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

A Phase II Study of JS212 in Combination With JS111 in Patients With Epidermal Growth Factor Receptor (EGFR)-Mutant Advanced Non-Small Cell Lung Cancer (NSCLC)

This is a Phase II study evaluating the safety, tolerability, pharmacokinetics, and preliminary efficacy of JS212 in combination with JS111 in patients with advanced or metastatic non-small cell lung cancer (NSCLC) harboring EGFR-sensitizing mutations who have progressed after prior EGFR-TKI therapy.

The study consists of two parts: a dose-escalation phase followed by an expansion phase. Approximately 30 participants will be enrolled. The dose-escalation phase will explore the safety and tolerability of escalating doses of JS212 in combination with a fixed dose of JS111, using a Bayesian optimal interval (BOIN) design. Based on safety and tolerability data, a recommended Phase III dose (RP3D) will be determined. The expansion phase will further evaluate safety and preliminary anti-tumor activity at the selected dose level.

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.

Inclusion Criteria:

Participants must meet all of the following criteria to be eligible for this study:

1. Age between 18 and 75 years (inclusive) at the time of signing the informed consent form (ICF), regardless of sex;

2. Histologically or cytologically confirmed recurrent or metastatic non-squamous NSCLC that is unresectable and not amenable to curative chemoradiotherapy;

3. Confirmed EGFR-sensitizing mutation, including:

   Exon 19 deletion or L858R mutation,Either alone or in combination with other EGFR mutations, Including those with concurrent T790M mutation positivity.Local laboratory reports are acceptable, provided that the test method is well-validated, or has passed external quality assessment (EQA), or is conducted by a certified molecular pathology/genetic testing laboratory, or is approved by NMPA;

4. Prior treatment with:

   EGFR-TKIs, and If applicable, ≤1 line of platinum-based doublet chemotherapy, with radiologically confirmed disease progression per RECIST v1.1;

5. At least one measurable lesion per RECIST v1.1;

6. Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1;

7. Estimated life expectancy of ≥12 weeks;

8. Adequate organ function meeting the following criteria (Note: No blood transfusion or hematopoietic growth factors are allowed within 14 days prior to screening assessments):

   1. Absolute neutrophil count ≥1.5 × 10⁹/L;
   2. Platelet count ≥100 × 10⁹/L;
   3. Hemoglobin ≥90 g/L (≥9 g/dL);
   4. ALT and AST ≤2.5 × ULN (≤5 × ULN in case of liver metastases);
   5. Total bilirubin ≤1.5 × ULN;
   6. Creatinine clearance ≥50 mL/min (calculated by Cockcroft-Gault formula);
   7. Activated partial thromboplastin time (APTT) ≤1.5 × ULN and international normalized ratio (INR) ≤1.5(patients on stable anticoagulant therapy such as low molecular weight heparin or warfarin are allowed if INR is within the therapeutic range);

9. Female participants of childbearing potential (WOCBP) who are sexually active with non-sterilized male partners must:

   Have a negative serum pregnancy test within 7 days prior to first dose, and Agree to highly effective contraception and have no plans for pregnancy from signing the ICF until: 7 months after the last dose of JS212, and 2 months after the last dose of JS111, whichever period is longer (definition of WOCBP is provided in Section 10.3);

10. Non-sterilized male participants who are sexually active with women of childbearing potential must: Agree to use effective contraception as described in Section 10.3.2 from signing the ICF until 4 months after the last dose of JS212 or JS111, and Refrain from sperm donation during this period;

11. Participants must voluntarily participate in this study and provide written informed consent.

Exclusion Criteria:

Participants meeting any of the following criteria will be excluded from the study:

1. Disease-related conditions:

   a. Histologically or cytologically confirmed presence of: Small cell lung cancer component, or Large cell neuroendocrine carcinoma, or Sarcomatoid features, or Squamous component >10%; b. Known leptomeningeal metastases; c. Symptomatic brain metastases; Asymptomatic brain metastases may be eligible if assessed as stable by the investigator, including: i. Previously treated brain metastases (e.g., radiotherapy) that are stable, defined as: No CNS-related symptoms,Discontinuation of corticosteroids and osmotic agents (e.g., mannitol) ≥7 days prior to first dose, No radiographic progression compared with pre-treatment imaging (interval ≥4 weeks); ii. Untreated asymptomatic brain metastases meeting all of the following: No use of corticosteroids or osmotic agents,No lesion with longest diameter ≥1 cm, No metastases in midbrain, pons, medulla, or spinal cord, No history of intracranial hemorrhage; d. Uncontrolled pleural effusion, pericardial effusion, or ascites requiring repeated drainage (≥ once per month); e. Untreated spinal cord compression, or previously treated spinal cord compression without evidence of stability for ≥4 weeks prior to enrollment;

