Phase 1b/2 to Evaluate the Safety, Tolerability, and Efficacy of TXN10128 in Combination With TOPO-I Inhibitor-based Therapies (Irinotecan or TROP2 ADC) in Advanced or Metastatic EGFR Mutated NSCLC (ENRISE)

Inclusion Criteria:

• 1) Males and females aged 19 or older at the time of written informed consent. 2) Participants must have histologically or cytologically confirmed advanced or metastatic non-squamous NSCLC (Stage IIIB, IIIC, or IV per AJCC 8th edition) with an EGFR TKI-sensitizing mutation.

They must also meet the prior treatment requirements for each cohort.

* EGFR TKI-sensitizing mutations: mutations that are highly responsive to TKIs, such as exon 19 deletion or exon 21 L858R point mutation.

3) Participants who have experienced disease progression on or after prior third-generation EGFR TKI therapy, either during or after treatment, and who meet the following criteria

(1) Part A:

• No prior treatment with a TROP2 ADC,

• Have received no more than four* prior lines of anticancer therapy, including one platinum-based doublet chemotherapy regimen.

  (2) Part B: Prior treatment with a TROP2 ADC (3) Part C:

• No prior treatment with a TROP2 ADC, and

• Have received no more than three* prior lines of anticancer therapy, including one platinum-based doublet chemotherapy regimen

  *Counting of prior lines of anticancer therapy Neoadjuvant and adjuvant anticancer therapies are, in principle, not counted as prior lines. However, if disease recurrence or progression occurs within 6 months after completion of adjuvant therapy, such therapy will be counted as a prior line.

  4) Participants with documented evidence of an EGFR TKI-sensitizing mutation in the tumor, as confirmed by liquid biopsy or tissue biopsy performed prior to enrollment in this study, with the result* properly documented

  *EGFR mutation testing must be performed using a validated polymerase chain reaction (PCR) or next-generation sequencing (NGS) assay at an appropriately certified/accredited laboratory (e.g., a study specimen analysis facility or a laboratory holding a clinical laboratory standard accreditation).

  5) Participants with at least one measurable lesion per RECIST v1.1. If the participant has received prior radiotherapy, the measurable lesion must be located outside the prior radiation field unless there is clear evidence of progression of a lesion within the irradiated field.

  6) Participants who agree to provide either: a fresh tumor biopsy (core needle biopsy or excisional biopsy) obtained before the first dose of TXN10128 (C1D1), or an archival tumor specimen collected after the most recent prior anticancer therapy.

  7) Participants with an Eastern Cooperative Oncology Group (ECOG) performance status (PS) of 0 or 1.

  8) Participants with a life expectancy of at least 12 weeks. 9) Adequate hematologic and adequate major organ/cardiac function, as defined by the following laboratory results obtained within 7 days prior to the first dose of TXN10128 (C1D1):

  1. Adequate bone marrow function*: platelet count ≥100,000/mm³, hemoglobin (Hb) ≥10 g/dL, absolute neutrophil count (ANC) ≥1,500/mm³.

     * Hematologic parameters must be met without transfusion, granulocyte colony-stimulating factor (G-CSF), or other hematopoietic growth factor support within 1 week prior to the relevant laboratory assessment.

  2. Adequate hepatic function: aspartate aminotransferase (AST)/alanine aminotransferase (ALT) ≤2.5×upper limit of normal (ULN) (≤5×ULN in the presence of liver metastases or hepatocellular carcinoma); total bilirubin (TBL) ≤1.5×ULN (<3×ULN in participants with Gilbert's syndrome).

  3. Adequate renal function: creatinine clearance (CrCl) ≥50 mL/min*. * CrCl = [140 - age (years)] × weight (kg) (× 0.85 for female participants) / [serum creatinine (mg/dL) × 72]

  4. Adequate coagulation function: international normalized ratio (INR)/prothrombin time (PT)/activated partial thromboplastin time (aPTT) ≤1.5×ULN.

  5. Systolic blood pressure≤160 mmHg, diastolic blood pressure≤100 mmHg

  6. QTcF interval*: Mean QTcF value from triplicate ECGs ≤480 msec *In cases where QTc assessment is difficult due to structural abnormalities of the cardiac conduction system, such as right bundle branch block (RBBB) or left bundle branch block (LBBB), a specific formula may be applied in consultation with the sponsor. Once selected, the same method must be used consistently for subsequent assessments of QTc changes.

  10) Recovery from adverse events (AEs) of prior therapy to Grade ≤1 (except for alopecia or stable CTCAE Grade 2 peripheral neuropathy).

  11) For participants of reproductive potential, agreement to practice adequate abstinence and contraception, and agreement not to donate ova or sperm. Males and females of childbearing potential must agree to use one of the following medically acceptable methods of contraception from the last dose of TXN10128 through 28 weeks after the last dose.

• Hormonal contraceptives (oral, injectable, or implantable

• Intrauterine device (IUD) or intrauterine system (IUS);

• Sterilization procedures or surgery (e.g., hysterectomy, bilateral oophorectomy, or bilateral salpingectomy);

• Vasectomized partner;

• Male participants must use a condom during sexual intercourse with a female partner of childbearing potential or a pregnant partner during the period of IP administration and for 4 months after the last dose. Sexual abstinence:

Complete abstinence from sexual intercourse is also acceptable when, in the investigator's judgment, the participant's age, occupation, lifestyle, or sexual orientation assures contraception. Periodic abstinence (e.g., calendar, ovulation, symptothermal, or post-ovulation methods), abstinence, and withdrawal are not considered acceptable methods of contraception.

