QL1706 Combined With Chemotherapy in the Treatment of Immune-mediated NSCLC

A Randomized Controlled Study Comparing the Efficacy of QL1706 Combined With Chemotherapy in the Treatment of Immune-mediated Non-small Cell Lung Cancer

Lung cancer is the leading cause of cancer-related deaths worldwide. According to the 2023 global cancer statistics, there are approximately 2.47 million new cases and 1.76 million deaths of lung cancer annually, accounting for 18.4% of all cancer deaths. Among them, driver gene negative NSCLC accounts for about 30% -40% of all NSCLC. In China, the incidence rate and mortality of lung cancer rank first. In 2022, there will be about 870000 new cases and 760000 deaths. In Chinese NSCLC patients, the EGFR mutation rate is about 50%, ALK fusion is about 5%, other mutations (ROS1, RET, etc.) are about 5% -10%, and the negative proportion of driver genes is about 30% -40%. Traditional treatment for late stage non-small cell lung cancer with negative driver genes has limited clinical efficacy. In recent years, the emergence of immune checkpoint inhibitors (ICIs) has greatly changed the treatment pattern of advanced non-small cell lung cancer patients, significantly prolonging the overall survival of advanced cancer patients. For the follow-up treatment of patients with previous immunotherapy, the current standard treatment regimen is still mainly chemotherapy. However, these plans have mediocre efficacy and significant side effects, making it difficult to meet the current clinical treatment needs. At present, there is no unified treatment plan for first-line immunotherapy or immunotherapy combined with chemotherapy in patients with driver gene negative advanced NSCLC. Second line chemotherapy such as docetaxel is currently recommended as the standard treatment plan in NCCN guidelines and CSCO guidelines. Research suggests that for patients with first-line immune resistance or immune combined chemotherapy resistance, second-line immune re challenge can still bring certain survival benefits to patients, but the benefits are limited and new treatment options need to be explored.

Iparomlimab injection (drug number QL-1706) is a novel combination antibody independently developed by Qilu Company. It consists of Iparomlimab, an IgG4 antibody targeting PD-1, and Tuvonralimab, an IgG1 antibody targeting CTLA-4, in a fixed ratio. It has a synergistic mechanism of simultaneously blocking PD-1 and CTLA-4. In summary, ICIs are still an important treatment strategy for advanced non-small cell lung cancer. However, the emergence of drug resistance after immunotherapy seriously affects the survival time and prognosis of patients. Preliminary research has been conducted on the resistance mechanism of immunotherapy, but more research is needed to clarify the main mechanisms of action, in order to further prevent and overcome drug resistance. QL1706 has shown promising preliminary efficacy and good tolerability in PD-1 resistant NSCLC in preclinical and phase I clinical studies. Based on this, this study aims to conduct an exploratory study on QL1706 combined with chemotherapy compared to chemotherapy alone in the treatment of immune regulated non-small cell lung cancer with negative driver genes.

This study is a prospective, multicenter, open label randomized controlled trial design, recruiting 96 immunocompromised driver gene negative patients with locally advanced or recurrent/metastatic non-small cell lung cancer. The experimental group received QL1706 combined with docetaxel or gemcitabine treatment in a 1:1 ratio, while the control group received docetaxel or gemcitabine treatment.

Inclusion Criteria:

• Voluntarily participate in the research and sign an informed consent form; Age ≥ 18 years old, ≤ 75 years old;
• Diagnosed with NSCLC through histology or cytology;
• No EGFR sensitive mutations or ALK gene translocation changes;
• Previously received PD-1/PD-L1 inhibitors combined with platinum based dual therapy or sequential therapy as first-line treatment for advanced metastatic or recurrent NSCLC, and disease progression occurred during or after treatment; At least one measurable lesion should be used as the target lesion (RECIST v1.1 standard);
• ECOG score: 0-2 points;
• Expected survival period is not less than 12 weeks;
• Women of childbearing age must undergo a pregnancy test (serum or urine) with a negative result within 28 days before enrollment, and voluntarily use appropriate contraception methods during the observation period and within 8 weeks after the last dose; For males, surgical sterilization or consent to use appropriate contraception methods during the observation period and within 8 weeks after the last dose should be provided;
• The laboratory test results during the screening period indicate that the patient has good organ function: a) Hematology (no blood transfusion within 14 days and no treatment with blood components or granulocyte colony-factor): Neutrophil count (NEU) ≥ 1.5 × 10 ^ 9/L (1500/mm3); Platelet count (PLT) ≥ 100 × 10 ^ 9/L (100000/mm3); Hemoglobin ≥ 90 g/L; b) Liver: serum total bilirubin (TBil) ≤ ULN; Glutamate aminotransferase (AST) and alanine aminotransferase (ALT) ≤ 1.5 × ULN; AST or ALT should be 1.5-3.5 × ULN, and alkaline phosphatase (ALP) should be ≤ 2.5 × ULN; c) Kidney: creatinine clearance rate (CrCl) calculated value ≥ 30 mL/min; d) Coagulation function: International normalized ratio (INR) ≤ 1.5, and prothrombin time (PT) or activated partial thromboplastin time (APTT) ≤ 1.5 × ULN; j) International Normalized Ratio (INR) ≤ 1.5; Activated partial thromboplastin time (APTT) ≤ 1.5 × ULN;
• Patients whom researchers believe can benefit.

