A Phase II Study of Anlotinib and Platinum-Based Chemotherapy in Patients With SMARCA4-Deficient, Locally Advanced or Metastatic Lung Cancer.

Prior treatment

• Failure to recover from acute toxicities of prior anti-cancer therapy to ≤ Grade 1 per NCI CTCAE v5.0 or to baseline levels specified in the inclusion criteria (excluding alopecia or fatigue) within 4 weeks prior to the first dose.
• Major surgical procedure, significant traumatic injury within 4 weeks prior to the first dose, or anticipated need for major surgery during the study treatment period (unless specified in the protocol); OR presence of non-healing wounds or fractures. (Major surgery is defined as Grade 3 or higher according to the National Surgery Classification Catalog 2022 edition).
• Any arterial or venous thromboembolic event (e.g., cerebrovascular accident, transient ischemic attack, deep vein thrombosis, pulmonary embolism) within 6 months prior to the first dose; OR any bleeding or hemorrhagic event ≥ Grade 3 per CTCAE v5.0 within 4 weeks prior to the first dose.
• Prior or planned allogeneic bone marrow transplantation or solid organ transplantation.
• Concurrent participation in another interventional clinical trial, or an observational (non-interventional) clinical study, or being in the follow-up phase of an interventional study.
• Major surgical procedure (as defined by the investigator, e.g., craniotomy, thoracotomy, laparotomy, vascular intervention) within 4 weeks prior to the first study drug dose, OR presence of unhealed wounds, ulcers, or fractures. Note: Palliative local surgery for isolated lesions is acceptable.
• Use of any other investigational drug or therapy within 4 weeks prior to the first study dose.
• Use of any Chinese herbal medicine with anti-tumor activity within 2 weeks prior to initiation of study treatment.
• Planned administration or administration of a live vaccine within 28 days prior to the first study dose.

Other illness

• Conditions that compromise intravenous access or oral drug administration (e.g., inability to swallow, chronic diarrhea, intestinal obstruction); OR unwillingness or inability to undergo a repeat biopsy or provide sufficient tissue samples for comprehensive analysis (whole-exome sequencing, transcriptome sequencing, multiplex fluorescence immunohistochemistry).
• History of psychotropic substance abuse with inability to abstain, or presence of psychiatric disorders.
• History of hepatic encephalopathy.
• Active gastrointestinal diseases or other conditions that may significantly affect drug absorption, metabolism, or excretion, including but not limited to: malabsorption syndrome, inflammatory bowel disease, partial or complete intestinal obstruction, gastrectomy, or small bowel resection.
• Severe underlying pulmonary disease or history thereof, such as moderate to severe chronic obstructive pulmonary disease (COPD), history of interstitial lung disease (ILD), drug-induced ILD, acute or chronic infectious pneumonia, or lung transplantation.
• Known history of allogeneic organ transplantation or allogeneic hematopoietic stem cell transplantation.
• HIV infection (HIV 1/2 antibody positive).
• Known active syphilis infection or active tuberculosis.
• Documented history of psychiatric disorder requiring medication.
• History of drug abuse or substance addiction.
• History of other malignancies (excluding non-melanoma skin cancer and carcinoma in situ of the bladder, stomach, colon, endometrium, cervix/dysplasia, melanoma, or breast), unless the subject has been in complete remission for at least 2 years prior to enrollment and requires no other treatment during the study.
• Known hypersensitivity or intolerance to the study drug(s) or any of their excipients.
• Any other condition that, in the investigator's opinion, makes the subject unsuitable for participation in this clinical trial.

