Efficacy and Safety of SKB264 Plus Anlotinib in EGFR-TKI-Resistant Advanced NSCLC With Liver Metastasis

Efficacy and Safety of SKB264 Plus Anlotinib in EGFR-TKI-Resistant Advanced NSCLC With Liver Metastasis

The goal of this clinical trial is to learn if the combination therapy with SKB264 and anlotinib works to treat EGFR-TKI-resistant, liver-metastatic non-squamous non-small cell lung cancer (NSCLC). It will also learn about the safety of the combination therapy with SKB264 and anlotinib. The main questions it aims to answer are:

Does combination therapy with SKB264 and anlotinib increase response rate and disease control rate, prolong duation of response and progressioin-free survival.

What medical problems do participants have when taking combination therapy with SKB264 and anlotinib? Researchers will compare combination therapy with SKB264 and anlotinib to a historical data (the response rate of other drugs reported in literature) to see if combination therapy with SKB264 and anlotinib works better to treat EGFR-TKI-resistant, liver-metastatic non-squamous non-small cell lung cancer (NSCLC).

Participants will:

1. receive SKB264 4 mg/kg intravenously on a 14-day cycle, and take anti-H1/H2 antihistamines, acetaminophen, and dexamethasone is recommended before infusion for the first 4 infusions to prevent side effects; the regimen may be simplified starting from the 5th infusion.
2. take anlotinib 10 mg orally once daily for 14 consecutive days, followed by a 7-day rest period.
3. Visit the clinic once every week for checkups and tests

This study is a prospective, multicenter, single-arm, phase II clinical trial to evaluate the efficacy and safety of combination therapy with SKB264 and anlotinib in patients with EGFR-TKI-resistant, liver-metastatic non-squamous non-small cell lung cancer (NSCLC).

Inclusion critiera

To be eligible for this study, participants must meet all of the following criteria:

1. Aged ≥ 18 years, both male and female;

2. ECOG performance status score of 0-1;

3. Histologically or cytologically confirmed non-small cell lung cancer (NSCLC) that is locally advanced (stage IIIB/IIIC) or metastatic (stage IV) and not amenable to curative surgery and/or curative radiotherapy (with or without concurrent chemotherapy), according to the IASLC 9th edition lung cancer TNM staging system.

4. At least one measurable target lesion in the liver (according to RECIST version 1.1);

5. Has previously received EGFR-TKI therapy for locally advanced or metastatic NSCLC with treatment failure (radiographic disease progression)；

6. Life expectancy ≥12 weeks.

7. Adequate organ and bone marrow function (without receiving blood transfusion, recombinant human thrombopoietin, or colony-stimulating factor therapy within 2 weeks prior to the first dose), defined as follows:

   1. Complete blood count: absolute neutrophil count (NEUT#) ≥ 1.5 × 10⁹/L; platelet count (PLT) ≥ 100 × 10⁹/L; hemoglobin ≥ 9 g/dL;
   2. Liver function: aspartate aminotransferase (AST), alanine aminotransferase (ALT), alkaline phosphatase (ALP) ≤ 2.5 × upper limit of normal (ULN); total bilirubin (TBIL) ≤ 1.5 × ULN;
   3. Renal function: creatinine clearance (Ccr) ≥ 60 mL/min (Cockcroft-Gault formula see appendix);
   4. Cardiac function: left ventricular ejection fraction (LVEF) ≥ 50% as assessed by echocardiography (ECHO) or multigated acquisition (MUGA) scan;

8. Female participants of childbearing potential and male participants with partners of childbearing potential must use a medically approved contraceptive method (e.g., intrauterine device, contraceptive pills, or condoms) during the study treatment period and for 6 months after the last dose;

9. Participants voluntarily enroll in this study, sign the informed consent form, have good compliance, and cooperate with follow-up visits.

