A Multicenter Exploratory Clinical Study of Iruplaltinib Combined With Pemetrexed as Neoadjuvant Therapy for Resectable ALK-Positive Non-Squamous Non-Small Cell Lung Cancer

A Multicenter Exploratory Clinical Study of Iruplaltinib Combined With Pemetrexed as Neoadjuvant Therapy for Resectable ALK-Positive Non-Squamous Non-Small Cell Lung Cancer

This is a single-arm clinical study planning to enroll 30 treatment-naive patients with resectable ALK-positive non-squamous non-small cell lung cancer (NSCLC). The study consists of two phases: a safety lead-in phase and an expansion phase.

Safety Lead-in Phase A total of 6 subjects will be enrolled and treated with the regimen: iruplaltinib 60 mg orally once daily on Days 1-7, followed by 180 mg orally once daily starting on Day 8, combined with pemetrexed 500 mg/m² intravenously every 3 weeks for one cycle (3 weeks).

Adopting the modified Toxicity Probability Interval-2 (mTPI-2) design with a target dose-limiting toxicity (DLT) rate of 30%, DLTs occurring within the 21-day observation period after the first dose among the 6 subjects will be evaluated. Unlike standard mTPI-2 design with decisions of "stay" or "escalate", if the decision in this safety lead-in phase is "stay" or "escalate", the lead-in phase will be completed and the study will proceed to the expansion phase. If the decision is "de-escalate" or "exclude this dose from the study", the study will be terminated.

Expansion Phase Eligible screened patients will receive iruplaltinib (60 mg po QD d1-7; then 180 mg po QD starting on Day 8) plus pemetrexed (500 mg/m² iv Q3W). Patients will receive 6 weeks of pre-operative treatment followed by curative resection, which is scheduled to be performed within 4 weeks after completion of neoadjuvant therapy. Patients with progressive disease (PD) will receive subsequent therapy such as alectinib or brigatinib at the investigator's discretion. Four weeks after curative surgery, patients will receive adjuvant iruplaltinib for up to 2 years.

Inclusion Criteria:

• Voluntarily participate in this study and provide written informed consent.
• Aged between 18 and 75 years inclusive.
• Histologically or cytologically confirmed non-squamous non-small cell lung cancer (NSCLC) via core needle biopsy; stage IIA-IIIB disease assessed by the investigator; confirmed ALK-positive status by genetic testing.
• Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1.
• The primary NSCLC is considered potentially completely resectable based on multidisciplinary team (MDT) evaluation, which must include a thoracic surgeon specialized in oncologic surgery.
• At least one measurable lesion per RECIST version 1.1.
• Expected survival duration ≥ 3 months.
• Able to swallow oral tablets intact.
• Pulmonary function sufficient to tolerate surgical resection.
• No administration of any blood products or hematopoietic growth factors within 14 days prior to the first study drug dose.
• Adequate function of other major organs (liver, kidney, hematologic system, etc.) meeting all of the following criteria: Absolute neutrophil count ≥ 1.5 × 10⁹/L; Platelet count ≥ 100 × 10⁹/L; Hemoglobin ≥ 90 g/L; Serum albumin ≥ 30 g/L; Total bilirubin (TBIL) ≤ 1.5 × upper limit of normal (ULN). For participants diagnosed with Gilbert's syndrome, TBIL ≤ 3.0 × ULN with direct bilirubin (DBIL) ≤ 1.5 × ULN; Alanine transaminase (ALT) and aspartate transaminase (AST) ≤ 2.5 × ULN; if liver metastases are present, ALT and AST ≤ 5 × ULN; Alkaline phosphatase (ALP) ≤ 2.5 × ULN; Serum creatinine ≤ 1.5 × ULN; Urine protein < 2+; if urine protein ≥ 2+, 24-hour urinary protein quantification ≤ 1 g; International normalized ratio (INR) ≤ 1.5 (for participants not receiving anticoagulant therapy).
• For women of childbearing potential without surgical sterilization: serum or urine human chorionic gonadotropin (HCG) test must be negative within 7 days before the first study dose. They must not be breastfeeding and must adopt a medically approved contraceptive method (e.g., intrauterine device, oral contraceptives, condoms) throughout study treatment and for 3 months after the last dose of study treatment.
• Men who have not undergone sterilization must agree to use effective contraception for at least 120 days during the study.

