A Phase Ib Study of Tislelizumab Plus SYS6010 in Immunotherapy-Pretreated Locally Advanced or Metastatic NSCLC (SYS6010)

Introduction: Patients with driver gene-negative non-small cell lung cancer (NSCLC) who experience treatment failure following immune checkpoint inhibitor (ICI) therapy have limited subsequent treatment options, representing an unmet clinical need. EGFR is commonly expressed in EGFR wild-type NSCLC and represents a potential target for therapeutic intervention. Antibody-drug conjugates (ADCs) combine the high targeting specificity of antibodies with the potent cytotoxic effects of payloads. SYS6010 is an EGFR-targeting ADC conjugated to a topoisomerase I inhibitor. Preclinical and clinical studies suggest that the combination of ADCs and ICIs can synergistically enhance anti-tumor efficacy through multiple immunomodulatory mechanisms. Tislelizumab is an approved PD-1 inhibitor for advanced NSCLC. This study aims to evaluate the safety and efficacy of SYS6010 in combination with tislelizumab in patients with driver gene-negative NSCLC who have failed prior PD-1/PD-L1 inhibitor therapy.

Methods: This is an exploratory clinical trial enrolling patients with driver gene-negative NSCLC who have failed prior PD-1 or PD-L1 inhibitor therapy. The primary objective is to evaluate the safety of the combination therapy, with primary endpoints including the incidence, severity, and type of adverse events (AEs) according to NCI-CTCAE v6.0 criteria. Secondary objectives include assessing efficacy (objective response rate [ORR], disease control rate [DCR], duration of response [DOR], progression-free survival [PFS], overall survival [OS]) and exploring the association of potential predictive or prognostic biomarkers (e.g., EGFR and PD-L1 expression levels) with response to study treatment.

Study Overview

• Status: Not yet recruiting
• Conditions: NSCLC
• Intervention / Treatment: Drug: SYS6010

• Study Type: Interventional
• Enrollment (Estimated): 21
• Phase: Phase 1

Contacts and Locations

• Study Contact: Name: Benxia Zhang, PhD; Phone Number: 86（028）85421606; Email: zhangbenxia1007@outlook.com

Study Locations

• China
  • Please Select
    • Chengdu, Please Select, China, 610041
      • West China Hospital, Sichuan University
      • Contact: Benxia Zhang, PhD; Phone Number: 8602885421606; Email: zhangbenxia1007@outlook.com

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Adult; Older Adult
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

• Subjects must meet all of the following inclusion criteria to be eligible for enrollment in this study:

Have histologically or cytologically confirmed locally advanced or metastatic NSCLC that is not amenable to curative surgery or radiotherapy.

Have no known EGFR mutations, ALK rearrangements, or ROS1 rearrangements.

Have experienced radiographic disease progression per RECIST v1.1 after prior treatment with an anti-PD-(L)1 antibody for locally advanced or metastatic NSCLC, with prior therapy including:

Progression on anti-PD-(L)1 antibody combined with platinum-based chemotherapy (second-line); or

Progression on platinum-based chemotherapy following prior anti-PD-(L)1 monotherapy (third-line); or

Progression on anti-PD-(L)1 monotherapy and considered unfit for platinum-based chemotherapy (second-line); or

Progression on anti-PD-(L)1-containing therapy following prior platinum-based chemotherapy (third-line).

a. Adjuvant or neoadjuvant therapy is counted as one prior line of therapy if the time between the last dose of chemotherapy and tumour recurrence is ≤ 6 months.

Have at least one evaluable tumour lesion per RECIST v1.1 (see Appendix 1).

Have an Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1 (see Appendix 2).

Have a life expectancy of ≥ 3 months as assessed by the investigator.

Agree to undergo tumour tissue biopsy before the first study treatment and during the treatment period, whenever clinically feasible.

Have adequate bone marrow, hepatic, renal, and coagulation function confirmed by laboratory tests obtained within 7 days before the first dose (transfusion or growth factor support is not permitted within 2 weeks prior to the screening assessment):

Bone marrow function: Absolute neutrophil count ≥ 1.5 × 10⁹/L; platelet count ≥ 100 × 10⁹/L; haemoglobin ≥ 90 g/L.

Hepatic function: Total bilirubin ≤ 1.5 × upper limit of normal (ULN) (or ≤ 3 × ULN in the presence of liver metastases); aspartate aminotransferase (AST) and alanine aminotransferase (ALT) ≤ 2.5 × ULN (or ≤ 5.0 × ULN in the presence of liver metastases); albumin ≥ 28 g/L.

Renal function: Serum creatinine ≤ 1.5 × ULN or creatinine clearance ≥ 50 mL/min (calculated using the Cockcroft-Gault formula; see Appendix 3).

Coagulation function: International normalised ratio (INR) and activated partial thromboplastin time (APTT) ≤ 1.5 × ULN.

Subjects with chronic hepatitis B virus (HBV) infection must have HBV-DNA < 1000 IU/mL and be willing to receive antiviral therapy throughout the study period.

Toxicities from prior therapy must have recovered to ≤ Grade 1 (CTCAE v5.0) or to a stable condition per investigator assessment at the time of the first study dose (alopecia and pigmentation excepted).

Subjects of childbearing potential must agree to use highly effective contraceptive methods (including vasectomy, abstinence, etc.; see Appendix 4) throughout the study period (from signing the ICF until 6 months after the last dose of investigational product).

Subjects must be able to communicate well with the investigator and comply with protocol-required follow-up.

