JS212 in Combination With JS111 as First-Line Treatment in EGFR-Mutant Advanced NSCLC

Inclusion Criteria:

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

  1. Male or female participants aged 18 to 75 years, inclusive, at the time of signing the informed consent form.
  2. Histologically or cytologically confirmed recurrent or metastatic solid tumor that is unresectable and not amenable to curative radiotherapy or chemoradiotherapy.
  3. Confirmed EGFR-sensitizing mutation, defined as an exon 19 deletion or L858R mutation, either occurring alone or together with other EGFR mutations, including concomitant T790M mutation. Local laboratory test reports are acceptable, provided that testing is performed using a well-validated assay, an assay that has passed external quality assessment, a laboratory qualified for molecular pathology diagnosis or genetic testing, or an assay approved by the National Medical Products Administration (NMPA). Participants must not have received prior systemic antitumor therapy for locally advanced or metastatic nonsquamous NSCLC. Participants with recurrent NSCLC who previously received adjuvant or neoadjuvant therapy, including chemotherapy, radiotherapy, or other treatment, or definitive radiotherapy or chemoradiotherapy, may be enrolled if the interval between the last treatment and disease recurrence is more than 6 months.
  4. At least 1 measurable lesion according to Response Evaluation Criteria in Solid Tumors, version 1.1 (RECIST v1.1).
  5. Eastern Cooperative Oncology Group performance status (ECOG PS) of 0 or 1.
  6. Life expectancy of at least 12 weeks.
  7. Adequate major organ function.
  8. Women of childbearing potential (WOCBP) who are sexually active with a nonsterilized male partner must have a negative serum pregnancy test within 7 days before the first dose and must agree to have no plans for pregnancy and to use highly effective contraception from the time of signing the informed consent form until 7 months after the last dose of JS212 or 2 months after the last dose of JS111, whichever contraception period is longer.
  9. Nonsterilized male participants who are sexually active with a female partner of childbearing potential must agree to use effective contraception, as described in Appendix 2, from the time of signing the informed consent form until 4 months after the last dose of JS212 or JS111. Sperm donation is prohibited during this period.
  10. The participant voluntarily agrees to participate in the study and signs the informed consent form.

Exclusion Criteria:

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

  1. Any of the following disease-related conditions:

  1. Histologically or cytologically confirmed tumor containing a small-cell lung cancer component, large-cell neuroendocrine carcinoma, sarcomatoid features, or a squamous cell carcinoma component greater than 10%;
  2. Known leptomeningeal metastases;
  3. Symptomatic brain parenchymal metastases. Participants with asymptomatic brain metastases may be enrolled if considered stable by the investigator.
  4. Uncontrolled pleural effusion or pericardial effusion, or ascites requiring repeated drainage once per month or more frequently;
  5. Spinal cord compression not treated with surgery and/or radiotherapy, or previously diagnosed spinal cord compression without clinical evidence of disease stability for at least 4 weeks before enrollment following treatment.

  2. Receipt of any of the following treatments:

  1. Chemotherapy or other systemic antitumor therapy within 3 weeks or 5 half-lives before the first dose, whichever is shorter; small-molecule targeted therapy within 2 weeks before the first dose; or limited-field local radiotherapy, such as palliative radiotherapy for bone metastases, within 2 weeks before the first dose;
  2. Use of a strong CYP3A inhibitor or inducer within 14 days before the first dose of study treatment, or anticipated need for continued treatment with such medications during the study;
  3. Current treatment with medications known to prolong the QT interval or potentially cause torsades de pointes, or anticipated need for continued treatment with such medications during the study;
  4. Receipt of any investigational drug within 4 weeks or 5 half-lives before the first dose of study treatment, whichever is shorter;
  5. Concurrent enrollment in another clinical study, unless it is an observational, noninterventional study or the participant is in the follow-up phase of an interventional clinical study;
  6. Major surgery, such as craniotomy, thoracotomy, or laparotomy, within 4 weeks before the first dose of study treatment;
  7. Prior treatment with any EGFR tyrosine kinase inhibitor, any antibody-drug conjugate with a topoisomerase I inhibitor payload, or any antibody and/or antibody-drug conjugate targeting EGFR and/or HER3;

