This study is to evaluate the efficacy and safety of neoadjuvant pembrolizumab plus chemotherapy following by pembrolizumab adjuvant in stage IIA-IIIB (N2) NSCLC participants without sensitizing EGFR/ALK mutation. The study will also investigate the role of CXCL13+PD1+ CD8 T cells in association with pathological response / resistance to neoadjuvant immunotherapy by comparing the proportion of CXCL13+PD1+ CD8 T cells in all CD8 T cells in post-treatment (surgical sample) between MPR group and non-MPR group.
Lung cancer is still the world's leading cancer in terms of mortality. Although the early screening of lung cancer has made great achievements, for example, many lung cancer patients were already in the middle and late stage of lung cancer when they were diagnosed. The majority of patients with resected Stage II and IIIA NSCLC are destined to suffer tumor recurrence despite the administration of standard adjuvant or neoadjuvant therapy. In recent years, neoadjuvant immunotherapy based on PD-1 receptor has provided new opportunities for surgery of locally advanced NSCLC, including the positive results from KEYNOTE-671 and KEYNOTE-091 study. However the mechanism of immunotherapy response and resistance are still less understood. CXCL13+ PD1+ CD8 T cells demonstrate an exhausted phenotype and have been proposed as a surrogate of tumor antigen-specific T cell, a key subset of tumor-infiltrating immune cells that have successfully recognized and killed tumor cells but kept from continued functioning by immune checkpoints including PD-L1. Research on T cell exhaustion in chronic viral infection has also suggested that T cell exhaustion is a result of chronic antigen stimulation, corroborating with the notion that exhausted T cells inside the tumor microenvironment represents successful tumor immune recognition Therefore, in this study, we hypothesize that patients with resectable stage IIA-ⅢB(N2) non-small cell lung cancer (NSCLC) without sensitizing EGFR/ALK mutation could benefit from pembrolizumab combined with chemotherapy. Based on the single cell analysis of the pre-treatment and post-treatment samples, we hypothesize that lack of CXCL13+PD1+ T cells is one of the major resistance mechanisms of PD1/PD-L1 blockade.
Study Type
INTERVENTIONAL
Allocation
NA
Purpose
TREATMENT
Masking
NONE
Enrollment
70
Biological: Pembrolizumab 200 mg IV infusion Drug: nab-paclitaxel IV infusion Drug: Carboplatin IV infusion Drug: Pemetrexed IV infusion
Peking University
Beijing, Beijing Municipality, China
Shanghai Pulmonary Hospital
Shanghai, Shanghai Municipality, China
pCR rate
pCR in eligible stage IIA-IIIB (N2) NSCLC participants (AJCC Version 8, no known sensitizing EGFR or ALK alterations) following neoadjuvant pembrolizumab plus chemotherapy
Time frame: Up to approximately 16 months
Post-treatment proportion of CXCL13+PD1+ CD8 T cells in all CD8 T cells
Post-treatment proportion of CXCL13+PD1+ CD8 T cells in all CD8 T cells in single cell RNA-seq data
Time frame: Up to approximately 16 months
MPR in eligible stage IIA-IIIB (N2) NSCLC participants (AJCC Version 8, no known sensitizing EGFR or ALK alterations) following neoadjuvant pembrolizumab plus chemotherapy
MPR rate evaluated by investigator based on protocol defined criteria (the proportion of participants having ≤10% viable tumor cells in the resected primary tumor and all resected lymph nodes).
Time frame: Up to approximately 16 months
Event-free survival (EFS)
EFS is defined as the time from study intervention to the first of the following events: * Radiographic disease progression per RECIST 1.1 (for participants who have not had or will not have surgery, participants who have gross residual disease after an incomplete resection \[R2 resection\]); * Local progression (primary tumor or regional lymph nodes) precluding planned surgery; * Inability to resect the tumor; * Local or distant recurrence (for participants who are disease free after surgery or participants with microscopic positive margins \[R1 resection\]); * Death due to any cause.
Time frame: Up to approximately 46 months
Number of Participants with One or More Adverse Events
Participant experiencing AEs, participant discontinuing study intervention due to AEs, and participant experiencing perioperative complications.
Time frame: Up to approximately 46 months
PD-L1 TPS(Tumor Proportion Score) evaluation in pre-treatment patients
PD-L1 TPS(Tumor Proportion Score) evaluation in pre-treatment patients of pre-treatment tumor biopsy
Time frame: Up to approximately 16 months
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