Advanced non-squamous non-small-cell lung cancer that has progressed after third-generation EGFR-TKI therapy
Conditions
Interventions
Dose-escalation cohort:AK112 (20 mg/kg Q3W) + pemetrexed combined with carboplatin + third-generation EGFR-TKI, after 4 cycles, maintenance treatment with AK112 (20 mg/kg Q3W) + pemetrexed +EGFR-TKI
Dose-expansion cohort:AK112 (20 mg/kg Q3W) + pemetrexed combined with carboplatin + third-generation EGFR-TKI, after 4 cycles, maintenance treatment with AK112 (20 mg/kg Q3W) + pemetrexed +EGFR-TKI
Sponsors
Zhejiang Cancer Hospital
Eligibility
Sex/Gender
All
Age
18 Years to 75 Years
Inclusion criteria
Inclusion criteria: 1. Voluntarily sign the written informed consent form. 2. Age >=18 years and =3 months. 5. Histologically or cytologically confirmed locally advanced (stage IIIB/IIIC) or metastatic (stage IV) non-squamous NSCLC (according to the 8th edition of the TNM staging system of the Union for International Cancer Control and the American Joint Committee on Cancer) that is not amenable to complete surgical resection and is not eligible for curative-intent concurrent/sequential chemoradiotherapy. 6. Confirmed presence of EGFR-sensitive mutations, including exon 19 deletion (19Del) and exon 21 L858R point mutation, by tumor histology, cytology, or hematology before enrollment. 7. Prior treatment with third-generation EGFR-TKIs (e.g., osimertinib, almonertinib, furmonertinib, etc.) and treatment failure. 8. At least one measurable lesion according to RECIST v1.1 that is suitable for repeated and accurate measurement; brain metastases cannot be used as target lesions. 9. Adequate organ function as determined by the following criteria (test results within 14 days before the start of study treatment are required): (1) Hematology (without any blood component or cell growth factor support therapy within 7 days before the start of study treatment): 1) Absolute neutrophil count (ANC) >=1.5×10^9/L; 2) Platelet count >=100×10^9/L; 3) Hemoglobin >=90 g/L. (2) Renal: 1) Serum creatinine (Cr) =50 mL/min; *CrCl will be calculated using the Cockcroft-Gault formula: CrCl (mL/min) = {(140-age) × body weight (kg) × F}/(SCr (mg/dL) × 72); where F = 1 for males, F = 0.85 for females; SCr = serum creatinine; 2) Urine protein =28 g/L. (4) Coagulation function: international normalized ratio (INR), and partial thromboplastin time (PTT) or activated partial thromboplastin time (APTT) =50%. 10. Female subjects of childbearing potential must have a negative urine or serum pregnancy test within 3 days before the first dose (if the urine pregnancy test cannot be confirmed as negative, a serum pregnancy test is required, and the serum result will prevail). If a female subject of childbearing potential has sexual intercourse with a non-sterilized male partner, she must use acceptable contraception from screening and must agree to continue using contraception for 120 days after the last dose of the study drug; whether to discontinue contraception after this time point should be discussed with the investigator. 11. If a non-sterilized male subject has sexual intercourse with a female partner of childbearing potential, he must use effective contraception from screening until 120 days after the last dose; whether to discontinue contraception after this time point should be discussed with the investigator. 12. Subjects are willing and able to comply with scheduled visits, treatment plans, laboratory
Exclusion criteria
Exclusion criteria: 1. Histological or cytological evidence of small cell carcinoma components, or predominantly squamous cell carcinoma. 2. Reports confirming the presence of other driver gene mutations with known targeted therapies. 3. Prior receipt of immunotherapy, including immune checkpoint inhibitors (e.g., anti-PD-1/L1 antibodies, anti-CTLA-4 antibodies, anti-LAG-3 antibodies, etc.), immune checkpoint agonists (e.g., ICOS, CD40, CD137, GITR, OX40 antibodies, etc.), immune cell therapy, or any other treatment targeting tumor immune mechanisms. 4. Prior systemic antitumor therapy other than EGFR-TKIs for advanced NSCLC (stage IIIB-IV), including cytotoxic chemotherapy used with radiotherapy, systemic chemotherapy, and anti-angiogenic therapy; for patients who have previously received adjuvant/neoadjuvant chemotherapy for non-metastatic disease with curative intent, enrollment is allowed if disease progression occurred >=6 months after the last chemotherapy cycle. 5. Concurrent enrollment in another clinical study, unless it is a non-interventional study or the follow-up phase of an interventional study (defined as the time from the first dose to the last dose of the previous study drug being >=4 weeks or >=5 half-lives of that drug, whichever is shorter). 6. Imaging at screening shows tumor encasement of major vessels, or significant necrosis or cavitation, and the investigator judges that study participation would carry a risk of bleeding. 7. Imaging at screening shows tumor invasion of surrounding vital organs and vessels (e.g., heart and pericardium, trachea, esophagus, aorta, superior vena cava, etc.) or risk of esophagotracheal fistula or esophagopleural fistula. 8. Symptomatic central nervous system metastases; for patients with asymptomatic brain metastases or those with stable symptoms after treatment of brain metastases for >=2 weeks before the first dose, participation is allowed if all the following criteria are met: no leptomeningeal, midbrain, pons, cerebellum, medulla, spinal cord metastases or spinal cord compression; no history of intracranial hemorrhage; discontinuation of hormone therapy for >2 weeks before the first dose; no significant perilesional edema; no brain metastasis with longest diameter >1.5 cm in prior history or concurrent disease. 9. Other malignancies other than NSCLC within 3 years before the first dose; subjects with other malignancies that have been cured by local therapy, such as basal or squamous cell carcinoma of the skin, superficial bladder cancer, or carcinoma in situ of the cervix or breast, are allowed. 10. Active autoimmune disease requiring systemic treatment (e.g., with disease-modifying agents, corticosteroids, immunosuppressants) within 2 years before the first dose (excluding irAE caused by PD-1/L1 inhibitors). Replacement therapy (e.g., thyroxine, insulin, or physiological corticosteroid replacement for adrenal or pituitary insufficiency) is not considered systemic therapy. 11. History of major diseases within 1 year before the first dose, specifically: unstable angina requiring hospitalization, myocardial infarction, congestive heart failure (NYHA class >=2), or vascular disease (e.g., aortic aneurysm with risk of rupture), or other cardiac impairment that may affect the safety evaluation of the study drug (e.g., poorly controlled arrhythmia, myocardial ischemia, etc.) within 12 months before the first dose; history of esophagogastric varices, severe ulcer, unhealed wound, abdom
Design outcomes
Primary
| Measure | Time frame |
|---|---|
| Incidence of grade >=3 hepatitis or pneumonitis within 28 days; | — |
Secondary
| Measure | Time frame |
|---|---|
| Other grade >=3 adverse events occurring within 28 days;Overall survival;Objective remission rate;Disease control rate;Duration of Response;Progression free survival; | — |
Countries
China
Contacts
Public ContactJing Qin
Zhejiang Cancer Hospital
Outcome results
None listed