Neoadjuvant Iruplinalkib and Bevacizumab in ALK-positive NSCLC: A Phase II Single-arm Trial

• Bevacizumab combined with iruplinalkib as neoadjuvant therapy in ALK-positive NSCLC: (Drug): Eligible patients receive 4 cycles (Q3W) of bevacizumab (15 mg/kg IV on D1) plus iruplinalkib (60 mg oral lead-in for 7 days, then 180 mg daily). Surgery is performed 4 weeks after neoadjuvant therapy, followed by adjuvant iruplinalkib monotherapy for up to 2 years (starting within 4-8 weeks post-surgery), continued until progression, unacceptable toxicity, or loss of benefit.

Primary outcomes

• Pathological complete response (pCR) rate [up to 30 months]: The proportion of subjects undergoing lung cancer resection who have no residual viable tumor cells in both the postoperative tumor bed and lymph nodes.

Secondary outcomes

• Progression-free survival (PFS) [up to 40 months]: Time from enrollment to tumor progression or death from any cause, whichever occurs first.

Sex: All, ages: 18 Years to 80 Years

Inclusion Criteria:

* Signed informed consent.

Age 18-80 years, both sexes.

Histologically or cytologically confirmed NSCLC.

Stage II-III NSCLC per investigator, and ALK-positive.

At least one measurable lesion per RECIST 1.1.

ECOG performance status 0-1.

Adequate organ and bone marrow function (within 7 days before first dose, no transfusion or growth factor support within 14 days):

Hb ≥90 g/L, ANC ≥1.5×10⁹/L, PLT ≥90×10⁹/L;

Cr ≤1.5×ULN; TBIL ≤1.5×ULN; ALT/AST ≤3.0×ULN (or ≤5.0×ULN if liver metastases), ALB ≥25 g/L;

INR ≤1.5×ULN, PT/APTT ≤1.5×ULN (or within therapeutic range for anticoagulated patients).

FEV₁ >60% predicted.

Women of childbearing potential: negative pregnancy test (serum/urine) within 7 days before enrollment and use of reliable contraception from screening to 3 months after last study drug. Men: adequate contraception or surgically sterile.

Expected survival ≥12 weeks.

Exclusion Criteria:

* Hypersensitivity to iruplinalkib, bevacizumab, or any excipients.

Prior targeted therapy (TKI or mAb), immunotherapy, or investigational drugs for NSCLC.

Mixed small-cell and non-small-cell histology.

Other malignancy within 5 years, except cured basal cell carcinoma, early GI cancer (endoscopically resected), cervical CIS, DCIS, papillary thyroid cancer, or other cured cancers deemed not to affect survival.

Unstable systemic disease: active infection, uncontrolled hypertension (>160/110 mmHg), unstable angina or angina within 3 months, CHF (NYHA ≥II), MI within 6 months, clinically significant arrhythmia requiring treatment, or QTc >480 ms (average of 3 consecutive measurements if prolonged).

History of extensive diffuse interstitial lung disease or grade 3/4 pulmonary fibrosis/ILD (excluding localized radiation pneumonitis).

Congenital or acquired immunodeficiency (e.g., HIV).

Major surgery within 4 weeks before study treatment, or planned major surgery during study.

Inability to swallow tablets or malabsorption affecting GI absorption.

Known risk of GI perforation or intestinal obstruction.

Pregnant or lactating women.

Any other condition (e.g., alcohol/drug abuse, serious concomitant disease including psychiatric, severe laboratory abnormalities, or social factors) that, in the investigator's opinion, could interfere with study conduct or patient safety.

History of abdominal fistula, GI perforation, intra-abdominal abscess, or thrombotic disease within 6 months, or judged intolerant to bevacizumab.

Evidence of hereditary bleeding diathesis or coagulopathy.

Minor surgery (e.g., catheter placement) within 48 hours before first bevacizumab infusion.

Imaging evidence of tumor invasion of major vessels (e.g., pulmonary artery or SVC) with bleeding risk per investigator.

Other factors making the patient unsuitable for the study per investigator.