SYS6010 Versus Docetaxel for Previously Treated EGFR Wild-type NSCLC: Phase Ⅲ

A Randomized, Open-label, Multicenter Phase III Study Comparing SYS6010 With Docetaxel in Patients With Locally Advanced or Metastatic EGFR Wild-type Non-squamous Non-small Cell Lung Cancer Who Have Failed Standard Therapy

This is a randomized, open-label, multicenter Phase III clinical trial, designed to evaluate the efficacy and safety of SYS6010 versus docetaxel in participants with Locally Advanced or Metastatic EGFR Wild-type Non-squamous Non-small Cell Lung Cancer who Have Failed Standard Therapy. The primary Objective is to evaluate the efficacy of SYS6010 versus docetaxel in participants with EGFR wild-type locally advanced or metastatic non-squamous non-small cell lung cancer (nsq-NSCLC). Secondary Objectives includes safety, quality of life, immunogenicity, biomarkers, and efficacy correlations of SYS6010 compared to docetaxel in the same patient population.

This is a randomized, open-label, multicenter, Phase III clinical study designed to evaluate the efficacy and safety of SYS6010 compared with docetaxel in participants with locally advanced or metastatic EGFR wild-type nsq-NSCLC who have failed standard therapy.

Approximately 506 participants will be enrolled and randomized 1:1 to receive either SYS6010 or docetaxel. Randomization will be stratified by: (1) brain metastases (yes vs no) and (2) EGFR high expression (yes vs no). EGFR protein expression will be assessed by immunohistochemistry (IHC).

Key eligibility criteria include: age ≥18 years; histologically or cytologically confirmed locally advanced or metastatic nsq-NSCLC; and EGFR mutation negative confirmed for the EGFR wild-type population. For participants who are driver gene-negative, prior therapy must have included immunotherapy and platinum-based chemotherapy ± anti-angiogenic therapy with documented treatment failure. For participants who are driver gene-positive, prior therapy must have included appropriate targeted therapy for the driver alteration and platinum-based chemotherapy, with treatment failure.

The study includes a screening/baseline period, treatment period, safety follow-up (30 days after the last dose), PFS follow-up, and survival follow-up.

Study Treatments:

SYS6010: intravenous infusion 4.5 mg/kg Q3W. Docetaxel: intravenous infusion 75 mg/m² Q3W. Treatment will continue until meeting any protocol-defined treatment discontinuation criteria.

Dose modifications may include dose interruption, dose reduction, and permanent discontinuation.

Safety Assessments: Safety will be assessed from informed consent through 30 days after the last dose, including collection of all adverse events (AEs), clinical symptoms, vital signs, and laboratory abnormalities, and assessment of relationship to study treatment. Safety-related examinations (e.g., physical examination, ECOG performance status, laboratory tests) will be performed during screening/baseline and throughout treatment.

Efficacy Assessments: Tumor response will be evaluated per RECIST v1.1. The first post-randomization tumor assessment will occur at 6 weeks (+7 days). Subsequent assessments will be performed every 6 weeks (±7 days) through Week 54 (excluding the first assessment), and every 12 weeks (±7 days) from Week 55 onward, and at the end of treatment if no assessment has been performed within the prior 4 weeks. Participants who discontinue treatment prior to disease progression will enter PFS follow-up until disease progression, initiation of new anticancer therapy, death, loss to follow-up, or withdrawal (whichever occurs first).

Pharmacokinetics and Immunogenicity: Participants in the SYS6010 arm will undergo blood sampling for pharmacokinetics (PK) and immunogenicity assessments during the study.

Inclusion Criteria:

1. Voluntarily participate in this clinical study, understand the study procedures, and be able to sign the written ICF (Informed Consent Form); 2. Age ≥18 years, with no restriction on sex; 3. Patients with pathologically confirmed locally advanced or metastatic EGFR wild-type non-squamous non-small cell lung cancer (nsq-NSCLC). Stage IIIB or IIIC patients unsuitable for surgical resection or radical chemoradiotherapy, or Stage IV NSCLC patients. EGFR mutations (currently approved by regulatory authorities for targeted therapy) must be confirmed negative. If test results are unavailable, participants need to provide tumor tissue to undergo genetic testing.

4. Meet either of the following requirements regarding prior treatment for locally advanced or metastatic EGFR wild-type nsq-NSCLC:

1. Driver gene-negative population must have failed only immune therapy and platinum-based chemotherapy ± anti-angiogenic therapy (limited to first-line regimens approved by regulatory authorities).

2. Other driver gene-positive populations must have received and failed only targeted therapy for the driver gene and platinum-based chemotherapy ± anti-angiogenic therapy (limited to first-line regimens approved by regulatory authorities).

