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

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.

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.