Exclusion Criteria:

• Prior receipt of any systemic anti-tumor therapy for NSCLC, including chemotherapy, biotherapy, immunotherapy or any investigational agent, or prior locoregional radiotherapy.
• Pathological diagnosis of mixed small cell lung cancer, small cell lung cancer, or squamous non-small cell lung cancer.
• History of malignancies other than NSCLC within 5 years prior to enrollment, except cured basal cell carcinoma of the skin, early gastrointestinal (GI) carcinoma resected endoscopically, cervical carcinoma in situ, ductal carcinoma in situ of the breast, papillary thyroid carcinoma, or any cured malignancy deemed not to affect survival related to current NSCLC.
• Participation in another clinical study or receiving other investigational products; or receipt of other investigational products within 4 weeks before the first dose of study drug. The interval from the last dose of other anti-tumor therapy to the first study drug is less than 2 weeks if the half-life ≤ 3 days, or less than 4 weeks if the half-life > 3 days.
• Presence of any unstable systemic disease (including uncontrolled diabetes, thyroid disorders, active infection, uncontrolled hypertension (systolic blood pressure ≥140 mmHg or diastolic blood pressure ≥90 mmHg despite antihypertensive treatment)).
• Any clinically significant cardiovascular or cerebrovascular disease within 6 months prior to the first study drug administration, such as unstable angina, congestive heart failure (NYHA Class II or higher), myocardial infarction, cerebrovascular accident (including transient ischemic attack).
• Atrial fibrillation or ventricular fibrillation of any grade; clinically significant supraventricular or ventricular arrhythmia requiring treatment or intervention; QTc >450 ms (male); QTc >470 ms (female). Use of drugs that may prolong QT interval or induce torsades de pointes within 14 days before the first dose or during the study.
• Pleural effusion, ascites or pericardial effusion requiring drainage. Patients may be enrolled if symptoms are assessed stable by the investigator after drainage.
• Congenital or acquired immunodeficiency (e.g., HIV infection).
• Use of corticosteroids (dose >10 mg/day prednisone or equivalent) within 2 weeks before enrollment, continuous corticosteroid use for more than 30 days, or requirement for long-term corticosteroids or other immunosuppressants.
• Positive hepatitis B surface antigen (HBsAg) with hepatitis B virus deoxyribonucleic acid (HBV DNA) ≥2000 IU/ml, or positive hepatitis C virus antibody.
• Risk of gastrointestinal perforation or bowel obstruction; presence of nausea, vomiting or diarrhea ≥Grade 1 (CTCAE Version 6.0); other gastrointestinal dysfunction or gastrointestinal diseases that may affect drug absorption, distribution, metabolism or excretion (e.g., ulcerative disorders or malabsorption syndrome).
• Receipt of other major surgical procedures (excluding diagnostic procedures) within 4 weeks prior to study initiation, or planned major surgery during the study.
• Known hypersensitivity to study drugs or any excipients.
• Unable to discontinue strong CYP3A4 inducers or inhibitors at least 1 week before study entry or requiring concomitant use of such agents during the study. Examples include but are not limited to carbamazepine, phenobarbital, phenytoin, rifabutin, rifampicin, rifapentine, tipranavir, ritonavir, St. John's Wort, ketoconazole. Unable to discontinue drugs mainly metabolized by CYP3A4 with narrow therapeutic index at least 1 week before study entry or requiring administration during the study, including but not limited to crizotinib, ceritinib, alectinib, erythromycin, atorvastatin.
• Administration of live vaccines within 4 weeks prior to study treatment or planned live vaccination during the study.
• Previous history of extensive bilateral diffuse interstitial fibrosis, or known Grade 3 or 4 interstitial fibrosis / interstitial lung disease, including pneumonitis, hypersensitivity pneumonitis, interstitial pneumonia, bronchiolitis obliterans and pulmonary fibrosis. History of localized radiation pneumonitis or radiation pulmonary fibrosis is excluded.
• Pregnant or breastfeeding women.
• Illicit drug use, chronic alcohol abuse or other harmful addictions; neurological or psychiatric disorders leading to poor compliance.
• Other conditions deemed inappropriate for enrollment at the investigator's discretion.