Exclusion critiera

Participants who meet any of the following criteria will not be enrolled in this study:

1. Histologically or cytologically confirmed presence of small cell lung cancer, neuroendocrine carcinoma, or carcinosarcoma components;
2. Previous treatment with TROP2-targeted therapy and/or topoisomerase I inhibitors;
3. Has had other malignant tumors within the past 5 years, excluding cured cervical carcinoma in situ, basal cell carcinoma of the skin, or squamous cell carcinoma of the skin;
4. Known or screening-detected symptomatic active central nervous system (CNS) metastases or carcinomatous meningitis (Note: ① Patients who have been treated and have stable disease for ≥4 weeks and have discontinued systemic corticosteroids (at any dose) for >3 days may be enrolled. ② Patients with asymptomatic brain metastases (i.e., no neurological symptoms, no requirement for corticosteroids, and no lesion >1.5 cm) are eligible but require regular brain imaging as part of disease site evaluation)；
5. Known history of allergy to the study drugs or their components, history of immunodeficiency, or history of organ transplantation;
6. History of (non-infectious) interstitial lung disease (ILD) or non-infectious pneumonitis requiring steroid treatment; current ILD or non-infectious pneumonitis; or suspected ILD or non-infectious pneumonitis that cannot be ruled out by imaging at screening; clinically severe pulmonary impairment due to concurrent pulmonary diseases, including but not limited to any underlying pulmonary disease (e.g., pulmonary embolism within 3 months prior to dosing, severe asthma, severe chronic obstructive pulmonary disease, restrictive lung disease, pleural effusion, etc.) or any autoimmune, connective tissue, or inflammatory disease that may affect the lungs (e.g., rheumatoid arthritis, Sjögren's syndrome, sarcoidosis, etc.), or prior pneumonectomy;
7. Active infection requiring systemic therapy within 2 weeks prior to the first dose;
8. According to the investigator's judgment, presence of concomitant diseases that seriously jeopardize patient safety or affect the patient's ability to complete the study, including but not limited to hypertension uncontrolled by medication, severe diabetes, active infection, etc;
9. Occurrence of arterial/venous thrombotic events, such as cerebrovascular accident (including transient ischemic attack, cerebral hemorrhage, cerebral infarction), deep vein thrombosis, and pulmonary embolism, within 12 weeks prior to signing the informed consent form;
10. Current active bleeding, or central lung cancer with potential for massive hemorrhage; or history of bleeding disorders (e.g., von Willebrand disease or hemophilia); clinically significant bleeding within 6 months prior to enrollment (e.g., gross hematuria, gastrointestinal bleeding, and hemoptysis); or receipt of therapeutic anticoagulants or aspirin within 14 days prior to enrollment;
11. Major surgical procedure, open biopsy, or significant traumatic injury within 28 days prior to enrollment, or minor surgical procedure within 7 days prior to enrollment;
12. Documented severe dry eye syndrome, severe meibomian gland disease and/or blepharitis, or a history of corneal disease that prevents or delays corneal healing;
13. Any other conditions that, in the investigator's opinion, make the patient unsuitable for participation in this study.

Intervention Patients will receive combination therapy with SKB264 and anlotinib until up to 2 years or until disease progression, death, intolerable toxicity, investigator-determined no further benefit, or patient withdrawal of consent.

1. SKB264 4 mg/kg intravenously on a 14-day cycle, and take anti-H1/H2 antihistamines, acetaminophen, and dexamethasone is recommended before infusion for the first 4 infusions to prevent side effects; the regimen may be simplified starting from the 5th infusion.
2. Anlotinib 10 mg orally once daily for 14 consecutive days, followed by a 7-day rest period.

No comparison.

Outcomes The primary endpoint is the investigator -assessed objective response rate (ORR) according to the Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1. Secondary endpoints include investigator -assessed disease control rate (DCR), duration of response (DOR), time to response (TTR), progression-free survival (PFS) according to Response RECIST v1.1; overall survival (OS); quality of life; incidence and severity of adverse events (AEs) and serious adverse events (SAEs) as assessed by the investigator according to the Common Terminology Criteria for Adverse Events (CTCAE) version 5.0; as well as laboratory tests, ECG, physical examination, and vital signs.

