimab combination antibody combined with platinum-based chemotherapy versus placebo combined with platinum-based chemotherapy as adjuvant therapy in patients with completely resected stage I-IIIB NSCLC without EGFR-sensitive mutations and ALK fusion genes. This study randomizes subjects 1:1 into two groups, with approximately 316 subjects in each group (experimental and control). Subjects will receive either the Iparomlimab/Tuvonralimab combination antibody or placebo, concurrently with adjuvant chemotherapy for 2-4 cycles. The Iparomlimab/Tuvonralimab combination antibody or placebo will be administered for 16 cycles, unless: disease recurrence; intolerable adverse events; intercurrent illness preventing continued treatment; investigator decision to withdraw subject; subject withdrawal of consent; subject pregnancy; non-compliance with trial treatment or procedures; other administrative reasons.

In summary, based on relevant study results, perioperative immunotherapy can significantly improve EFS and pCR in patients with N2 stage disease without increasing surgical difficulty, providing a new treatment option for patients with resectable NSCLC, especially those with poorer prognosis stage III-N2 disease. Therefore, this study protocol aims to explore the efficacy and safety of the Iparomlimab/Tuvonralimab combination antibody combined with chemotherapy in the perioperative treatment of resectable stage III-N2b NSCLC, with the expectation of exploring a more effective and safer new perioperative immunotherapy regimen.

Inclusion Criteria:

1. Voluntarily join the study and sign the Informed Consent Form (ICF).

2. ≥18 years old, male or female.

3. Histologically or cytologically confirmed T_anyN2b stage NSCLC (American Joint Committee on Cancer [AJCC] 9th edition). Lymph node status must be confirmed by endobronchial ultrasound (EBUS/EUS) or mediastinoscopy for mediastinal lymph nodes. For left-sided stations 5/6 lymph nodes, parasternal mediastinoscopy is recommended to confirm lymph node status; if mediastinoscopy is not performed, station 5/6 lymph node status is diagnosed based on imaging diagnostic criteria.

4. Based on MDT assessment (which must include a thoracic surgeon specialized in oncology), the primary NSCLC is deemed to be completely resectable (R0).

5. At least one measurable lesion as assessed by the investigator per RECIST v1.1.

6. Eastern Cooperative Oncology Group (ECOG) Performance Status score of 0 or 1.

7. Adequate organ function meeting the following requirements (no use of any blood components, cell growth factors, etc., within 14 days before the first dose):

   1. Absolute neutrophil count ≥1.5×10⁹/L;
   2. Platelet count ≥100×10⁹/L;
   3. Hemoglobin ≥90 g/L;
   4. Serum creatinine ≤1.5×upper limit of normal (ULN) or creatinine clearance (CLcr) ≥40 mL/min calculated by the Cockcroft-Gault formula;
   5. Total bilirubin ≤1.5×ULN (patients with Gilbert's syndrome may have ≤3×ULN);
   6. AST and ALT ≤3×ULN;
   7. International normalized ratio (INR) or activated partial thromboplastin time (APTT) ≤1.5×ULN, unless the subject is receiving anticoagulant therapy;
   8. Left ventricular ejection fraction (LVEF) ≥50%.

8. For female patients of non-surgical sterilized or childbearing potential, must agree to use a medically accepted contraceptive method (e.g., intrauterine device, contraceptive pills, or condoms) during the study treatment period and for 3 months after the study treatment period ends; female patients of childbearing potential who are not surgically sterilized must have a negative serum or urine HCG test within 72 hours before the first dose; and must be non-lactating; for male patients with partners of childbearing potential, must agree to use effective contraception during the trial and for 3 months after the last dose of Iparomlimab/Tuvonralimab.

Exclusion Criteria:

1. Known presence of EGFR or ALK positive mutations.

2. History of or concurrent other malignancy within the past 5 years (excluding adequately treated cervical carcinoma in situ, basal cell or squamous cell skin cancer, localized prostate cancer after radical surgery, ductal carcinoma in situ after radical surgery).

3. Prior receipt of any anti-tumor therapy for the current lung cancer (e.g., radiotherapy, chemotherapy, targeted therapy, ablation, or other systemic or local anti-tumor therapies).

4. Current use of immunosuppressants or systemic hormone therapy for immunosuppressive purposes (dose >10 mg/day prednisone or equivalent) and continued use within 2 weeks before enrollment (Note: Inhaled or topical corticosteroids and adrenal replacement steroids are permitted in the absence of active autoimmune disease).

5. Any active autoimmune disease or history of autoimmune disease, including but not limited to: autoimmune hepatitis, interstitial pneumonia, pulmonary fibrosis, uveitis, enteritis, hepatitis, hypophysitis, vasculitis, nephritis, hyperthyroidism, hypothyroidism.

   1. Subjects with hypothyroidism controlled by hormone replacement therapy alone are eligible;
   2. Subjects with skin diseases not requiring systemic treatment such as vitiligo, psoriasis, alopecia, type 1 diabetes, or childhood asthma that has completely resolved and requires no intervention in adulthood are eligible;
   3. Patients with asthma requiring medical intervention with steroids are not eligible.

6. History of allogeneic hematopoietic stem cell transplantation or organ transplantation (except corneal transplantation).

7. Congenital or acquired immunodeficiency (e.g., HIV-infected individuals).

8. Uncontrolled active hepatitis B (defined as positive hepatitis B surface antigen [HBsAg] test at screening with concurrent HBV-DNA test value above the upper limit of normal of the research center's laboratory; subjects with HBV-DNA <500 IU/mL measured within 28 days before study drug administration and who have received standard local antiviral therapy for at least 4 weeks and are willing to continue antiviral therapy during the study may be enrolled). Subjects with active hepatitis C (defined as positive hepatitis C virus antibody [HCsAb] test at screening and positive HCV-RNA).

9. History of severe allergic reactions to other monoclonal antibodies.

10. Vaccination with live vaccine within 30 days before the first dose of study treatment (continuing until 90 days after the last dose of study treatment). Note: Live vaccines include but are not limited to measles, mumps, rubella, varicella/zoster (chickenpox), yellow fever, rabies, BCG, and typhoid vaccines. Inactivated seasonal influenza vaccines, inactivated COVID-19 vaccines, etc., are permitted.

11. Clinically significant cardiovascular or cerebrovascular diseases, including but not limited to:

    1. Myocardial infarction or unstable angina pectoris within 6 months before the first dose;
    2. Stroke or transient ischemic attack within 6 months before the first dose;
    3. Hypertension not controlled with optimal antihypertensive therapy (systolic blood pressure ≥160 mmHg and/or diastolic blood pressure ≥100 mmHg);
    4. Clinically significant arrhythmia that has been stable for ≥14 days before the first dose may be enrolled;
    5. Congestive heart failure (New York Heart Association [NYHA] functional class III-IV);
    6. Myocarditis.

12. Systemic infection or other severe infection requiring intravenous antibiotics for >7 days within 2 weeks before the first study treatment, or unexplained fever >38.5°C during screening or before enrollment (fever due to tumor causes as judged by the investigator is excluded).

13. Any other condition that, in the investigator's judgment, might affect the study results or lead to premature termination of the study, such as alcoholism, drug abuse, other severe diseases (including mental illness) requiring concomitant treatment, severe laboratory abnormalities, or family or social factors, which could affect patient safety.