Phase II Study to Evaluate Telisotuzumab Adizutecan in Combination With RC148 as First-Line Treatment for Patients With Non-Squamous Non-Small-Cell Lung Cancer

Prior treatment

• Received thoracic radiotherapy \>30 Gy within 6 months prior to randomization; palliative local therapy for non-target lesions within 2 weeks prior to randomization; non-specific immunomodulatory therapy within 2 weeks prior to the first dose of study drug; or traditional Chinese herbal/proprietary medicine with anti-neoplastic indications within 1 week prior to randomization
• Prior immunotherapy, including immune checkpoint inhibitors, immune checkpoint agonists, immune-cell therapy, or any other therapies targeting tumor immune mechanisms
• Prior systemic anti-neoplastic therapies other than chemotherapy and PD-1/PD-L1 antibodies
• Systemic treatment with corticosteroids or other immunosuppressive medications within 2 weeks prior to randomization
• Administration of any live or live-attenuated vaccine within 4 weeks prior to randomization, or planned administration of any live or live-attenuated vaccine during the study
• Participation in another clinical trial within 4 weeks prior to randomization
• Major surgery, interventional therapy, or severe trauma within 4 weeks prior to randomization, or planned major surgery during the study period; core-needle biopsy or other minor surgery within 7 days prior to the first dose
• History of severe coagulation disorders; or subjects receiving anticoagulant therapy, excluding prophylactic-dose anticoagulants such as low-molecular-weight heparin
• Toxicities from prior anti-neoplastic therapy not recovered to Grade 0-1 as defined by CTCAE v6.0; except for alopecia, pigmentation, expected irrecoverable endocrinopathies from prior immunotherapy that are stably controlled with medication, and other conditions assessed by the investigator not interfering with study drug treatment
• For subjects previously exposed to PD-1/PD-L1 inhibitors: prior occurrence of immune-related adverse events (irAEs) Grade 3 or higher due to immunotherapy, irAEs leading to permanent treatment discontinuation, Grade 2 immune-related cardiac toxicity, or any-grade neurological or ocular irAEs; prior adverse events requiring immunosuppressive agents other than corticosteroids, or recurrent adverse events during prior immunotherapy requiring re-initiation of systemic corticosteroid therapy
• Hemoptysis, active gastrointestinal bleeding, peptic ulcer, epistaxis, or other bleeding events requiring intervention within 4 weeks prior to randomization; or severe esophagogastric varices, vasculitis, vascular ulcer, aneurysm, or vascular dissection judged by the investigator to carry a high bleeding risk
• Severe arterial/venous thromboembolic events or cerebrovascular accident within 6 months prior to the first dose
• History of interstitial lung disease or pulmonary inflammation requiring systemic steroid therapy; or chest-CT at screening showing any evidence of active ILD/pulmonary inflammation, idiopathic pulmonary fibrosis, organizing pneumonia, treatment-induced pneumonitis, idiopathic pneumonia, radiation pneumonitis, severe impaired pulmonary function, or acute exacerbation of chronic obstructive pulmonary disease within 1 month prior to randomization
• History of gastrointestinal perforation and/or fistula, or gastrointestinal obstruction within 6 months prior to randomization
• Active autoimmune disease, or prior history of autoimmune disease with potential for recurrence
• Other malignancy diagnosed within 3 years prior to initiation of study drug administration

Other illness

• Screening-period imaging shows obvious tumor necrosis or cavitation, with bleeding risk upon study entry as judged by the investigator
• Presence of severe acute or chronic infection
• Active or clinically significant cardiac disease
• Presence of systemic diseases that are not stably controlled as judged by the investigator
• Subjects with a history of other acquired or congenital immunodeficiency diseases, or history of organ transplantation
• Known hypersensitivity or delayed-type allergic reaction to any components of the study drug or analogous medicinal products
• Local or systemic disease not caused by malignancy, or diseases/symptoms secondary to the tumor, that may result in substantial medical risk and/or uncertainty in survival-time assessment, such as manifestations of cachexia

Lab values

• Any other past or present disease, abnormal physical finding, or laboratory abnormality, in the investigator's opinion, rendering the subject unsuitable for study drug administration, likely to confound interpretation of study results, or placing the subject at high-risk

Other

• Histologically confirmed presence of any squamous NSCLC, small-cell carcinoma, neuroendocrine carcinoma, or sarcoma component
• Known positive driver gene or gene mutations with approved first-line treatment options
• Presence of active brain metastases
• Clinically symptomatic third-space effusion or third-space effusion requiring intervention
• Poor compliance; subjects expected to be unable to cooperate with completion of trial procedures

• Voluntarily agrees to participate in the study and provides signed informed consent
• Willing and able to comply with study and follow-up procedures
• Male or female, aged 18-80 years
• Expected survival≥3 months
• Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1
• Histopathologically or cytologically confirmed locally advanced or metastatic non-squamous NSCLC not amenable to curative-intent therapy
• No prior systemic anti-neoplastic therapy for advanced or metastatic non-squamous NSCLC
• At least one measurable non-cerebral lesion per RECIST v1.1
• Availability of c-Met expression, PD-L1 expression and driver gene test results including at minimum EGFR and ALK for enrollment
• Adequate cardiac, bone-marrow, hepatic, renal and coagulation function meeting relevant criteria
• Female study participants must be post-menopausal, surgically sterilized, or, if of child-bearing potential, have a negative serum pregnancy test within 7 days prior to the first dose, agree to use at least one medically-accepted contraceptive method during study treatment and for 12 months after the end of study treatment, and refrain from oocyte donation and breastfeeding during this period; male study participants must agree to use at least one medically-accepted contraceptive method during study treatment and for 12 months after the end of study treatment and refrain from sperm donation during this period