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

A Multicenter Clinical Study Evaluating the Efficacy and Safety of Sacituzumab Tirumotecan Combined With Anlotinib as Second-Line Treatment for Patients With Driver Gene-Negative Locally Advanced or Metastatic Non-Squamous Non-Small Cell Lung Cancer

The goal of this clinical trial is to evaluate whether sacituzumab govitecan (TROP2 antibody-drug conjugate) in combination with anlotinib (multi-target tyrosine kinase inhibitor) can improve treatment efficacy and safety in patients with driver gene-negative locally advanced or metastatic non-squamous non-small cell lung cancer (nsq-NSCLC) after failure of first-line immunotherapy combined with platinum-based chemotherapy.

The main questions it aims to answer are:

Can the combination of sacituzumab govitecan and anlotinib improve progression-free survival (PFS) compared to historical second-line chemotherapy outcomes? What is the objective response rate (ORR) and safety profile of this combination therapy in this patient population? Can baseline multi-omics biomarkers (metabolomics, proteomics, and ctDNA genomics) predict response or resistance to sacituzumab govitecan?

If there is a comparison group:

This is an exploratory single-arm study, and outcomes will be compared with historical controls of second-line chemotherapy in similar patient populations.

Participants will:

Receive sacituzumab govitecan combined with anlotinib according to the study treatment schedule Undergo routine imaging evaluations to assess tumor response Provide peripheral blood samples before treatment for metabolomic, proteomic, and ctDNA genomic analyses Be monitored regularly for treatment response and adverse events

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.

Inclusion Criteria:

1. Age ≥18 years, regardless of gender.
2. 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.
3. No known driver gene alterations such as EGFR, ALK, ROS1, NTRK, BRAF, MET, KRAS, HER2, RET, etc.
4. At least one measurable target lesion not previously irradiated, assessed by the investigator per RECIST v1.1.
5. ECOG performance status score of 0 or 1.
6. Asymptomatic or locally treated and stable brain metastases are allowed.
7. Life expectancy ≥ 12 weeks.
8. Adequate organ and bone marrow function.
9. Agreement to use effective medical contraception from signing informed consent until 6 months after the last dose.
10. Voluntary participation, signed informed consent, and ability to comply with the protocol.

Exclusion Criteria:

1. Tumors histologically or cytologically confirmed with mixed small cell lung cancer, squamous cell carcinoma, neuroendocrine carcinoma, or carcinosarcoma components.
2. Prior treatment with TROP2-targeted therapy or any drug targeting topoisomerase I (including ADCs).
3. Known meningeal, brainstem, spinal cord metastases and/or compression, or active central nervous system (CNS) metastases.
4. 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.).
5. 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).
6. Poorly controlled hypertension (systolic > 160 mmHg and/or diastolic > 100 mmHg).
7. History of (non-infectious) interstitial lung disease (ILD) or non-infectious pneumonitis requiring steroid treatment, or current active/suspected ILD/pneumonitis.
8. Documented severe dry eye syndrome, severe meibomian gland disease and/or blepharitis, or corneal disease preventing/delaying healing.
9. Active chronic inflammatory bowel disease, gastrointestinal obstruction, severe ulcer, gastrointestinal perforation, abdominal abscess, or acute gastrointestinal bleeding.
10. Risk of esophageal-tracheal or esophageal-pleural fistula.
11. Tumors invading major blood vessels or high risk of fatal bleeding.
12. Bleeding symptoms or any ≥CTCAE grade 3 bleeding event with unhealed wounds, ulcers, or fractures within 1 month prior to first dose.
13. Known active tuberculosis.
14. History of allogeneic organ transplant or allogeneic hematopoietic stem cell transplant.
15. HIV positive, history of AIDS, or active syphilis infection.
16. Major surgery within 4 weeks prior to dosing or planned major surgery during the study.
17. Current use of strong CYP3A4 inducers (must be avoided at least 3 weeks prior).
18. Live vaccine within 30 days prior to dosing or planned during the study.
19. Pregnant or lactating women.
20. Any condition that, in the investigator's opinion, interferes with the evaluation of the study drug or compromises subject safety.