Study of SIM0518 in Participants With ALK-Positive or ROS1-Positive Locally Advanced or Metastatic Non-Small Cell Lung Cancer

• Participants must meet all of the following inclusion criteria:
• Voluntary participation and signing of informed consent.
• Age ≥ 18 years, male or female.
• Histologically and/or cytologically confirmed stage IIIB-IV non-curatively treatable (surgery, radiotherapy) Non-Small Cell Lung Cancer.
• It was confirmed that trial participants carried ALK or ROS1 rearrangements from previous local test reports, in which testing was performed using kits approved by regulatory authorities.

Part 1:

• a: Heavily pretreated advanced.
• b: Presence of at least one measurable or evaluable tumor lesion per Response Evaluation Criteria in Solid Tumors, version 1.1.

（RECIST 1.1. ）Participants enrolled in the backfill phase must have measurable disease. Lesions previously irradiated cannot be considered target lesions unless the lesion progresses significantly.

Part 2 of 3:

- a: Cohort 1, Cohort 2, Cohort 4, and Cohort 5: disease progression or intolerance during/after treatment with at least one ALK inhibitor or a ROS1 inhibitor, with no more than 3 ALK/ROS1 inhibitors; and progression or intolerance after a maximum of one-line chemotherapy regimen.

Cohort 3: has not received ALK inhibitor therapy and has progressed or is intolerant after up to one chemotherapy regimen.

• b. Presence of at least one measurable lesion per RECIST 1.1; lesions previously irradiated cannot be considered target lesions unless the lesion progresses significantly.
• Eastern Cooperative Oncology Group Performance Status(ECOG) score 0 or 1.
• Expected survival ≥ 12 weeks.
• Adequate organ and bone marrow function.

Trial participants must confirm at screening that archival formalin-fixed paraffin-embedded (FFPE) tumor tissue samples obtained within 3 years of signing the informed consent form or fresh biopsy samples collected prior to the first dose for retrospective testing of the ALK/ROS1 gene are available.

-Women of childbearing potential must have a negative blood pregnancy test within 3 days prior to the first dose. Female trial participants of childbearing potential or male trial participants with female partners of childbearing potential are required to use effective methods of contraception from signing the informed consent form until 180 days after the last dose of study drug and refrain from donating sperm/eggs.

Exclusion Criteria:

• Target disease to be excluded
• NSCLC trial participants have driver gene mutations other than ALK/ROS1 that have corresponding marketed targeted agents, such as EGFR sensitivity mutations, HER2 mutations, KRASG12C mutations, BRAFV600 mutations, RET fusions, MET14 exon skipping mutations, MET amplifications, NTRK fusions.
• Trial participants had symptomatic Central Nervous System metastases (CNS) metastases within 2 weeks prior to the first dose of study treatment, or CNS metastases requiring CNS-directed local therapy (e.g., radiotherapy or surgery) or corticosteroid therapy.
• The trial participant had spinal cord compression (due to tumor) unless the trial participant achieved good pain control by treatment and neurological function fully recovered within 4 weeks prior to the first dose.

Medical Status and Prior/Concomitant Diseases

• History of other active malignancies within the past 3 years with the following exceptions: adequately treated basal cell carcinoma or squamous cell skin cancer, carcinoma in situ of the breast or carcinoma in situ of the cervix, low-risk prostate cancer (Gleason score ≤ 6) under surveillance without any treatment intervention plan (e.g., surgery, radiotherapy, or castration therapy), and other concomitant malignancies assessed by the investigator in consultation with the sponsor as low risk of recurrence.
• Gastrointestinal disorders affecting drug administration/absorption: including dysphagia/inability to swallow the drug; major gastrointestinal surgery (e.g., bowel resection with clinically significant sequelae, total gastrectomy, etc.) affecting absorption; chronic diarrhea, symptomatic diverticulosis; subjects with active or persistent gastrointestinal bleeding, active peptic ulcer requiring treatment, or malabsorption syndrome within 180 days prior to signing the informed consent form; intestinal obstruction or other gastrointestinal disease that, in the opinion of the investigator, is not suitable for enrollment within 90 days prior to signing the informed consent form.
• Any psychiatric or cognitive disorder that may limit their understanding and execution of informed consent.
• Uncontrollable or pleural effusion, pericardial effusion, or ascites requiring drainage or medical intervention within 4 weeks prior to the first dose of study treatment.
• Trial participants with any active infection requiring systemic treatment by intravenous infusion within 2 weeks prior to start of study treatment.
• History of pneumonitis or interstitial lung disease requiring oral or intravenous steroids. Current interstitial lung disease or pneumonitis or suspected interstitial lung disease or pneumonitis at screening that cannot be screened by imaging.
• Trial participants had a history of active tuberculosis infection within 1 year; trial participants with a history of active tuberculosis, unless judged by the investigator to have no evidence of active tuberculosis for more than 1 year prior to the first dose of study treatment.
• Known human immunodeficiency virus (HIV) infection or known acquired immunodeficiency syndrome (AIDS).
• Active or chronic hepatitis B (HBsAg or HBcAb positive and HBV DNA ≥ 2000 IU/mL or ≥ 10,000 copies/mL) or hepatitis C (HCV antibody positive and HCV RNA ≥ ULN) infection; trial participants who are HBsAg positive or HBV-DNA positive at screening should receive antiviral therapy during the study in accordance with local practice.