   5. Have at least one measurable lesion confirmed by CT or MRI according to RECIST v1.1 criteria; 6. ECOG performance status score 0-1; 7. Expected survival ≥3 months as judged by the investigator. 8. Within 7 days before the first administration, the body organs and bone marrow function meet the requirements, defined as follows (Note: For hematological tests, participants must not have received blood component transfusion, G-CSF, TPO, TPO-RA, IL-11, or EPO within 2 weeks prior to randomization):

   1. ANC ≥1.5×10⁹/L
   2. Platelets (PLT) ≥100×10⁹/L
   3. Hemoglobin (HGB) ≥100 g/L
   4. Serum creatinine (Cr) ≤1.5×ULN AND creatinine clearance ≥50 mL/min (calculated by Cockcroft-Gault formula)
   5. Total bilirubin (TBIL): ≤1.5×ULN for patients without liver metastases; ≤3×ULN for patients with Gilbert's syndrome or liver metastases
   6. ALT/AST: ≤2.5×ULN for patients without liver metastases; ≤5×ULN for patients with liver metastases
   7. APTT and INR ≤1.5×ULN 9. Female participants of childbearing potential must have a negative pregnancy test within 7 days before randomization. All participants must agree to use effective contraception from the time of signing the ICF until 7 months after the last dose. During this period, female participants must not be breastfeeding, and male participants must refrain from sperm donation.

   Exclusion Criteria:

   1. Histologically or cytologically confirmed small cell lung cancer, squamous cell carcinoma, neuroendocrine carcinoma, or sarcomatoid carcinoma

   2. Patients with: Leptomeningeal metastasis, brainstem metastasis, spinal cord metastasis and/or compression, or active CNS metastases.

      Exception: Supratentorial and/or cerebellar metastases (excluding midbrain, pons, or medulla) are allowed if: Received local therapy (e.g., radiation/surgery) Stable for ≥2 weeks before randomization (no new lesions/enlargement on imaging, stable/improved neurological symptoms). No corticosteroids or ≤10 mg prednisone (or equivalent) daily.

   3. Other malignancies within 3 years before randomization, except: Cured basal/squamous cell skin cancer, superficial bladder cancer, prostate/cervical carcinoma in situ.

   4. Known allergies: To any component of SYS6010 or humanized monoclonal antibodies. Contraindications/hypersensitivity to docetaxel.

   5. Residual toxicities from prior antitumor therapy > Grade 1 (per NCI-CTCAE v6.0), except: Grade 2 alopecia or other toxicities deemed non-risky by investigators.

   6. Prior treatment with topoisomerase I inhibitors (including ADCs).

   7. Inadequate washout periods:

   1. Major surgery (excluding biopsies) within 4 weeks before first dose.

   2. Last antitumor therapy before first dose:

      Chemotherapy/radical radiotherapy/targeted/immunotherapy: ≥4 weeks. Small-molecule targeted drugs/TCM with antitumor claims/palliative radiotherapy/local therapy: ≥2 weeks.

   3. Within 2 weeks before first dose: IV antibiotics/antifungals/antivirals for the purpose of anti-infective therapy; strong CYP3A4 inducers/inhibitors; OATP1B1/1B3 inhibitors.

   4. Investigational drugs/live vaccines within 4 weeks before first dose. 8. Severe cardiovascular diseases within 6 months before randomization, including: Clinically significant arrhythmias (e.g., ventricular arrhythmia, AV block ≥ Grade III); QTcF >470 ms (Fridericia's formula) Myocardial infarction, unstable angina, aortic dissection, angioplasty, CABG. Heart failure ≥ NYHA Class II or LVEF <50%. Stroke or Grade ≥3 cardiovascular events. Pulmonary embolism. 9. History of ILD/non-infectious pneumonitis requiring steroids; current ILD; or suspected ILD on imaging/pulmonary function tests (severe ventilation/diffusion impairment).

   10. Severe infections within 4 weeks before randomization (e.g., bacteremia, severe pneumonia, active TB); active infections requiring IV antibiotics within 2 weeks.

   11. History of ulcerative colitis or Crohn's disease. 12. Pleural/pericardial effusion requiring intervention within 2 weeks. 13. Active HBV/HCV infection: HBV: HBsAg+ and/or HBcAb+ with HBV DNA ≥10⁴ copies/mL (or ≥2000 IU/mL).

   HCV: HCV Ab+ with HCV RNA above detection limit. Note: Antiviral therapy (e.g., entecavir/tenofovir) is recommended for HBsAg+ patients before randomization.

   14. Immunodeficiency (HIV+, congenital/acquired immune disorders) or allogeneic transplant history.

   15. Other conditions deemed ineligible by investigators (e.g., uncontrolled psychiatric disorders, hypertension/diabetes).