Sacituzumab Tirumotecan in Combination With Anlotinib in Previously Treated Patients With Extensive-Stage Small Cell Lung Cancer (ES-SCLC)

Sacituzumab Tirumotecan in Combination With Anlotinib in Previously Treated Patients With Extensive-Stage Small Cell Lung Cancer (ES-SCLC): A Prospective, Single-Arm, Phase II Study (STAR-01)

This is an single-arm, multicenter phase II study to evaluate the safety and efficacy of Sacituzumab Tirumotecan (sac-TMT) plus anlotinib in previously treated extensive-stage small cell lung cancer (ES-SCLC). The study is expected to enroll up to 33 eligible patients.

Extensive-stage small cell lung cancer (ES-SCLC) is among the most aggressive lung cancer subtypes, with rapid progression and poor prognosis. Despite first-line immunotherapy plus chemotherapy improving outcomes, most patients relapse within one year and face limited options. Topotecan, the standard second-line therapy, yields only 10-20% ORR and median PFS of ~3 months. Therefore, identifying novel therapeutic strategies with improved efficacy in ES-SCLC represent an urgent unmet medical need.

Sacituzumab tirumotecan, a structurally optimized Trop-2-directed ADC, and anlotinib, a multi-target TKI inhibiting VEGFR, FGFR, and MET, offer complementary mechanisms of action. We hypothesize that their combination may synergistically overcome acquired resistance to chemotherapy and immunotherapy, providing a novel therapeutic strategy for previously treated ES-SCLC.

Eligible participants will receive Sacituzumab Tirumotecan (4mg/Kg intravenously on Day 1, Q2W) plus Anlotinib (8 mg orally once daily on Days 1-14, Q3W). The primary objective is Objective Response Rate (ORR), and the secondary objectives including but not limited Progression-Free Survival (PFS), Overall Survival (OS) and Disease control response (DCR) .

Inclusion Criteria:

• 1.Voluntary participation with written informed consent obtained prior to any study-specific procedures.
• 2.Age ≥ 18 years and ≤ 75 years, regardless of sex.
• 3.Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1.
• 4.Life expectancy of at least 3 months.
• 5.Histologically or cytologically confirmed small cell lung cancer (SCLC) based on pathology and immunohistochemistry/immunophenotyping results; disease staged as extensive-stage SCLC (ES-SCLC) according to the Veterans Administration Lung Study Group (VALG) staging system.
• 6.Disease progression (at the time of enrollment) after at least two cycles of platinum-based systemic therapy with or without PD-1/L1 inhibitors; no more than two prior lines of therapy.

Note: Adjuvant therapy is considered one prior line if disease progression occurs during treatment or within 6 months of the last adjuvant dose.

• 7.At least one measurable lesion as defined by RECIST version 1.1. Lesions previously treated with local therapy may be considered target lesions only if progression has been clearly documented at that site post-treatment. Brain lesions as sole target lesions are not acceptable.
• 8.Adequate bone marrow function without transfusion or growth factor support within 14 days prior to screening: Absolute neutrophil count (ANC) ≥ 1.5 × 10⁹/L; Platelet count ≥ 100 × 10⁹/L; Hemoglobin ≥ 90 g/L.
• 9.Adequate hepatic function: Total bilirubin (TBIL) ≤ 1.5 × upper limit of normal (ULN), or ≤ 2 × ULN for patients with Gilbert's syndrome; TBIL ≤ 3.0 × ULN is permitted if direct bilirubin suggests extrahepatic obstruction. Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) ≤ 3 × ULN (or ≤ 5 × ULN in the presence of liver metastases).
• 10.Adequate renal function: Creatinine (Cr) ≤ 1.5 × ULN and creatinine clearance (Ccr) ≥ 50 mL/min (calculated by Cockcroft-Gault formula or other clinically validated method).
• 11.Adequate coagulation function: Activated partial thromboplastin time (APTT) ≤ 1.5 × ULN; International normalized ratio (INR) ≤ 1.5 × ULN;
• 12.Adequate cardiac function: Left ventricular ejection fraction (LVEF) ≥ 50% assessed by echocardiography within 28 days prior to enrollment. New York Heart Association (NYHA) classification < 3.
• 13.Female patients of childbearing potential must agree to use medically effective contraception from the time of signing informed consent until 6 months after the last dose of study treatment.

Exclusion Criteria:

• 1.History of other primary malignancies within 5 years prior to signing informed consent, except for: radically treated malignancies with no recurrence within 5 years; adequately treated non-melanoma skin cancer, cervical carcinoma in situ, thyroid cancer, or other malignancies considered cured.
• 2.Prior pathological diagnosis of combined small cell lung cancer (e.g., mixed SCLC and NSCLC), transformed NSCLC (SCLC transformed to NSCLC), or transformed SCLC (NSCLC transformed to SCLC).
• 3.Prior anti-tumor therapy within specified washout periods before first study dose: chemotherapy, radiotherapy, biologics, endocrine therapy, immunotherapy within 4 weeks; topical anti-tumor agents within 5 half-lives; nitrosoureas or mitomycin C within 6 weeks; oral fluoropyrimidines or small-molecule targeted agents within 5 half-lives; anti-tumor traditional Chinese medicine within 2 weeks.
• 4.Treatment with any other investigational drug or therapy within 4 weeks prior to first study dose.
• 5.Prior or current use of topoisomerase I inhibitors, including antibody-drug conjugates with topoisomerase I inhibitor payloads (e.g., topotecan, irinotecan, trastuzumab deruxtecan, sacituzumab govitecan, datopotamab deruxtecan [DS-1062]).
• 6.Brain metastases unless asymptomatic (stable for ≥4 weeks, requiring ≤10 mg/day prednisone or equivalent for ≥14 days prior to first dose, and no significant peritumoral edema on imaging); leptomeningeal or brainstem metastases; spinal cord compression (radiographically confirmed, symptomatic or asymptomatic); bone marrow metastases.
• 7.Imaging evidence of tumor lesions located ≤5 mm from major blood vessels, invading major vessels, or assessed by the investigator as having high risk of major bleeding during the study.
• 8.History of deep vein or arterial thromboembolic events within 6 months (e.g., cerebrovascular accident including TIA, deep vein thrombosis, pulmonary embolism); DVT adequately treated or superficial vein thrombosis with low bleeding risk per investigator may be enrolled.
• 9.Prior treatment-related toxicities (CTCAE v5.0) ≥ Grade 2, except for alopecia, residual neurotoxicity, or stable hypothyroidism on hormone replacement.
• 10.Major surgery (excluding biopsy or vascular access) or significant trauma within 4 weeks prior to first study dose, or planned elective surgery during the study period.
• 11.Receipt of live or live-attenuated vaccines within 4 weeks prior to first study dose.
• 12.Systemic corticosteroids (prednisone >10 mg/day or equivalent) or other immunosuppressive agents within 14 days prior to first study dose, except for: topical, ocular, intra-articular, intranasal, or inhaled corticosteroids; short-term corticosteroids for prophylaxis (e.g., contrast allergy).
• 13.History of non-infectious interstitial lung disease/pneumonitis requiring steroid maintenance (requiring 14-day washout), current ILD, or suspected ILD not ruled out by imaging at screening.
• 14.Active tuberculosis; active or uncontrolled autoimmune disease; acquired or congenital immunodeficiency disorders; history of allogeneic stem cell, bone marrow, or solid organ transplantation.
• 15.Serious infection within 4 weeks prior to first study dose, including but not limited to infection requiring systemic antibiotics, bacteremia, or severe pneumonia.
• 16.Positive serology results: HIV antibody positive; untreated active hepatitis B (HBsAg positive with HBV-DNA > ULN); Note: Patients meeting certain criteria may be enrolled with antiviral prophylaxis/monitoring; HCV-Ab positive with detectable HCV-RNA.
• 17.Significant cardiovascular disease history, including but not limited to: severe cardiac arrhythmia or conduction abnormalities (e.g., requiring intervention, Mobitz II or third-degree AV block); QTcF >450 ms (male) or >470 ms (female); congestive heart failure (NYHA class ≥II), unstable angina, acute coronary syndrome, aortic dissection, stroke or TIA within 6 months; deep vein thrombosis or pulmonary embolism within 6 months (excluding catheter-related or superficial thrombosis); uncontrolled hypertension (systolic >160 mmHg and/or diastolic >100 mmHg).
• 18.Clinically uncontrolled third-space fluid collections (e.g., pleural or ascitic effusion requiring intervention; patients with stable effusions >1 week post-drainage may enroll); pericardial effusion (asymptomatic minimal effusion not requiring intervention may enroll). If intra-cavity anti-tumor agents were used, a washout of ≥5 half-lives or 4 weeks (whichever is shorter) is required.
• 19.Known hypersensitivity or delayed allergic reaction to any component of the study drugs or comparators (e.g., topotecan, irinotecan, paclitaxel monotherapy).
• 20.Substance abuse, alcohol/drug dependence, or any medical condition (e.g., anxiety, depression) that may interfere with study participation or outcomes per investigator judgment.
• 21.Pregnant or breastfeeding women; men or women planning to conceive during the study.
• 22.Expected poor compliance, or any other severe systemic disease or condition that, in the investigator's opinion, makes the patient unsuitable for this study.
• 23.Bleeding diathesis (e.g., active peptic ulcer) or requirement for anticoagulants/vitamin K antagonists (e.g., warfarin, heparin); low-dose prophylactic warfarin (≤1 mg/d), heparin (≤12,000 U/d), or aspirin (≤100 mg/d) permitted if INR ≤1.5. Imaging evidence of tumor invasion, significant necrosis, or cavitation with high bleeding risk per investigator.
• 24.Any severe or uncontrolled systemic disease, including but not limited to: active tuberculosis/pulmonary fibrosis; active or uncontrolled infection requiring systemic therapy; clinically active diverticulitis, intra-abdominal abscess, GI obstruction; liver disease (e.g., cirrhosis, decompensated liver disease, acute/chronic hepatitis); poorly controlled diabetes (two consecutive FBG >10 mmol/L); urine protein ≥2+ confirmed by 24-hour urine protein >1.0 g; uncontrolled hypercalcemia (>1.5 mmol/L ionized calcium or >12 mg/dL calcium or corrected serum calcium >ULN) or symptomatic hypercalcemia requiring bisphosphonates; non-healing wounds or fractures; psychiatric disorders interfering with treatment compliance.
• 25.Factors affecting oral drug absorption (e.g., inability to swallow, post-, chronic diarrhea, intestinal obstruction).
• 26.Documented severe dry eye syndrome, severe meibomian gland disease and/or blepharitis, or history of corneal disease affecting/delaying corneal healing.
• 27.Any other condition deemed unsuitable for participation by the investigator.