12) Participants who are willing and able to comply with the procedures required by this clinical study protocol, including hospitalization, procedures and interventions, tumor biopsy (core needle biopsy or excisional biopsy), and laboratory tests, and who have voluntarily provided written informed consent.

Exclusion Criteria:

• 1) Participants with any of the following concurrent medical conditions:

  1. Symptoms of spinal cord compression
  2. Active central nervous system (CNS) metastases

However, at the investigator's discretion, participants may be enrolled if they meet any of the following:

- Neurologically stable CNS metastases that have either been off corticosteroids for at least 4 weeks prior to the first dose of TXN10128 or have been maintained on a stable dose of corticosteroids [hydrocortisone ≤30 mg/day, dexamethasone ≤2 mg/day, or prednisone ≤10 mg/day (or equivalent)].

- At least 2 weeks have elapsed since the completion of brain radiotherapy. (3) Pathologically confirmed leptomeningeal metastases (4) Clinically significant coagulation disorders, including disseminated intravascular coagulation (DIC).) (5) Participants with histologically mixed small cell lung cancer (SCLC) and NSCLC.

(6) Uncontrolled diarrhea of Grade ≥2 per NCI-CTCAE version 6.0 2) Participants with any of the following medical history:

1. Clinically significant (e.g., active) cardiovascular disease within 24 weeks prior to the first dose of TXN10128 (C1D1):

   - History of long QT syndrome;

   • Stroke, Myocardial Infarction;
   • Unstable angina or significant cardiac arrhythmia requiring pharmacologic treatment;
   • Congestive heart failure (New York Heart Association [NYHA] Classification ≥Class 3).

2. Prior allogeneic hematopoietic stem cell transplantation, or prior autologous or allogeneic CAR-T cell therapy, or solid organ transplantation.

3. Known positive status for human immunodeficiency virus (HIV) infection.

4. Active hepatitis B or C infection (however, participants may be eligible if HBV DNA or HCV RNA is controlled to below the institutional lower limit of detection).

5. Active infection requiring intravenous antibiotic therapy within 2 weeks prior to study enrollment.

6. Active interstitial lung disease (ILD) requiring steroid or immunosuppressive therapy, or a history of ILD, or suspected ILD findings on screening imaging assessment.

7. Pulmonary disease including pneumonia or pulmonary fibrosis, or severe impairment of pulmonary function resulting therefrom.

8. History of another primary malignancy within 2 years prior to screening (however, participants with a history within 2 years of basal cell or squamous cell carcinoma of the skin, superficial bladder cancer, papillary thyroid carcinoma, or carcinoma in situ at other sites may be eligible if successfully treated and without recurrence, based on the investigator's medical judgment).

9. Inability to take oral medications, gastrointestinal disorders causing malabsorption syndrome, or uncontrolled inflammatory gastrointestinal (GI) disease (e.g., intestinal paralysis, intestinal obstruction, Crohn's disease, ulcerative colitis).

10. Uncontrolled pleural effusion, pericardial effusion, or ascites requiring recurrent drainage procedures.

11. Participants who experienced a Grade ≥3 immune-related adverse event (irAE) with prior immunotherapy, excluding clinically non-significant laboratory abnormalities.

12. Active autoimmune disease requiring systemic therapy within the past 2 years (i.e., use of disease-modifying agents, corticosteroids, or immunosuppressive drugs). Chronic systemic steroid therapy (at doses exceeding 10 mg/day prednisone equivalent) or any other form of immunosuppressive therapy within 2 weeks (14 days) prior to the first dose of TXN10128 is not permitted. However, replacement therapies such as thyroxine, insulin, or physiologic corticosteroid replacement therapy for adrenal or pituitary insufficiency are not considered forms of systemic therapy and are permitted.

3) Participants who have received any of the following treatments:

1. Prior treatment with an IP targeting ENPP1 inhibitors or STING agonists.

2. Use of the following anticancer therapies within the specified timeframes prior to the first dose of TXN10128 (C1D1):

   - Cytotoxic chemotherapy, targeted therapy, or hormonal therapy within 2 weeks; however, nitrosourea or mitomycin administered within 6 weeks prior to the first dose;

   - Prior antibody or protein-based immunotherapy, or IP within 4 weeks;

   • Radiotherapy administered to a wide field, including the spine and pelvis, within 4 weeks; however, limited-field radiation administered for symptom palliation within 2 weeks.

3. Major surgery within 4 weeks prior to the first dose of TXN10128 (C1D1) (placement of a central venous catheter is not considered major surgery).

4. Administration of live vaccines, live-attenuated vaccines, or mRNA vaccines, within 4 weeks prior to the first dose of TXN10128 (C1D1).

5. Participants who are receiving strong CYP3A4 inhibitors/inducers (e.g., ketoconazole, rifampin, carbamazepine) within 2 weeks prior to the first dose of the IP, or who require continuation of such agents during the study period.

4) Participants with a history of hypersensitivity to the combination anticancer therapy, any of its components, or agents of similar class, including anaphylaxis/anaphylactoid reactions and angioedema, or who have any other contraindications to treatment.

5) Pregnant or lactating women. 6) Participants who, in the opinion of the investigator, are not suitable for study participation [Part A, B] 7) Participants who are homozygous (UGT1A1*6/*6, UGT1A1*28/*28) or compound heterozygous (UGT1A1*6/*28) for UGT1A1*6 or UGT1A1*28.

8) Participants who are receiving atazanavir sulfate.

[Part C] 9) Clinically significant corneal disease that may affect treatment or assessment, as judged by the investigator.

10) Participants who, at screening, are receiving strong inhibitors (e.g., cyclosporine, verapamil) or inducers of major drug transporters (P-gp, OATP1B1/1B3, BCRP, MRP1, MATE2-K), and who require continuation of such agents during the study period.