History of clinically significant cardiovascular disease.

• QTcF interval (corrected by Fridericia' s formula) > 450 milliseconds by electrocardiogram, hereditary long QT syndrome.
• Uncontrolled hyperglycemia, acute onset of cholelithiasis, or participants with susceptibility characteristics for acute pancreatitis as judged by the investigator within 28 days prior to the first dose.
• History of allogeneic organ transplantation or graft-versus-host disease.
• Known allergy to study drug or any excipients.

Prior/concomitant therapy

• Prior four-generation ALK inhibitors or ALK molecular gels.
• Has not recovered from an AE due to prior anti-tumor therapy.
• Currently participating in or participating in studies of other investigational drugs or investigational devices within 4 weeks prior to the first dose of SIM0518.
• Major surgery within 4 weeks prior to the first dose of study treatment.

The following medications were administered before the first dose of study treatment:

• Administration of strong or moderate CytochromeP450 3A4 (CYP3A4)inhibitors and/or strong CytochromeP450 2C8(CYP2C8) inhibitors ≤ 7 days or 5 half-lives (whichever is longer) prior to the first dose of study treatment;
• Administration of strong or moderate CYP3A4 inducers ≤ 14 days or 5 half-lives (whichever is longer) prior to the first dose of study treatment;
• Administer medications known to be at risk for torsades de pointes (TdP) ≤ 14 days or 5 half-lives, whichever is longer, prior to the first dose of study treatment;
• Medications that may prolong the QT interval ≤ 14 days prior to the first dose of study treatment (TdP risk is uncertain);
• Proton pump inhibitors (PPIs) or H2 blockers were administered ≤ 7 days before the first dose of study treatment;
• Received the following anti-tumor therapies prior to the first dose of study treatment:
• Received anti-tumor antibody or Antibody-Drug Conjugate(ADC) therapy (whichever is shorter) within 4 weeks or 5 half-lives (whichever is shorter) before the first dose of study treatment.
• Cytotoxic therapy, anti-tumor targeted small molecules (e.g. tyrosine kinase inhibitors) within 2 weeks prior to the first dose of study treatment.
• Traditional Chinese medicine/traditional Chinese medicine preparations with anti-tumor indications within 2 weeks prior to the first dose of study treatment.
• Traditional Chinese medicine/traditional Chinese medicine preparations (except topical medication) within 7 days prior to the first dose of study treatment.

Radiotherapy (except whole brain radiotherapy, which requires 4 weeks) within 2 weeks prior to the first dose of study treatment.

• Use of any live vaccines within 4 weeks prior to the first dose of study treatment.
• Trial participants are pregnant or breastfeeding, or are expected to become pregnant or have children during the planned study.
• Other circumstances considered unsuitable for inclusion by the investigator
• Additional Exclusion Criteria for Trial Participants in Part 3 (Drug Interaction Studies)
• (Part 3 Cohort 4 only) Study participants are expected to use any CYP3A4 inhibitor or inducer within ≤ 7 days (for 3A4 inhibitors) or ≤ 14 days (for 3A4 inducers) or 5 half-lives (whichever is longer) prior to the first dose of midazolam (as CYP3A4 probe substrate) until completion of the Drug-Drug Interaction(DDI)assessment on Cycle2Day2;
• (Part 3 Cohort 5 only) Study participants are expected to use inhibitors and inducers of any specific metabolic enzyme/transporter (CYP2B6, CYP2C8, CYP2C9, P-gp, and BCRP) within ≤ 7 days (inhibitor) or ≤ 14 days (inducer) or 5 half-lives (whichever is longer) prior to the first dose of the specific probe substrate to be used by trial participants until the completion of the DDI assessment on Cycle2Day2; .
• (Part 3 only) Trial participants with contraindications to the administration of the drug according to the current labeling of probe substrates (midazolam, bupropion, repaglinide, tolbutamide, fexofenadine, rosuvastatin) to be used in the cohort in which the trial participant is participating;