A Phase Ⅰ/Ⅱa Clinical Study of GEN-725 in Combination With Dositinib

Inclusion Criteria: 1. 18-75 years old (including 18 and 75 years old), male or female. 2. Patients with histologically or cytologically confirmed locally advanced or metastatic non-small cell lung cancer (NSCLC) who are not amenable to curative surgery or radiotherapy. (For subjects naive to EGFR-TKI therapy, paraffin-embedded tissue blocks, unstained slides, or fresh tumor tissue samples must be available for EGFR testing.) 3. Patients with a positive EGFR mutation. (For patients with prior third-generation EGFR-TKI therapy, post-progression EGFR mutation test results are recommended.) 4. a) Phase Ⅰ Dose Escalation Stage: EGFR-mutant NSCLC patients who have received at least one prior line of therapy (chemotherapy or targeted therapy are allowed). Patients who have received prior neoadjuvant, adjuvant, and/or radical concurrent/sequential chemoradiotherapy (including chemotherapy, immunotherapy, targeted therapy, etc.) must have documented disease recurrence or progression within \<6 months of completing the last regimen. b) Phase Ⅱa Dose Expansion Stage: Cohort 1: NSCLC patients with disease progression on a prior third-generation EGFR-TKI. Cohort 2: EGFR mutant NSCLC patients who are EGFR-TKI-naive. 5. Patients with at least one measurable or evaluable lesion per RECIST 1.1 criteria. 6. Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1, and a life expectancy of at least 12 weeks. 7. Adequate organ function must meet the following criteria (with no transfusion of blood, blood products, no administration of hematopoietic growth factors, or no infusion of albumin/blood products within 14 days before laboratory testing): 1. Absolute neutrophil (NE) count ≥ 1.5 × 10\^9/L. 2. Platelet (PLT) count ≥ 100 × 10\^9/L. 3. Hemoglobin (HGB) ≥ 100 g/L. 4. Serum total bilirubin (TBIL) ≤ 1.5 × upper limit of normal (ULN); Aspartate aminotransferase (AST) and Alanine aminotransferase (ALT) ≤ 2.5 × ULN (for patients with liver metastases, TBIL ≤ 3 × ULN and AST/ALT ≤ 5 × ULN are acceptable). 5. Serum creatinine (SCr) ≤ 1.5 × ULN, or creatinine clearance ≥ 50 mL/min. Note: If the investigator deems retesting necessary (with the reason documented), the above laboratory tests may be repeated only once. If the retesting results meet the criteria, they will be considered eligible. 8. Patients with stable intracranial metastatic lesions are eligible. Stable intracranial metastasis is defined as: stable signs and symptoms for at least 2 weeks before enrollment, and discontinuation of corticosteroid treatment for intracranial metastasis for at least 14 days before enrollment. Patients with stable intracranial metastases (including newly identified intracranial metastasis that are treatment-naive) who do not require treatment are eligible. Patients with stable meningeal metastasis are eligible following confirmation by the investigator (Applicable only to dose expansion stage). 9. Women of childbearing potential must have a negative blood pregnancy test and agree to use effective contraception during the study treatment and for 180 days after the last administration. According to the judgment of the investigator, women of childbearing potential in this study are defined as sexually mature women: 1) have not undergone a hysterectomy or bilateral oophorectomy; 2) have not experienced natural menopause last for 12 consecutive months (amenorrhea following cancer treatment does not preclude the possibility of fertility) (i.e., have experienced menstruation with the last 12 consecutive months). Male patients with female partners of childbearing potential must agree to use effective contraception during the study treatment and for 180 days after the last administration. 10. Subjects have been fully informed, have voluntarily sign the informed consent form, and are willing to comply with the study procedures and visit schedule. Exclusion Criteria: 1. Patients have previously received any of the following treatments: 1. Undergone major surgery within 4 weeks prior to the first administration; 2. Antitumor therapy including chemotherapy, immunotherapy, targeted therapy, etc., within 4 weeks prior to the first administration; for oral small-molecule targeted drugs, within 2 weeks or within 5 half-lives prior to the first administration (whichever is shorter); 3. Radiation therapy involving \>30% of the bone marrow or large-field radiation therapy within 4 weeks prior to the first administration; 4. Strong inhibitors or inducers of CYP3A4 within 7 days prior to the first administration; 5. Traditional Chinese medicine (TCM) or TCM preparations that have antitumor indications, or that are intended for tumor adjuvant therapy within 14 days prior to the first administration; 2. Presence of unresolved toxicities from previous anticancer therapy, with Common Terminology Criteria for Adverse Events (CTCAE) v5.0 grade \>1 (except alopecia) at the start of study treatment. The pre-existing neuropathy from previous platinum-therapy is allowed up to grade 2; 3. Patients with meaningful bypass mutations of corresponding marketed drugs, including but not limited to: MET exon 14 skipping mutation, MET amplification, ALK fusion, HER-2 mutation, ROS-1 fusion, RET fusion, BRAF V600E mutation, KRAS G12C, NTRK fusion, etc. (Applicable only to the dose expansion period, and will be adjusted according to the gene detection results from the dose escalation period); 4. Patients with disease progression (PD) or stable disease (SD) with a duration of ≤3 months following treatment with a third-generation EGFR-TKI; 5. Patients with any uncontrolled systemic disease, as determined by the investigator, such as uncontrolled hypertension (systolic blood pressure ≥160 mmHg or diastolic blood pressure ≥100 mmHg after optimal medical therapy), uncontrolled diabetes, coronary artery stenosis, aortic dissection, aortic aneurysm, active bleeding diathesis, etc.; 6. Patients with any clinically significa