Second-Line Sacituzumab Tirumotecan Plus Anlotinib for Advanced Driver Gene-Negative Non-Squamous NSCLC

• Scientific Rationale and Hypotheses This study investigates the synergistic efficacy and safety of combining Lukang-sacituzumab (SKB264/MK-2870), a third-generation TROP2-directed antibody-drug conjugate (ADC), with Anlotinib, a multi-targeted tyrosine kinase inhibitor (TKI).

Mechanism of Synergy: Preclinical data suggest that anti-angiogenic agents like Anlotinib can "normalize" the tumor vasculature. This process reduces tumor interstitial fluid pressure and improves blood perfusion, which is hypothesized to enhance the delivery and intra-tumoral penetration of large-molecule ADCs like Lukang-sacituzumab.

Target Population Strategy: For driver-gene-negative non-squamous non-small cell lung cancer (nsq-NSCLC) patients who have progressed after first-line immuno-chemotherapy, there is a critical need for chemotherapy-free or novel cytotoxic-enhanced regimens. TROP2 is an ideal target due to its widespread overexpression in this histological subtype.

• Detailed Statistical Methodology (Simon's Two-Stage Optimal Design) The study utilizes a Simon's Two-Stage Optimal Design to minimize the number of subjects exposed to an potentially ineffective treatment (Type I error rate $\\alpha$ = 0.05, Power $1-\\beta$ = 0.80).

Stage 1 (Futility Assessment): Initially, 9 evaluable subjects will be enrolled. If 1 or 0 subjects achieve an objective response (CR or PR), the trial will be terminated early for lack of efficacy.

Stage 2 (Expansion): If 2 or more objective responses are observed in the first 9 subjects, enrollment will continue until a total of 38 evaluable subjects is reached.

Final Evaluation: At the completion of Stage 2, if 7 or more objective responses are observed across the total 38 subjects, the combination therapy will be considered to have sufficient clinical activity to warrant further phase III investigation.

• Treatment Administration and Strategy Lukang-sacituzumab Administration: Administered at a dose of 4 mg/kg via intravenous infusion on Day 1 of every 2-week cycle (Q2W). Premedication (e.g., antipyretics and antihistamines) may be administered per institutional guidelines to mitigate infusion-related reactions (IRRs).

Anlotinib Administration: Administered at a dose of 10 mg orally once daily, from Day 1 to Day 14 of every 3-week cycle (Q3W), followed by a 7-day rest period.

Dose Intensity Management: If the dosing schedules of the two drugs (Q2W vs Q3W) lead to logistical misalignment, the investigator may adjust the administration window by ±3 days to ensure patient compliance and safety.

• Safety Management and Toxicities of Interest

The protocol includes predefined management algorithms for adverse events (AEs) of special interest:

Hematologic Toxicities: Detailed protocols for the use of Granulocyte Colony-Stimulating Factor (G-CSF) are established for Grade 3/4 neutropenia. Lukang-sacituzumab will be delayed until the absolute neutrophil count (ANC) recovers to $\\geq 1.5 \\times 10^9/L$.

Anlotinib-Specific AEs: Mandatory blood pressure monitoring is required. For Grade 3 hypertension (refractory to medication), Anlotinib will be suspended and reduced by one dose level (e.g., 10mg $\\to$ 8mg).

Immune/ADC-Related Events: Specific monitoring for Interstitial Lung Disease (ILD) or pneumonitis through high-resolution CT (HRCT) scans. Any Grade 2 or higher ILD attributed to the ADC will result in permanent discontinuation.

• Exploratory Biomarker Research

To further understand the mechanisms of response and resistance, this study includes a mandatory translational research component:

Baseline and Longitudinal Testing: Collection of blood-based biomarkers (ctDNA, circulating proteins) at screening, Cycle 3, and at the time of disease progression (PD).

Correlation Analysis: Researchers will analyze the correlation between TROP2 expression levels (if archival tissue is available) and the depth of response, as well as the impact of multi-target inhibition on the tumor immune microenvironment.

Inclusion criteria

• Age ≥18 years, regardless of gender.
• Histologically or cytologically confirmed locally advanced (Stage IIIB/IIIC) or metastatic (Stage IV) non-squamous NSCLC, progressing after prior anti-PD-1/L1 monoclonal antibody combined with platinum-based doublet chemotherapy.
• No known driver gene alterations such as EGFR, ALK, ROS1, NTRK, BRAF, MET, KRAS, HER2, RET, etc.
• At least one measurable target lesion not previously irradiated, assessed by the investigator per RECIST v1.1.
• ECOG performance status score of 0 or 1.
• Asymptomatic or locally treated and stable brain metastases are allowed.
• Life expectancy ≥ 12 weeks.
• Adequate organ and bone marrow function.
• Agreement to use effective medical contraception from signing informed consent until 6 months after the last dose.
• Voluntary participation, signed informed consent, and ability to comply with the protocol.

Exclusion criteria

• Tumors histologically or cytologically confirmed with mixed small cell lung cancer, squamous cell carcinoma, neuroendocrine carcinoma, or carcinosarcoma components.
• Prior treatment with TROP2-targeted therapy or any drug targeting topoisomerase I (including ADCs).
• Known meningeal, brainstem, spinal cord metastases and/or compression, or active central nervous system (CNS) metastases.
• Other malignancies within 3 years prior to dosing (except locally cured tumors like basal cell carcinoma, squamous cell carcinoma of the skin, cervical carcinoma in situ, etc.).
• Presence of major cardiovascular diseases or risk factors within 6 months prior to dosing (e.g., myocardial infarction, severe arrhythmias, active myocarditis, major vascular disease requiring surgery).
• Poorly controlled hypertension (systolic > 160 mmHg and/or diastolic > 100 mmHg).
• History of (non-infectious) interstitial lung disease (ILD) or non-infectious pneumonitis requiring steroid treatment, or current active/suspected ILD/pneumonitis.
• Documented severe dry eye syndrome, severe meibomian gland disease and/or blepharitis, or corneal disease preventing/delaying healing.
• Active chronic inflammatory bowel disease, gastrointestinal obstruction, severe ulcer, gastrointestinal perforation, abdominal abscess, or acute gastrointestinal bleeding.
• Risk of esophageal-tracheal or esophageal-pleural fistula.
• Tumors invading major blood vessels or high risk of fatal bleeding.
• Bleeding symptoms or any ≥CTCAE grade 3 bleeding event with unhealed wounds, ulcers, or fractures within 1 month prior to first dose.
• Known active tuberculosis.
• History of allogeneic organ transplant or allogeneic hematopoietic stem cell transplant.
• HIV positive, history of AIDS, or active syphilis infection.
• Major surgery within 4 weeks prior to dosing or planned major surgery during the study.
• Current use of strong CYP3A4 inducers (must be avoided at least 3 weeks prior).
• Live vaccine within 30 days prior to dosing or planned during the study.
• Pregnant or lactating women.
• Any condition that, in the investigator's opinion, interferes with the evaluation of the study drug or compromises subject safety.