Sample size Sample size was calculated using Simon's two-stage optimal design. Based on retrospective studies and real-world analyses in the general population, the salvage treatment ORR after progression on EGFR-TKI and platinum-based chemotherapy ranges from 0% to 14.1%, with a higher ORR of 20%-30% in the second-line setting. Since this study enrolls both second-line and third-line patients, H₀ is set at an intermediate value. The expected ORR of SKB264 combined with anlotinib is anticipated to increase from the historical control of 20% to 45%, with a one-sided alpha of 0.05 and a power of 80%. Based on Simon's two-stage optimal design, the calculated sample size is N=22. Accounting for a 20% loss to follow-up rate, the expected sample size is 27.

Using Simon's two-stage optimal design: In the first stage, 10 paticipants will be enrolled. If ≤2 participants achieve partial response (PR) or complete response (CR), the study will be terminated. If >2 participants achieve PR or CR, the study proceeds to the second stage. In the second stage, an additional 12 participants will be enrolled, bringing the total to 22 subjects. If >7 out of the 22 subjects achieve PR or CR, the study will be considered successful.

Statistical Analysis Statistical analyses will be performed using SAS version 9.4 or higher. Descriptive statistics will be used to summarize baseline characteristics, demographic data, dosing information, and other features of the subjects. Unless otherwise specified, continuous variables will be described by number of cases, mean, standard deviation, maximum, minimum, and median; categorical variables will be described by number of cases and percentages.

The number and percentage of subjects experiencing treatment-emergent adverse events, study drug-related adverse events, and serious adverse events will be summarized, and all adverse events will be listed.

The primary endpoint is investigator-assessed ORR. The best overall response (BOR) will be summarized. The 95% confidence interval (CI) for ORR will be calculated using the Clopper-Pearson method. Progression-free survival (PFS) and overall survival (OS) will be analyzed using the Kaplan-Meier (K-M) method, with median estimates and 95% CIs provided, and corresponding K-M curves will be plotted. Descriptive statistics for time to response (TTR) will also be presented.

Final Analysis The final analysis of the study will be conducted after all subjects have experienced investigator-assessed radiographic disease progression per RECIST 1.1 criteria or have discontinued treatment due to intolerance.

Study schedule and assessment The study schedule includes a screening period (Day -28 to -1), followed by treatment cycles (each cycle of 14 days). During the first 12 weeks of treatment, tumor assessments are performed every 6 weeks; after 12 weeks, every 8 weeks; and after 48 weeks, every 12 weeks. Study visits occur on Day 1 of each cycle, with additional safety assessments on Day 8 (±3 days) of each cycle. A 7-day post-dose safety check is performed after Cycle 1 and Cycle 2. At the end of treatment, an end-of-treatment visit is conducted, followed by safety follow-up at 30 and 60 days after the last dose, and then survival follow-up every 12 weeks thereafter. Procedures include vital signs, physical examination, ECOG PS, ECG, laboratory tests (CBC, blood chemistry, urinalysis, coagulation, cardiac enzymes), adverse event monitoring, concomitant medication recording, and survival status tracking.

Inclusion Criteria:

To be eligible for this study, participants must meet all of the following criteria:

1. Aged ≥ 18 years, both male and female;

2. ECOG performance status score of 0-1;

3. Histologically or cytologically confirmed non-small cell lung cancer (NSCLC) that is locally advanced (stage IIIB/IIIC) or metastatic (stage IV) and not amenable to curative surgery and/or curative radiotherapy (with or without concurrent chemotherapy), according to the IASLC 9th edition lung cancer TNM staging system.