  3. Toxicities from prior antitumor therapy that have not recovered to Grade 1 or lower according to CTCAE.

  4. Known allergy or hypersensitivity to any study treatment or any of its excipients.

  5. Any of the following cardiac findings:

  1. Fridericia-corrected QT interval (QTcF) at rest of ≥450 milliseconds in male participants or ≥470 milliseconds in female participants, based on the mean of 3 QTcF measurements obtained during screening; 2. Clinically significant arrhythmia, including but not limited to complete left bundle branch block, third-degree atrioventricular block, second-degree atrioventricular block, or PR interval >250 milliseconds; 3. Risk factors for torsades de pointes, such as clinically significant hypokalemia as judged by the investigator, a family history of long QT syndrome, or a family history of arrhythmia, such as pre-excitation syndrome; 4. Left ventricular ejection fraction (LVEF) <50%. 6. Any condition that may affect the absorption, distribution, metabolism, or elimination of oral medication, including inability to swallow medication, frequent vomiting, persistent uncontrolled diarrhea, extensive gastrointestinal resection, Crohn's disease, or ulcerative colitis.

  7. Confirmed or suspected interstitial lung disease, drug-induced pneumonitis, a history of idiopathic pneumonitis or idiopathic pulmonary fibrosis, or another moderate or severe pulmonary disease that substantially impairs lung function, except for Grade 1 or lower radiation pneumonitis.

  8. Any severe or uncontrolled ocular disorder, particularly severe dry eye syndrome, keratoconjunctivitis sicca, severe exposure keratitis, or another condition that may increase the risk of epithelial injury, as judged by the physician; or an ocular abnormality requiring surgery or expected to require surgery during the study, except for cataracts not requiring urgent surgery.

  9. Severe infection of CTCAE Grade 3 or higher within 4 weeks before the first dose of study treatmen.

  10. A history of immunodeficiency, including a positive human immunodeficiency virus test, another acquired or congenital immunodeficiency disorder, a history of organ transplantation or allogeneic bone marrow transplantation, or autologous hematopoietic stem cell transplantation.

  11. Active tuberculosis infection identified by medical history or computed tomography, a history of active tuberculosis infection within 1 year before enrollment, or a history of active tuberculosis infection more than 1 year before enrollment without adequate standard treatment.

  12. Active hepatitis B, defined as hepatitis B surface antigen (HBsAg) positivity with hepatitis B e antibody (HBeAb) or hepatitis B core antibody (HBcAb) positivity and HBV DNA ≥1000 copies/mL or ≥200 IU/mL; or active hepatitis C, defined as hepatitis C virus antibody positivity with HCV RNA above the lower limit of detection of the assay.

  13. Any other malignancy diagnosed within 5 years before the first dose that required treatment, except for malignancies with a low risk of metastasis and a 5-year survival rate greater than 90%, such as adequately treated basal cell or squamous cell carcinoma of the skin, carcinoma in situ of the cervix or breast, adequately treated localized prostate cancer, or adequately treated papillary thyroid carcinoma.

  14. Female participants who are pregnant, breastfeeding, or planning to become pregnant during the study.

  15. Uncontrolled concomitant disease, including but not limited to symptomatic congestive heart failure within 6 months before the first dose of study treatment, uncontrolled hypertension, unstable angina pectoris, uncontrolled arrhythmia.

  16. Any other factor that, in the investigator's judgment, may cause the participant to discontinue the study prematurely, including a current or prior medical condition, including psychiatric illness, requiring concomitant treatment; a clinically significant laboratory abnormality; or family or social circumstances that may affect participant safety or the collection of study data.