Exclusion Criteria:

• Inclusion Criteria

Subjects must meet all of the following inclusion criteria to be eligible for enrollment in this study:

Have histologically or cytologically confirmed locally advanced or metastatic NSCLC that is not amenable to curative surgery or radiotherapy.

Have no known EGFR mutations, ALK rearrangements, or ROS1 rearrangements.

Have experienced radiographic disease progression per RECIST v1.1 after prior treatment with an anti-PD-(L)1 antibody for locally advanced or metastatic NSCLC, with prior therapy including:

Progression on anti-PD-(L)1 antibody combined with platinum-based chemotherapy (second-line); or

Progression on platinum-based chemotherapy following prior anti-PD-(L)1 monotherapy (third-line); or

Progression on anti-PD-(L)1 monotherapy and considered unfit for platinum-based chemotherapy (second-line); or

Progression on anti-PD-(L)1-containing therapy following prior platinum-based chemotherapy (third-line).

a. Adjuvant or neoadjuvant therapy is counted as one prior line of therapy if the time between the last dose of chemotherapy and tumour recurrence is ≤ 6 months.

Have at least one evaluable tumour lesion per RECIST v1.1 (see Appendix 1).

Have an Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1 (see Appendix 2).

Have a life expectancy of ≥ 3 months as assessed by the investigator.

Agree to undergo tumour tissue biopsy before the first study treatment and during the treatment period, whenever clinically feasible.

Have adequate bone marrow, hepatic, renal, and coagulation function confirmed by laboratory tests obtained within 7 days before the first dose (transfusion or growth factor support is not permitted within 2 weeks prior to the screening assessment):

Bone marrow function: Absolute neutrophil count ≥ 1.5 × 10⁹/L; platelet count ≥ 100 × 10⁹/L; haemoglobin ≥ 90 g/L.

Hepatic function: Total bilirubin ≤ 1.5 × upper limit of normal (ULN) (or ≤ 3 × ULN in the presence of liver metastases); aspartate aminotransferase (AST) and alanine aminotransferase (ALT) ≤ 2.5 × ULN (or ≤ 5.0 × ULN in the presence of liver metastases); albumin ≥ 28 g/L.

Renal function: Serum creatinine ≤ 1.5 × ULN or creatinine clearance ≥ 50 mL/min (calculated using the Cockcroft-Gault formula; see Appendix 3).

Coagulation function: International normalised ratio (INR) and activated partial thromboplastin time (APTT) ≤ 1.5 × ULN.

Subjects with chronic hepatitis B virus (HBV) infection must have HBV-DNA < 1000 IU/mL and be willing to receive antiviral therapy throughout the study period.

Toxicities from prior therapy must have recovered to ≤ Grade 1 (CTCAE v5.0) or to a stable condition per investigator assessment at the time of the first study dose (alopecia and pigmentation excepted).

Subjects of childbearing potential must agree to use highly effective contraceptive methods (including vasectomy, abstinence, etc.; see Appendix 4) throughout the study period (from signing the ICF until 6 months after the last dose of investigational product).

Subjects must be able to communicate well with the investigator and comply with protocol-required follow-up.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: N/A
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

1

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Tislelizumab plus SYS6010 in Immunotherapy-Pretreated Locally Advanced or Metastatic NSCLC	Drug: SYS6010; SYS6010 4.2mg/kg,Ivgtt，Q3W，plus Tislelizumab，200 mg，Ivgtt，Q3W

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Time Frame
incidence of adverse effect	From date of first administration up to approximately 3.5 years after the last patient is administrated

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Objective Response Rate（ORR）	ORR is the proportion of subjects with CR or PR , based on RECIST v1.1.	Approximately 9-11 weeks after the first dose
Overall Survival (OS)	OS will be defined as the time from the date of first dosing until death due to any cause	From date of first administration up to approximately 5.5 years after the last patient is administrated
Disease Control Rate（DCR）	It represents the total proportion of patients who achieved complete response (CR), partial response (PR), and disease stability (SD) after treatment, reflecting the overall control ability of the treatment on tumor growth.	From date of first administration up to approximately 3.5 years after the last patient is administrated
Duration of Response(DOR)	It refers to the period from when a patient starts receiving treatment until the tumor lesion shows an objective response (such as shrinking or disappearing) and then the disease progresses or recurs again.	From date of first administration up to approximately 3.5 years after the last patient is administrated
Progression-Free Survival(PFS)	Its definition is: the period from the start of randomization until tumor progression occurs objectively or until death due to any reason.	From date of first administration up to approximately 3.5 years after the last patient is administrated

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
EGFR protein expression	The correlation between EGFR protein expression and amplification level and the efficacy of ADC	From date of first administration up to approximately 5.5 years after the last patient is administrated
PD-L1 protein expression	The correlation between PD-L1 protein expression and the efficacy of combined treatment, etc.	From date of first administration up to approximately 5.5 years after the last patient is administrated

Collaborators and Investigators

• Sponsor: Sichuan University

Study record dates

Study Major Dates

• Study Start (Estimated): June 30, 2026
• Primary Completion (Estimated): December 31, 2027
• Study Completion (Estimated): December 31, 2028

Study Registration Dates

• First Submitted: July 2, 2026
• First Submitted That Met QC Criteria: July 2, 2026
• First Posted (Actual): July 9, 2026

Study Record Updates

• Last Update Posted (Actual): July 9, 2026
• Last Update Submitted That Met QC Criteria: July 2, 2026
• Last Verified: June 1, 2026

More Information

Terms related to this study

• Other Study ID Numbers: SYS6010-2025-11-17-YSW

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: YES

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No