EGFR-TKIs Plus PD-1 in EGFR-Mutant Advanced NSCLC

A Clinical Study Evaluating the Preliminary Antitumor Activity and Safety of EGFR-TKIs Combined With PD-1 Monoclonal Antibody as First-Line Therapy in Patients With EGFR-Mutant Advanced Non-Small Cell Lung Cancer

This study is an open-label, multicenter, single-arm clinical study.

This open-label, multicenter, single-arm exploratory clinical trial plans to enroll a total of 32 patients: 6 in a safety lead-in phase and the remaining 26 in an expansion phase. Eligible subjects are treatment-naïve patients with locally advanced or metastatic non-small cell lung cancer (NSCLC) harboring EGFR 19del or L858R mutations. All patients receive first-line oral therapy with standard-dose third-generation EGFR-TKIs (osimertinib, aumolertinib, or furmonertinib). Once stable disease is confirmed by two consecutive radiological assessments, sintilimab (200 mg intravenously every three weeks) is added as maintenance treatment until disease progression, unacceptable toxicity, or a maximum treatment duration of two years. The primary endpoint is progression-free survival (PFS). Secondary endpoints include objective response rate (ORR), disease control rate (DCR), overall survival (OS), and adverse events occurring throughout treatment. Exploratory analyses focus on the correlation of serum lipid profiles and the tumor immune microenvironment with the safe treatment window and mechanisms of drug resistance. The trial consists of screening, treatment, safety follow-up, and survival follow-up periods. Tumor imaging evaluations are performed every six weeks during the first 24 weeks of treatment and every nine weeks thereafter.

Inclusion Criteria:

1. Patients with histologically or cytologically confirmed, previously untreated EGFR-mutant (19del/L858R) locally advanced or metastatic (stage IIIB/IIIC or IV) non-small cell lung cancer (NSCLC), according to the 9th edition of the TNM staging system for lung cancer jointly issued by the International Association for the Study of Lung Cancer (IASLC) and the American Joint Committee on Cancer (AJCC);
2. Male or female patients aged ≥ 18 years;
3. Patients who are willing to receive third-generation EGFR-TKI targeted therapy, followed by maintenance therapy with a PD-1 antibody during the stable phase of the disease (defined as no further tumor shrinkage for at least two consecutive assessments based on RECIST v1.1 criteria);
4. Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1;
5. At least one measurable or non-measurable but evaluable lesion according to RECIST version 1.1;
6. Adequate organ function;
7. Female or male patients of childbearing potential must agree to use highly effective contraceptive measures throughout the study period;
8. Willing and able to comply with scheduled visits, treatment plans, laboratory tests, and other study requirements as specified in the visit schedule.

Exclusion Criteria:

1. Patients who are ineligible for standard anti-tumor therapy according to routine clinical practice;
2. Prior treatment with anti-PD-1/PD-L1 immunotherapy;
3. Concurrent enrollment in another clinical study;
4. Known history of allogeneic organ transplantation or allogeneic hematopoietic stem cell transplantation;
5. Receipt of systemic corticosteroids or other immunosuppressive therapy within 2 weeks prior to the first dose of study drug;
6. Receipt of any live vaccine within 4 weeks prior to the first dose of study drug, or planned receipt of live vaccine during the study period;
7. Presence of brainstem, leptomeningeal, spinal cord metastasis, or spinal cord compression;
8. Presence of uncontrolled concomitant diseases, including but not limited to decompensated cirrhosis, nephrotic syndrome, uncontrolled metabolic disorders, etc.;
9. History of severe gastrointestinal ulcer, gastrointestinal perforation, fistula or obstruction, intra-abdominal abscess, or acute gastrointestinal bleeding within 6 months prior to the first dose, or other gastrointestinal diseases that, in the investigator's opinion, may predispose to bleeding or perforation;
10. Presence of severe uncontrolled cardiovascular disease;
11. Interstitial lung disease (ILD) (including pulmonary fibrosis or radiation pneumonitis) requiring corticosteroid therapy, or current ILD/non-infectious pneumonitis;
12. Concomitant pulmonary disease resulting in clinically severe impairment of respiratory function;
13. Chronic autoimmune disease or inflammatory disease requiring systemic therapy or receiving systemic therapy within 2 years prior to the first dose;
14. Active or history of documented inflammatory bowel disease (e.g., Crohn's disease, ulcerative colitis, or chronic diarrhea), intestinal obstruction, or extensive bowel resection;
15. Diagnosis of Gilbert's syndrome;
16. Severe infection within 4 weeks prior to the first dose, including but not limited to complications requiring hospitalization, sepsis, or severe pneumonia;
17. Known active pulmonary tuberculosis;
18. Known active syphilis infection;
19. Known history of immunodeficiency, or positive test for human immunodeficiency virus (HIV) antibody;
20. Presence of active hepatitis B virus (HBV) or hepatitis C virus (HCV) infection;
21. Known allergy to any component of any study drug, history of severe allergic reactions (e.g., anaphylactic shock), history of severe hypersensitivity to other monoclonal antibodies or recombinant protein-based substances, or history of severe infusion reactions;
22. Women who are pregnant, breastfeeding, or planning to become pregnant or breastfeed during the study period;
23. Any disease, medical condition, organ system dysfunction, or social circumstance (including but not limited to psychiatric illness, substance/alcohol abuse, history of drug abuse, etc.) that, in the investigator's opinion, may interfere with the subject's ability to provide informed consent, adversely affect the subject's cooperation and participation in the study, or confound the interpretation of study results.