Inclusion
EGFR classic mutations: EGFR-TKIs alone or in combination (examples, gefitinib and osimertinib with or without chemotherapy) for ex19del and ex21 L858R. Osimertinib or other third-generation EGFR TKI for T790M mutation.
EGFR uncommon mutations: EGFR-TKIs or chemotherapy for uncommon mutations including but not limited to G719X, S768I, L861Q mutations.
EGFR exon 20 activating insertions: chemotherapy with or without amivantamab or country-specific approved EGFR TKIs. 5. For China only: the presence of MET amplification and/or overexpression in tumor tissue samples or pleural fluid or blood samples collected after progression on prior EGFR-TKI treatment, confirmed by a central /local laboratory.
Adequate hematologic status, defined as: absolute neutrophil count (ANC) ≥1.5×109/L, hemoglobin ≥90 g/L, platelets ≥75×109/L. Platelet transfusions are not permitted within 3 days, red blood cell transfusions are not permitted within 14 days, hematopoietic growth factors are not permitted within 7 days (14 days for PEGylated granulocyte colony stimulating factor \[G-CSF\] or erythropoietin) prior to obtaining these laboratory values.
Adequate hepatic function, defined as: serum TBIL ≤1.5× ULN (in participants with known Gilbert's syndrome, TBIL ≤3× ULN with direct bilirubin ≤1.5× ULN), serum ALT or AST ≤2.5× ULN (or 5.0× ULN for documented liver metastasis).
Adequate renal function, defined as: creatinine clearance ≥60 mL/min (calculated by Cockcroft-Gault formula or CKD EPI formula \[Appendix 4 of Section 12.4\]).
Adequate coagulation profile, defined as (including if receiving anticoagulant therapy):
Achieved postmenopausal status, refer to NCCN Guidelines for Breast Cancer (2024V3.0) for the detailed definition of menopause.
Documentation of irreversible surgical sterilization by hysterectomy, bilateral oophorectomy or bilateral salpingectomy but not tubal ligation. 11. Male participants of childbearing potential are required to use adequate contraception (i.e., barrier method of birth control), during their participation in the study and for 90 days following the EOT. Male participants must also refrain from donating sperm during their participation in the study and for 90 days following the last dose of study treatment. 12. Capable of giving signed informed consent which includes compliance with the requirements and restrictions listed in the informed consent form and in this study.
Exclusion
Nitrosourea or mitomycin-C within 6 weeks prior to the first dose of study treatment.
Chinese medicines with anti-tumor indications within 7 days prior to the first dose of study treatment. 5. Radiotherapy with a wide field of radiation within 28 days, or radiotherapy with a limited field of radiation for palliation within 14 days of the first dose of study treatment.
Participants with symptomatic CNS metastases may participate in the study providing that symptoms are controlled after treatment, clinically stable for at least 4 weeks and have no evidence of new or enlarged brain metastases.
Participants with carcinomatous meningitis or meningeal metastases, or spinal cord compression are excluded regardless of clinical stability.
Participants with asymptomatic CNS metastases with a maximum diameter of brain metastases \<3 cm by imaging (such as MRI) without significant cerebral edema are eligible for the study. 10. Participants with clinically uncontrollable third-space effusion, including but not limited to pleural effusion, peritoneal effusion or pericardial effusion, are assessed by the investigator to be unsuitable for the study treatment. 11. Participants receiving unstable or increasing doses of corticosteroids. For participants receiving corticosteroids for endocrine deficiencies or symptoms associated to their disease (excluding CNS disease), the dose must have been stabilized (or reduced) for at least 14 days before the first dose of study treatment. 12. Have a history of or ongoing severe retinopathy. 13. Presence of serious cardiovascular or cerebrovascular disease, including but not limited to:
Mean resting corrected QT interval corrected by Fridericia's formula (QTcF) \>470 msec obtained from triplicate 12-lead electrocardiograms (ECGs).
