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

1. 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.
2. 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.
3. 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.
4. 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.
5. 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.