Lab values

• Failure to recover from adverse reactions of prior therapies to ≤ Grade 1 per CTCAE v5.0, except for toxicities deemed by the investigator to pose no safety risk (e.g., Grade 2 alopecia, Grade 2 peripheral neuropathy, Grade 2 anemia, non-clinically significant and asymptomatic laboratory abnormalities, or stable hypothyroidism on hormone replacement therapy).
• Poorly controlled active viral hepatitis. Eligible subjects meeting the following criteria may be screened:
  • 9.1 HBsAg-positive subjects must have HBV DNA \< 2000 IU/mL (or 1×10⁴ copies/mL) OR have received at least 1 week of anti-HBV therapy prior to study initiation with at least a 10-fold (1-log) reduction in viral load, AND agree to receive continuous anti-HBV therapy throughout the study.
  • 9.2 HCV-infected subjects (HCV Ab or HCV RNA positive) must be in a stable condition as judged by the investigator OR be receiving approved antiviral therapy at enrollment and willing to continue it during the study.
• Significant cardiovascular disease, including any of the following:
  • 13.1 Cardiac insufficiency ≥ Class II per New York Heart Association (NYHA) criteria OR left ventricular ejection fraction (LVEF) \< 50% on echocardiography.
  • 13.2 History of clinically significant ventricular arrhythmia (e.g., sustained ventricular tachycardia, ventricular fibrillation, torsades de pointes) OR arrhythmia requiring ongoing antiarrhythmic medication.
  • 13.3 Unstable angina. 13.4 Myocardial infarction within the past 12 months. 13.5 QTcF interval \> 450 msec for males or \> 470 msec for females (if abnormal, the average of three consecutive readings taken at least 2 minutes apart).
  • 13.6 Personal or family history of congenital long QT syndrome. 13.7 History of deep vein thrombosis, pulmonary embolism, or any other severe thromboembolism within 3 months prior to randomization (thrombosis related to implanted ports/catheters or superficial thrombophlebitis are not considered "severe").
  • 13.8 Current use or recent use (within 7 days prior to treatment initiation) of aspirin (\>325 mg/day), dipyridamole, ticlopidine, clopidogrel, or cilostazol.
• Poorly controlled concurrent illnesses, such as:
  • 14.1 Serious infection within 4 weeks prior to treatment initiation requiring hospitalization; OR therapeutic oral/intravenous antibiotics within 2 weeks prior to treatment initiation (prophylactic antibiotic use is permitted, e.g., for urinary tract infection or COPD).
  • 14.2 Symptomatic congestive heart failure (NYHA Class II-IV) OR symptomatic/poorly controlled arrhythmia.
  • 14.3 Other active malignancy diagnosed within the past 5 years, except for curatively treated non-melanoma skin cancer, basal/squamous cell carcinoma, or carcinoma in situ (e.g., breast, cervix, bladder) with no evidence of recurrence.
  • 14.4 Suspected or confirmed acute promyelocytic leukemia (for patients with acute myeloid leukemia).
  • 14.5 Current carcinomatous meningitis or spinal cord compression. 14.6 Poorly controlled hypertension. 14.7 Symptomatic intrinsic lung disease. 14.8 Any arterial thromboembolic event within 6 months prior to enrollment, including myocardial infarction, unstable angina, cerebrovascular accident, or transient ischemic attack.
  • 14.9 Significant malnutrition requiring intravenous nutritional support, unless corrected and stable for ≥ 4 weeks prior to the first dose.
  • 14.10 Tumor invasion of adjacent vital organs or major blood vessels (e.g., mediastinal great vessels, superior vena cava, trachea, esophagus), or risk of esophageal-tracheal or esophageal-pleural fistula.
  • 14.11 History of esophageal or tracheal stent implantation. 14.12 Any other acute/chronic illness or laboratory abnormality that, in the investigator's judgment, increases risk associated with study participation or drug administration, OR interferes with the interpretation of study results.
  • 14.13 History of gastrointestinal perforation and/or fistula within 6 months prior to enrollment.
  • 14.14 Uncontrolled third-space effusions requiring repeated drainage (e.g., pleural, peritoneal, pericardial effusion). Subjects not requiring drainage or stable for 3 days after stopping drainage may be eligible.
• Any other condition that, in the judgment of the investigator, may affect study results, interfere with the subject's participation in the entire study process, or render the subject unsuitable for participation, including but not limited to existing or past medical conditions, treatments, laboratory abnormalities, or unwillingness to comply with study procedures and requirements.

Other

• Patients meeting any of the following criteria will be excluded from the trial:
• Pathological diagnosis containing a small cell carcinoma component.
• Symptomatic brain metastases.
• Leptomeningeal carcinomatosis.
• Pregnant or lactating women.

• Patients must meet ALL the following criteria to be eligible for trial participation:
• Voluntary participation and provision of written informed consent.
• Age ≥ 18 years.
• Life expectancy ≥ 3 months.
• Diagnosed with unresectable, locally advanced (Stage IIIB) or metastatic (Stage IV) lung cancer not amenable to curative radiotherapy.
• Tumor confirmed by immunohistochemistry (IHC) to be deficient in the BRG1 protein (encoded by the SMARCA4 gene).
• No prior systemic anti-cancer therapy.
• Eastern Cooperative Oncology Group (ECOG) Performance Status of 0 or 1.
• Willing and able to provide archival or fresh tumor tissue samples from primary or metastatic sites for biomarker analysis. Enrollment may be considered after investigator assessment if tissue is unavailable, provided all other criteria are met.
• At least one measurable lesion per Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1.
• Adequate organ and bone marrow function as defined by the following laboratory values (within screening period):
  • 10.1. Absolute neutrophil count (ANC) ≥ 1.5 × 10⁹/L. 10.2. Platelet count ≥ 100 × 10⁹/L. 10.3. Hemoglobin ≥ 90 g/L (without blood transfusion within 14 days). 10.4. Serum creatinine ≤ 1 × Upper Limit of Normal (ULN) OR estimated creatinine clearance \> 50 mL/min (Cockcroft-Gault formula).
  • 10.5. Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) ≤ 2.5 × ULN (≤ 5 × ULN if liver metastases are present).
  • 10.6. Total bilirubin ≤ 1.5 × ULN (For subjects with Gilbert's syndrome, total bilirubin must be \< 51.3 µmol/L).
  • 10.7. Prothrombin time (PT), activated partial thromboplastin time (APTT), and International Normalized Ratio (INR) ≤ 1.5 × ULN (for subjects not receiving anticoagulant therapy).