The goal of this clinical trial is to evaluate whether individualized sequencing of immunotherapy and chemotherapy based on immune dynamics can improve treatment outcomes in adults with advanced non-small cell lung cancer (NSCLC) without driver gene mutations. This study will also assess the safety and feasibility of different infusion strategies.
The main questions it aims to answer are:
Does optimizing the timing of PD-1 inhibitor infusion relative to chemotherapy improve the objective response rate (ORR)?
Does individualized infusion sequencing enhance progression-free survival (PFS) compared to standard or fixed-delay administration?
What safety concerns or immune-related adverse events occur with different infusion timing strategies?
Researchers will compare three treatment strategies:
Group A (Standard Concurrent Group): Immunotherapy and chemotherapy administered on the same day (D1).
Group B (Fixed Delay Group): Chemotherapy on D1, followed by PD-1 inhibitor infusion on Day 3.
Group C (Individualized Delay Group): Chemotherapy on D1, and PD-1 inhibitor infusion scheduled on D2-D6 based on daily immune monitoring.
Participants will:
Receive a PD-1 inhibitor (e.g., sintilimab, pembrolizumab, camrelizumab) combined with platinum-based chemotherapy.
Attend clinic visits for regular immune monitoring, imaging assessments, and safety checks during each treatment cycle.
Undergo blood tests to evaluate immune biomarkers (e.g., CD8⁺PD-1⁺ T cells, MDSC, Treg、IFN-γ、NLR、ALC、CRP) to guide individualized treatment decisions.
None
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Parallel
Arm 1： Standard Synchronous Group
DrugArm 1: Concurrent PD-1 + Chemotherapy (Standard Synchronous Group) Participants in this group will receive PD-1 inhibitor and chemotherapy on the same day (D1) during each treatment cycle.
Arm 2：Fixed Delay Group
DrugFixed Delay Arm Delayed PD-1 + Chemo PD-1 inhibitor (e.g., Sintilimab/Keytruda/Tislelizumab/Camrelizumab/Toripalimab/Nivolumab/Atezolizumab/Sugemalimab) Immune checkpoint inhibitor + Chemo (Day 3)
Arm 3： Individualized Delay Group
DrugArm 3: Individualized PD-1 Timing Based on Immune Window Score (IWS) (Individualized Group) Participants in this group will receive chemotherapy on D1 and undergo daily immune monitoring (CD8⁺PD-1⁺ T cells, Treg, IFN-γ, NLR, ALC, CRP). Based on the immune window score (IWS): If IWS ≥ 2, PD-1 inhibitor will be administered the same day. If IWS = 1-1.5, dosing may be delayed to D3-D5 depending on immune recovery. If IWS remains 0 by D5, PD-1 inhibitor will be administered on D6 as fallback.
Objective Response Rate (ORR)
The proportion of participants who achieve a complete response (CR) or partial response (PR) based on RECIST v1.1 criteria, as assessed by investigators. Imaging assessments will be performed every 6-8 weeks during treatment, and responses will be confirmed at least 4 weeks after initial documentation.
PFS
PFS is defined as the time from the start of treatment until disease progression as assessed by RECIST v1.1 criteria or death from any cause, whichever occurs first. Imaging assessments will be performed every 6-8 weeks.
Overall Survival (OS)
OS is defined as the time from the start of treatment until death from any cause. Participants alive at the time of analysis will be censored at the last date known to be alive.
Incidence of Immune-Related Adverse Events (irAEs)
The percentage of participants experiencing any grade immune-related adverse events, as defined by CTCAE v5.0, including but not limited to dermatitis, colitis, pneumonitis, hepatitis, and endocrinopathies.
Incidence of Treatment-Related Adverse Events (TRAEs)
The percentage of participants experiencing any grade treatment-related adverse events, assessed by investigators and graded according to CTCAE v5.0.
Proportion and Activation Status of CD8⁺PD-1⁺ T Cells
Flow cytometry will be used to measure the proportion and activation status of CD8⁺ T cells expressing PD-1 in peripheral blood. The dynamic changes in CD8⁺PD-1⁺ T cells will be analyzed in relation to treatment response and immune modulation.
Proportion of Regulatory T Cells (Treg)
Flow cytometry will be used to assess the percentage and absolute count of CD4⁺CD25⁺FoxP3⁺ regulatory T cells (Treg) in peripheral blood, and their association with treatment efficacy and immune-related adverse events.
Proportion of Myeloid-Derived Suppressor Cells (MDSC)
Flow cytometry will measure the proportion of MDSCs, including polymorphonuclear-MDSCs (PMN-MDSC) and monocytic-MDSCs (M-MDSC), in peripheral blood. The relationship between MDSC levels and therapeutic response will be analyzed.
Neutrophil-to-Lymphocyte Ratio (NLR)
NLR will be calculated from routine complete blood counts. The correlation between NLR dynamics and treatment response, progression-free survival (PFS), and immune-related adverse events will be assessed.
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