2. Prior/concomitant treatments:

   1. Within: 4 weeks or 5 half-lives (whichever is shorter) prior to first dose: chemotherapy or similar therapies;7 days: small molecule targeted therapy; 2 weeks: localized radiotherapy (e.g., palliative radiation for bone metastases);
   2. Use of strong CYP3A inhibitors or inducers within 14 days prior to first dose or requirement for continued use during study;
   3. Current use or requirement for use of medications known to prolong QT interval or cause torsades de pointes;
   4. Receipt of any investigational drug within 4 weeks or 5 half-lives prior to first dose (whichever is shorter);
   5. Participation in another clinical trial, unless it is: Observational (non-interventional), or The participant is in the follow-up phase of an interventional study;
   6. Major surgery (e.g., craniotomy, thoracotomy, laparotomy) within 4 weeks prior to first dose;

3. Toxicity Unresolved toxicities from prior anti-tumor therapy that have not recovered to:

   ≤ CTCAE Grade 1, or The level specified in inclusion/exclusion criteria,whichever is more severe (Grade 2 toxicities deemed not clinically significant by the investigator, such as alopecia, chemotherapy-induced neuropathy, or hypothyroidism, are allowed);

4. Hypersensitivity Known allergy or hypersensitivity to any study drug or its excipients;

5. Cardiac conditions:

   1. QTcF:≥450 ms (male), ≥470 ms (female), averaged from 3 ECG measurements;
   2. Clinically significant arrhythmias, including but not limited to:Complete left bundle branch block,Third-degree AV block,Second-degree AV block,PR interval >250 ms;
   3. Risk factors for torsades de pointes, such as: Clinically significant hypokalemia,Family history of long QT syndrome or arrhythmias;
   4. Left ventricular ejection fraction (LVEF) <50%;

6. Gastrointestinal conditions Conditions affecting drug absorption, distribution, metabolism, or excretion, such as: Inability to swallow oral medication, Persistent vomiting,Uncontrolled diarrhea,Extensive gastrointestinal resection,Crohn's disease, ulcerative colitis;

7. Pulmonary conditions History of or suspected: Interstitial lung disease, Drug-induced pneumonitis,Idiopathic pneumonitis,Idiopathic pulmonary fibrosis,or other significant pulmonary disease (≤Grade 1 radiation pneumonitis is allowed);

8. Ocular conditions Severe or uncontrolled ocular disorders that may increase risk, including:

   Severe dry eye syndrome,Keratoconjunctivitis sicca,Severe exposure keratitis, or other conditions predisposing to epithelial damage;or requiring surgery during the study (non-urgent cataract is allowed);

9. Infection Severe infection (CTCAE ≥ Grade 3) within 4 weeks prior to first dose; Evidence of active pulmonary inflammation on imaging at baseline; Infection requiring systemic antibiotics within 2 weeks prior to first dose (excluding prophylactic use);

10. Immunodeficiency History of immunodeficiency, including HIV positivity;Other acquired or congenital immunodeficiency;History of organ transplantation, allogeneic bone marrow transplantation, or autologous hematopoietic stem cell transplantation;

11. Tuberculosis Active tuberculosis, or History of active tuberculosis within 1 year prior to enrollment, or History of active tuberculosis >1 year ago without adequate treatment;

12. Viral hepatitis Active HBV infection: HBsAg positive with HBV DNA ≥1000 copies/mL or ≥200 IU/mL; Active HCV infection: HCV antibody positive with detectable HCV RNA above LLOQ;

13. Other malignancies Any other malignancy requiring treatment within 5 years prior to first dose, except: Malignancies with low metastatic risk and >90% 5-year survival, such as: Adequately treated basal or squamous cell skin cancer, Carcinoma in situ of cervix or breast, Localized prostate cancer, Papillary thyroid carcinoma;

14. Pregnancy and lactation Pregnant or breastfeeding women, or those planning pregnancy during the study;

15. Uncontrolled comorbidities Including but not limited to: Symptomatic congestive heart failure within 6 months, Uncontrolled hypertension, Unstable angina, Uncontrolled arrhythmia, Major seizure disorders,Superior vena cava syndrome,Aortic aneurysm requiring surgery, Arterial thromboembolism,≥Grade 3 venous thromboembolism (CTCAE v6.0),Stroke or transient ischemic attack; or psychiatric/social conditions that may affect compliance or informed consent;

16. Investigator judgment Any condition that, in the investigator's opinion, may: Lead to premature discontinuation,Compromise patient safety, or Affect data integrity, including abnormal laboratory values or unfavorable social/family circumstances.