Inclusion Criteria:
* Voluntary participation and signed written informed consent (ICF) before any study-specific procedure.
Age ≥ 18 years at screening. Histologically or cytologically confirmed, unresectable locally advanced (AJCC 9th edition stage IIIB or IIIC not amenable to multimodality therapy) or metastatic (stage IV) ROS1-positive non-small cell lung cancer (NSCLC).
ROS1 gene rearrangement/fusion positivity confirmed by a qualified local laboratory using PCR, NGS, or FISH. IHC alone is not acceptable. A written report of the ROS1 test must be provided.
Sufficient and adequate archival tumor tissue must be available for central laboratory ROS1 retesting per the Central Lab Manual; if no archival tissue is available, a fresh tumor biopsy is required.
No prior ROS1 TKI therapy. Prior systemic therapy limited to ≤1 line of standard chemotherapy:
A prior chemotherapy-based regimen administered for ≥1 cycle counts as one line.
Disease recurrence within 6 months after completion of adjuvant chemotherapy counts that adjuvant regimen as one prior line.
Asymptomatic central nervous system (CNS) metastases allowed (leptomeningeal carcinomatosis excluded). Previously treated and controlled/stabilized CNS metastases permitted if:
On non-enzyme-inducing antiepileptic drugs (non-EIAED) for seizure prophylaxis; or EIAED discontinued ≥14 days before randomization.
If corticosteroids needed, stable or tapering dose ≤10 mg/day prednisone (or equivalent) for ≥14 days before randomization.
Prior local therapy (WBRT, SRS/SRT) completed ≥14 days before randomization; treatment-related toxicities (except alopecia) resolved to ≤ Grade 1 (CTCAE v5.0).
At least one measurable lesion per RECIST v1.1. ECOG performance status 0-1. Expected survival ≥ 3 months.
Adequate organ function within 14 days before randomization (no blood products, growth factors, or platelet/ WBC boosters within 14 days):
1. ANC ≥ 1.5 × 10\^9/L
2. Platelets ≥ 100 × 10\^9/L
3. Hemoglobin ≥ 90 g/L (stable erythropoietin ≥3 months allowed)
4. CrCl \> 45 mL/min (Cockcroft-Gault)
5. Total bilirubin \< 1.5 × ULN (Gilbert syndrome ≤ 3.0 × ULN)
6. AST and ALT \< 2.5 × ULN (\< 5 × ULN if liver metastasis)
7. APTT and INR \< 1.5 × ULN Women of childbearing potential: negative serum pregnancy test within 7 days before randomization. All participants with reproductive potential (male and female) must agree to use highly effective contraception (hormonal, barrier, or abstinence) during treatment and for 6 months after last dose. Willing and able to comply with scheduled visits, treatment, labs, and procedures.
Exclusion Criteria:
* History of severe cardiovascular or cerebrovascular disease, including but not limited to: clinically significant cardiac rhythm or conduction abnormality (e.g., ventricular arrhythmia requiring intervention, 2nd-3rd degree AV block); acute coronary syndrome, congestive heart failure, aortic dissection, severe stable/unstable angina, coronary/peripheral vascular intervention, stroke or other ≥Grade 3 cerebrovascular event (including TIA), pulmonary embolism, DVT or other clinically significant thrombosis within 6 months before randomization; NYHA \> Class II heart failure or LVEF \< 50%; any uncontrolled atrial fibrillation; QTcF \> 470 ms or symptomatic bradycardia \< 45 bpm; known congenital long QT syndrome or history of QT prolongation.
Active infection requiring IV antibiotics or hospitalization at randomization. Acute flare of dysphagia or GI disease affecting absorption (Crohn's, UC, short bowel syndrome, or other malabsorption).
Failure to recover from prior antitumor therapy toxicity to baseline or ≤Grade 1 (CTCAE v5.0), except alopecia, Grade 2 peripheral neuropathy, or hypothyroidism controlled by replacement judged safe by investigator.
Major surgical procedure (other than dx/biopsy/drainage) within 4 weeks before randomization, or anticipated major surgery during study; vascular access placement and minor procedures (catheter, core needle biopsy) allowed.
Other primary malignancy except: adequately treated melanoma/skin carcinoma/cervical carcinoma in situ; treated non-metastatic prostate cancer; or other primary malignancy with no relapse ≥3 years.
Untreated spinal cord compression by tumor. Participated in another interventional trial within 4 weeks before first dose (screen failures exempt).
Interstitial fibrosis, ILD, or drug-induced pneumonitis within 6 months before first dose not recovered to Grade 1 (asymptomatic radiation pneumonitis exempt).
Systemic anticancer therapy (chemo-based or other) within 14 days or 5 half-lives (whichever shorter, minimum 14 days) before randomization.
Clinically uncontrolled serous effusion needing drainage \> once/month (pericardial/pleural/ascites), or \< 2 weeks observation after last drainage before randomization.
History of severe allergy or hypersensitivity to JYP0322 or crizotinib excipients.
Active HBV (HBsAg+ and HBV DNA ≥1000 IU/mL or 5000 copies/mL), active HCV (RNA+), syphilis requiring treatment (RPR ≤1:2 with TPHA+ allowed), or HIV infection.
Pregnant or lactating. Use of strong CYP3A4 inhibitors/inducers or narrow-therapeutic-index CYP3A4 substrates within 14 days or 5 half-lives (shorter) before randomization, or inability to discontinue during study.
Active or recurrent autoimmune disease, depression/affective disorder or suicidal risk, prior bone marrow/organ transplant, or any condition investigator judges unsafe.
Uncontrolled hyperthyroidism or hypothyroidism with prior severe comorbidity. Moderate-to-severe hepatic impairment history: prior ≥Grade 3 hepatotoxicity, or serious liver baseline (cirrhosis etc.).
Tumor invasion of great vessels (aorta, pulmonary artery/vein, vena cava) on imaging; OR any prior TKI therapy including ROS1-TKI.
