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

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.