A Phase III Study Comparing Taletrectinib With Standard Therapy in ROS1 Positive Locally Advanced or Metastatic Non-small Cell Lung Cancer Patients

Inclusion Criteria:

1. Histologically or cytologically confirmed diagnosis of locally advanced or recurrent (Stage IIIB not amenable for multimodality treatment) or metastatic (Stage IV)NSCLC.

2. Have documentation of ROS1 rearrangement by a positive result

3. Have at least 1 measurable (i.e., target) lesion by Investigator assessment perRECIST v1.1.

4. Prior brain or leptomeningeal metastases allowed if asymptomatic and diagnosedincidentally at study baseline. If participants have neurological symptoms or signsdue to CNS metastasis, participants need to complete local therapy (surgery and/orradiation) at least 7 days before enrollment and be clinically stable withoutrequiring for an increasing dose of corticosteroids or use of anticonvulsants tocontrol symptoms.

5. Age ≥18 years (or ≥20 years as required by local regulations).

6. Eastern Cooperative Oncology Group (ECOG) performance status zero (0) to 1.

7. Minimum life expectancy of 3 months or more.

8. Adequate organ function meeting the following criteria:

9. Aspartate aminotransferase (AST) and alanine aminotransferase (ALT): ≤3.0 ×upper limit of normal (ULN) (or ≤5.0 × ULN, for participants with concurrentliver metastases).

10. Serum total bilirubin: ≤1.5 × ULN (≤3.0 × ULN for participants with Gilbertsyndrome).

11. Absolute neutrophil count: ≥1500/μL.

12. Platelet count: ≥75,000/μL.

13. Hemoglobin: ≥9.0 g/dL.

14. Estimated creatinine clearance (CLcr) ≥45 mL/min as calculated using the methodstandard for the institution (e.g., Cockcroft-Gault Equation, i.e.,CCr={((140-age)×weight)/(72×SCr)}×0.85 (if female) (Cockcroft and Gault 1976).

15. All toxicities from prior anticancer therapy have resolved to ≤ Grade 1 according tothe National Cancer Institute Common Terminology Criteria for Adverse Events (NCICTCAE v5.0), or have resolved to previous baseline, at the time of randomization.

16. The participant is willing and capable of giving written informed consent.

Exclusion Criteria:

1. Previously received an investigational antineoplastic agent for NSCLC.

2. Previously received any prior TKI, including ROS1-targeted TKIs.

3. Received immune checkpoint inhibitors for locally advanced or metastatic disease.

4. Previously received more than 1 regimen of systemic anticancer therapy for locallyadvanced or metastatic disease.

5. Had major surgery within 28 days prior to randomization. Minor surgical procedures,such as catheter placement or minimally invasive biopsy, are allowed.

6. Have symptomatic CNS metastases (parenchymal or leptomeningeal) at Screening orasymptomatic disease requiring an increasing dose of corticosteroids to controlsymptoms within 7 days prior to randomization. Participants with no prior history ofsigns or symptoms of CNS metastases but who receive prophylactic steroids oranticonvulsants are allowed.

7. Have current spinal cord compression (symptomatic or asymptomatic and detected byradiographic imaging). Participants with leptomeningeal disease and without cordcompression are allowed.

8. Uncontrolled pleural, abdominal, or pericardial effusion within 28 days prior torandomization, which is associated with malignant effusion requiring recurrentdrainage procedures (once monthly or more frequently).

9. Have been diagnosed with another primary malignancy other than NSCLC except foradequately treated nonmelanoma skin cancer or cervical cancer in situ; definitivelytreated nonmetastatic prostate cancer; or participants with another primarymalignancy who are definitively relapse-free with at least 3 years elapsed since thediagnosis of the other primary malignancy.

10. Have clinically significant cardiovascular diseases within 6 months prior torandomization: myocardial infarction, severe/unstable angina, coronary/peripheralendovascular treatment, heart failure, cerebrovascular disorder including transientischemic attack, pulmonary embolism, deep venous thrombosis and or other clinicallysignificant thrombosis.

11. Have a known history of uncontrolled hypertension. Participants with hypertensionshould be under treatment on study entry to control blood pressure.

12. Have ongoing cardiac dysrhythmias of ≥CTCAE Grade 2, uncontrolled atrialfibrillation of any grade, or QT interval corrected for heart rate by Fredericia'sformula (QTcF) >470 milliseconds (female) or >450 milliseconds (male), orsymptomatic bradycardia <45 bpm within 6 months before enrollment; participantstreated with medications known to be associated with the development of TdP .

13. Have active and clinically significant bacterial, fungal, or viral infectionincluding but not limited to hepatitis B virus (HBV), hepatitis C virus (HCV), knownHIV or AIDS-related illness

14. Currently have or have a history of interstitial lung disease (ILD), drug-relatedpneumonitis, or radiation pneumonitis that required steroid treatment.

15. Be pregnant or breastfeeding