JS212 Plus JS111 in EGFR-Mutant Advanced NSCLC: A Phase II Study

This is an open-label, multicenter Phase II study designed to evaluate the safety, tolerability, pharmacokinetics (PK), and preliminary efficacy of JS212 in combination with JS111 in patients with EGFR-mutant advanced or metastatic NSCLC who have experienced disease progression following prior EGFR-TKI therapy. The study includes two sequential parts: a dose-escalation phase and a dose-expansion phase, with an overall planned enrollment of approximately 30 participants. Dose-Escalation Phase Up to approximately 15 participants will be enrolled in the dose-escalation phase. JS212 will be administered intravenously once every 3 weeks (Q3W) at predefined dose levels, starting at 4.2 mg/kg, with potential escalation to 4.6 mg/kg or other dose levels as determined by the Safety Monitoring Committee (SMC). JS111 will be administered orally at a fixed dose of 160 mg once daily (QD). A Bayesian optimal interval (BOIN) design will be used to guide dose escalation. Participants will be enrolled in cohorts of at least 3 subjects. Dose-escalation decisions will be based on the occurrence of dose-limiting toxicities (DLTs) observed within the first 21 days following the initial dose. The SMC will review safety data and make decisions regarding dose escalation, dose de-escalation, dose expansion, or study modification. Dose escalation will continue until one of the following conditions is met: The maximum planned sample size for dose escalation is reached (approximately 15 participants or as adjusted by the SMC); A dose level reaches sufficient evaluable participants with acceptable safety profile; Dose elimination criteria are met due to excessive toxicity; Early termination is determined by the sponsor and investigators. The SMC may also adjust dose levels, dosing schedules, or study design based on emerging safety data from this or other ongoing studies of JS212. Dose-Expansion Phase Following completion of the dose-escalation phase, one dose level of JS212 in combination with JS111 will be selected for further evaluation. Approximately 20 participants are planned to be enrolled in the expansion phase (subject to adjustment). Participants will receive JS212 in combination with JS111 every 21 days per cycle until disease progression, unacceptable toxicity, withdrawal of consent, or other discontinuation criteria are met. Dose-Limiting Toxicity (DLT) DLTs are defined as treatment-related adverse events occurring within 21 days after the first dose, graded according to NCI-CTCAE v6.0. These include: Hematologic toxicities, such as: Grade 4 thrombocytopenia or Grade 3 thrombocytopenia with bleeding; Febrile neutropenia ≥ Grade 3; Grade 4 neutropenia lasting \>7 days; Grade 4 anemia; Non-hematologic toxicities ≥ Grade 3, excluding: Transient (≤5 days) manageable Grade 3 gastrointestinal symptoms (e.g., nausea, vomiting, diarrhea); Transient (≤7 days) liver enzyme elevations not meeting Hy's law; Asymptomatic laboratory abnormalities; Correctable electrolyte abnormalities within 3 days; Skin toxicities or infusion-related reactions; Additional toxicities may be considered DLTs at the discretion of the SMC, including persistent or recurrent treatment-related adverse events leading to significant treatment delay or discontinuation. Study Objectives The primary objectives are to evaluate the safety and tolerability of JS212 in combination with JS111 and to determine the recommended Phase III dose (RP3D). Secondary objectives include assessment of pharmacokinetics and preliminary anti-tumor activity.