Symptomatic heart failure per New York Heart Association (NYHA) classification Class II or above.
Baseline left ventricular ejection fraction (LVEF) below institution's lower limit of normal (LLN) or \<50% if assessed by echocardiography (ECHO) or Multigated Radionuclide Angiography (MUGA).
Any clinically important abnormalities in rhythm, conduction or morphology of resting ECG, e.g., complete left bundle branch block, third degree heart block, cardiac ventricular arrhythmias requiring anti-arrhythmic therapy.
Presence of any factors that increase the risk of QTc prolongation or the risk of arrhythmia, such as heart failure, hypokalemia, congenital long QT syndrome, family history of long QT syndrome, or use of any concomitant medication known to prolong the QT interval within 14 days prior to the first dose of study treatment.
Any of the following within 6 months prior to the first dose of the study treatment: myocardial infarction, severe/unstable angina, coronary artery bypass graft, congestive heart failure, cardiomyopathy, pulmonary embolism, cerebrovascular accident, or transient ischemic attack. 14. As judged by the investigator, any evidence of severe or uncontrolled systemic diseases, including but not limited to:
Uncontrolled hypertension, defined as a systolic blood pressure (BP) ≥160 mmHg or diastolic BP ≥100 mmHg despite medical therapy. Participant with a history of hypertension is allowed if BP is stable and controlled within these limits by antihypertensive treatment.
Previous history of, or presence of clinically symptomatic or at high risk for interstitial lung disease or interstitial pneumonitis, including radiation pneumonitis (i.e., affecting activities of daily living or requiring therapeutic treatment).
Unstable or uncompensated respiratory and renal disease, active bleeding diseases. 15. Uncontrolled concurrent infection including but not limited to:
Active hepatitis B virus (HBV) or hepatitis C virus (HCV) infection.
If hepatitis B surface antigen (HBsAg) is positive, HBV DNA assay should be performed. Participants may be eligible if HBV DNA test value ≤ ULN.
If HCV antibody is positive, HCV ribonucleic acid (RNA) assay should be performed. Participants may be eligible if HCV RNA negative.
Known human immunodeficiency virus (HIV) infection or known history of acquired immunodeficiency syndrome (AIDS).
Syphilis positive.
Active tuberculosis infection.
Onset period of keratitis or ulcerative keratitis.
Other active infections requiring systemic treatment within 14 days prior to the first dose of study treatment. 16. Unwilling or unable to comply with the requirements of oral drug administration, or presence of gastrointestinal disorders such as refractory nausea and vomiting, any acute or chronic gastrointestinal disorder, inability to swallow the formulation, or prior major bowel resection that may prevent adequate absorption of ANS014004 or PLB1004. 17. Hypersensitivity to ANS014004, PLB1004 or their excipients, or history of allergic reactions to ANS014004 and PLB1004 with similar chemical or biological structure or similar drugs. 18. Concomitant use of drugs metabolized by P-glycoprotein (P-gp)/breast cancer resistance protein (BCRP) or OCT2/OATP1B1/MATE1, or moderate or strong inducers or inhibitors of P-gp/BCRP or CYP2B6/CYP2C9/CYP2C19/OCT2/OATP1B1/MATE1 within 5 half-lives before the use of the study treatment. For dose escalation part only: concomitant treatment with moderate or strong P-gp/BCRP or CYP2C8/CYP2D6/CYP3A4 inducers or inhibitors within 5 half-lives prior to administration of study treatment. 19. In receipt of any live attenuated vaccination within 30 days prior to the first dose of study therapy. 20. Have a known psychiatric or substance abuse disorder that would interfere with the participant's ability to cooperate with the requirements of the study. 21. Have prior or ongoing clinically significant illness, medical condition, surgical history, physical findings, or laboratory abnormality that, in the investigator's opinion, would not be in the best interest of the participant; or that could alter the absorption, distribution, metabolism, or excretion of the study treatment; or impair the assessment of study results.