This prospective, single-arm, exploratory multicenter clinical study aims to investigate the safety and efficacy of Becotatug vedotin combined with Pucotenlimab (with or without radiotherapy), followed by Pucotenlimab maintenance therapy, in patients with driver gene-negative (e.g., EGFR, ALK, ROS1), EGFR-overexpressing non-small cell lung cancer (NSCLC).
Study Population:
The study targets patients with driver gene-negative (EGFR, ALK, ROS1, and other actionable targets) non-squamous and squamous NSCLC. All subjects (regardless of smoking history) must provide testing reports for EGFR, ALK, and ROS1. If no prior report exists, baseline biopsy or submission of archived tissue for assessment of driver gene status (via local or central laboratory) is mandatory. Additionally, eligible patients must have an immunohistochemistry (IHC)-confirmed EGFR expression level of 2+ or higher, be previously untreated with systemic therapy for stage IV NSCLC, have measurable lesions, show no active central nervous system metastases or uncontrolled autoimmune diseases, and voluntarily sign the informed consent form.
Treatment Regimen:
Subjects meeting the inclusion/exclusion criteria will receive the following treatment regimen:
Pucotenlimab (HX008): Administered from Cycle 1 to Cycle 4 at a dose of 3 mg/kg (maximum 200 mg), once every 3 weeks on Day 1 (D1). Intravenous infusion (60 ± 15 minutes; first cycle infusion duration not less than 60 minutes).
Becotatug vedotin (MRG003): Administered from Cycle 1 to Cycle 4 at a dose of 2.0 mg/kg, once every 3 weeks on D1. Administration begins at least 30 minutes after the completion of Pucotenlimab infusion. Intravenous infusion (60 ± 10 minutes; first cycle infusion duration not less than 60 minutes).
Radiotherapy: Investigators may opt to include sequential radiotherapy based on tumor size, number, location, extent of invasion, and individual patient factors. Radiotherapy options are as follows:
Target Volume: Radiotherapy commences 2 weeks (±7 days) after the completion of Cycle 4 treatment, targeting only the primary tumor or specific 1-2 metastatic lesions.
Fractionation and Dosage:
Conventional Fractionation Group: Applicable for larger target volumes (\>5 cm diameter) or involvement of mediastinal lymph nodes. Total dose: 45-60 Gy; single fraction dose: 1.8-2.0 Gy; administered once daily (Qd).
Stereotactic Body Radiotherapy (SBRT) Group: Applicable for oligometastatic lesions (≤3 lesions, each ≤3 cm diameter). Total dose: 30-50 Gy delivered in 3-5 fractions; single fraction dose: 6-10 Gy.
Maintenance Therapy: Pucotenlimab (HX008) monotherapy until disease progression (defined by RECIST 1.1), investigator-assessed radiographic progression, unacceptable toxicity, withdrawal of consent, or fulfillment of criteria for discontinuation of intervention.
Voluntary participation with written informed consent obtained prior to any study-specific procedures, and willingness to comply with the study requirements.
Male or female patients aged between 18 and 75 years (inclusive) at the time of signing informed consent.
Histologically or cytologically confirmed Stage IV (M1a, M1b, or M1c according to the AJCC 8th Edition) squamous or non-squamous NSCLC.
No prior systemic therapy for advanced/metastatic disease is permitted. Patients who received adjuvant/neoadjuvant chemotherapy and relapsed ≥6 months after the last dose are allowed to enroll.
Conditions significantly affecting oral drug absorption, such as inability to swallow, chronic diarrhea, or clinically significant intestinal obstruction;
Renal insufficiency: urinalysis indicating proteinuria ≥++, or confirmed 24-hour urine protein ≥1.0 g;
Human Immunodeficiency Virus (HIV) infection or known Acquired Immunodeficiency Syndrome (AIDS); active hepatitis (Hepatitis B defined as HBV-DNA ≥ 500 IU/mL; Hepatitis C defined as HCV-RNA above the lower limit of detection) or co-infection with Hepatitis B and C;
Presence of any active autoimmune disease or history thereof (including but not limited to autoimmune hepatitis, enteritis, vasculitis, nephritis; subjects requiring bronchodilator therapy for asthma are excluded); however, subjects with vitiligo, psoriasis, alopecia not requiring systemic treatment, or well-controlled Type 1 diabetes are allowed;