4. At least one measurable target lesion in the liver (according to RECIST version 1.1);

5. Has previously received EGFR-TKI therapy for locally advanced or metastatic NSCLC with treatment failure (radiographic disease progression)；

6. Life expectancy ≥12 weeks.

7. Adequate organ and bone marrow function (without receiving blood transfusion, recombinant human thrombopoietin, or colony-stimulating factor therapy within 2 weeks prior to the first dose), defined as follows:

   1. Complete blood count: absolute neutrophil count (NEUT#) ≥ 1.5 × 10⁹/L; platelet count (PLT) ≥ 100 × 10⁹/L; hemoglobin ≥ 9 g/dL;
   2. Liver function: aspartate aminotransferase (AST), alanine aminotransferase (ALT), alkaline phosphatase (ALP) ≤ 2.5 × upper limit of normal (ULN); total bilirubin (TBIL) ≤ 1.5 × ULN;
   3. Renal function: creatinine clearance (Ccr) ≥ 60 mL/min (Cockcroft-Gault formula see appendix);
   4. Cardiac function: left ventricular ejection fraction (LVEF) ≥ 50% as assessed by echocardiography (ECHO) or multigated acquisition (MUGA) scan;

8. Female participants of childbearing potential and male participants with partners of childbearing potential must use a medically approved contraceptive method (e.g., intrauterine device, contraceptive pills, or condoms) during the study treatment period and for 6 months after the last dose;

9. Participants voluntarily enroll in this study, sign the informed consent form, have good compliance, and cooperate with follow-up visits.

Exclusion Criteria:

Participants who meet any of the following criteria will not be enrolled in this study:

1. Histologically or cytologically confirmed presence of small cell lung cancer, neuroendocrine carcinoma, or carcinosarcoma components;
2. Previous treatment with TROP2-targeted therapy and/or topoisomerase I inhibitors;
3. Has had other malignant tumors within the past 5 years, excluding cured cervical carcinoma in situ, basal cell carcinoma of the skin, or squamous cell carcinoma of the skin;
4. Known or screening-detected symptomatic active central nervous system (CNS) metastases or carcinomatous meningitis (Note: ① Patients who have been treated and have stable disease for ≥4 weeks and have discontinued systemic corticosteroids (at any dose) for >3 days may be enrolled. ② Patients with asymptomatic brain metastases (i.e., no neurological symptoms, no requirement for corticosteroids, and no lesion >1.5 cm) are eligible but require regular brain imaging as part of disease site evaluation)；
5. Known history of allergy to the study drugs or their components, history of immunodeficiency, or history of organ transplantation;
6. History of (non-infectious) interstitial lung disease (ILD) or non-infectious pneumonitis requiring steroid treatment; current ILD or non-infectious pneumonitis; or suspected ILD or non-infectious pneumonitis that cannot be ruled out by imaging at screening; clinically severe pulmonary impairment due to concurrent pulmonary diseases, including but not limited to any underlying pulmonary disease (e.g., pulmonary embolism within 3 months prior to dosing, severe asthma, severe chronic obstructive pulmonary disease, restrictive lung disease, pleural effusion, etc.) or any autoimmune, connective tissue, or inflammatory disease that may affect the lungs (e.g., rheumatoid arthritis, Sjögren's syndrome, sarcoidosis, etc.), or prior pneumonectomy;
7. Active infection requiring systemic therapy within 2 weeks prior to the first dose;
8. According to the investigator's judgment, presence of concomitant diseases that seriously jeopardize patient safety or affect the patient's ability to complete the study, including but not limited to hypertension uncontrolled by medication, severe diabetes, active infection, etc;
9. Occurrence of arterial/venous thrombotic events, such as cerebrovascular accident (including transient ischemic attack, cerebral hemorrhage, cerebral infarction), deep vein thrombosis, and pulmonary embolism, within 12 weeks prior to signing the informed consent form;
10. Current active bleeding, or central lung cancer with potential for massive hemorrhage; or history of bleeding disorders (e.g., von Willebrand disease or hemophilia); clinically significant bleeding within 6 months prior to enrollment (e.g., gross hematuria, gastrointestinal bleeding, and hemoptysis); or receipt of therapeutic anticoagulants or aspirin within 14 days prior to enrollment;
11. Major surgical procedure, open biopsy, or significant traumatic injury within 28 days prior to enrollment, or minor surgical procedure within 7 days prior to enrollment;
12. Documented severe dry eye syndrome, severe meibomian gland disease and/or blepharitis, or a history of corneal disease that prevents or delays corneal healing;
13. Any other conditions that, in the investigator's opinion, make the patient unsuitable for participation in this study.