Exclusion Criteria:

• There are EGFR sensitive mutations or ALK gene translocation changes present;
• Previously received PD1/CTLA4 bispecific antibody therapy;
• Adverse reactions caused by previous treatment have not recovered to CTCAE (version 5.0) grade 1 or below (excluding toxicity ≤ grade 2 that has been determined by the researcher to exist for a long time, cannot be recovered, and does not increase safety risks);
• Symptomatic central nervous system metastasis. Patients who have received treatment for brain metastases and have been deemed stable by researchers may consider participating in this study;
• For patients with poor control of cancer-related pain, those who require analgesic treatment must receive a stable dose of treatment before participating in the study;
• Chest fluid, ascites or pericardial effusion with clinical symptoms or unstable condition after symptomatic treatment;
• Known to have a history of severe allergic reactions to the drug and its components, planned chemotherapy drugs, and those with a history of severe allergic reactions;
• Suffering from or suspected of active autoimmune diseases, including but not limited to systemic lupus erythematosus, rheumatoid arthritis, inflammatory intestinal diseases, etc., except: type I diabetes and hypothyroidism that can be controlled through stable dose replacement treatment, and skin diseases that do not require systemic treatment (such as psoriasis, vitiligo);
• History of interstitial lung disease or drug-induced interstitial lung disease or pneumonia in the past;
• Corticosteroid drugs (prednisone>10mg/day or equivalent dose) or other immunosuppressive drugs received systemically within 14 days prior to the first study medication;
• Individuals with a history of immunodeficiency, including those with other acquired or congenital immunodeficiency diseases, those with a history of organ transplantation, or those who have received allogeneic hematopoietic stem cell transplantation or solid organ transplantation; Received live vaccination within 4 weeks before the first study medication;
• Suffering from serious cardiovascular and cerebrovascular diseases: a) poorly controlled hypertension or pulmonary arterial hypertension; b) Unstable angina or myocardial infarction, coronary artery bypass grafting or stent implantation within 6 months prior to study medication; c) Chronic heart failure with heart function ≥ 2 (NYHA classification by the New York Heart Association); d) Left ventricular ejection fraction (LVEF)<50%; e) Various severe arrhythmias requiring medication treatment (excluding atrial fibrillation or paroxysmal supraventricular tachycardia). For example, male QTcF>450 milliseconds or female QTcF>470 milliseconds, complete left bundle branch block, grade III block; f) Cerebrovascular accident (CVA) or transient ischemic attack (TIA) occurred within 6 months prior to the study medication;
• Positive result of human immunodeficiency virus (HIV) antibody test, active hepatitis B or C. The following conditions are allowed to participate in this study: a) hepatitis B core antibody (HBcAb) or hepatitis B surface antigen (HBsAg) is positive, but HBV DNA is lower than the lower limit of the detection value of the research center (negative) or less than 500IU/ML, and the active infection is excluded according to the judgment of the researcher based on clinical treatment and performance; b) Individuals with positive hepatitis C antibodies and HCV RNA below the lower limit (negative) of the detection value at the research center;
• Suffering from other active malignant tumors other than the research disease within 5 years, except for malignant tumors that can be expected to recover after treatment (including but not limited to fully treated thyroid cancer, cervical carcinoma in situ, basal or squamous cell carcinoma, or breast ductal carcinoma in situ treated with radical surgery);
• Individuals with a history of substance abuse and inability to quit, or those with a history of mental disorders;
• Pregnant or lactating women;
• The researcher believes that the patient is not suitable to participate in any other circumstances of this study.