his multicenter, open-label, single-arm phase I/II trial will evaluate the safety, tolerability, and preliminary efficacy of oral paclitaxel solution combined with an immune checkpoint inhibitor and concurrent stereotactic body radiotherapy (SBRT) as neoadjuvant therapy in patients aged 70 years or older with resectable stage IIA-IIIB non-small cell lung cancer (NSCLC) without sensitizing EGFR, ALK, or ROS1 alterations.
In Phase I, a 3+3 dose-escalation design will evaluate oral paclitaxel at 80, 120, and 160 mg/m² administered orally on Days 1 and 8 of each cycle, divided into morning and evening doses, in combination with an investigator-selected anti-PD-1 or anti-PD-L1 monoclonal antibody and SBRT at 8 Gy in 3 fractions. Phase II will expand enrollment at the recommended Phase II dose (RP2D). The principal efficacy outcome is pathologic complete response after surgery. Other outcomes include major pathologic response, radiographic response, event-free survival, overall survival, surgical resection and R0 resection rates, and exploratory biomarker changes.
Age 70 years or older, regardless of sex.
Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1.
Histologically confirmed non-small cell lung cancer, clinical stage IIA-IIIB according to the 8th edition of the AJCC staging system.
No evidence of distant metastasis and considered suitable for radical lung cancer surgery.
Prior lobectomy, thoracic radiotherapy, or systemic antitumor therapy.
Another concurrent malignancy or a history of another malignancy cured less than 5 years before enrollment, except adequately treated cervical carcinoma in situ or basal cell or squamous cell carcinoma of the skin.
Active autoimmune disease or a history of autoimmune disease requiring systemic immunosuppressive treatment.
Active infection requiring systemic treatment, active tuberculosis, human immunodeficiency virus infection, active hepatitis B or hepatitis C, active syphilis, or another active transmissible infection specified by the protocol.
Parallel
Oral Paclitaxel Solution
DrugPhase I dose levels: 80 mg/m², 120 mg/m², and 160 mg/m², administered orally on Days 1 and 8 of each cycle in divided morning and evening doses. Phase II: oral paclitaxel solution at the RP2D.
PD-1/PD-L1 inhibitor
DrugAn PD-1/PD-L1 inhibitor selected by the investigator according to standard of care and administered according to the approved prescribing information
Stereotactic Body Radiotherapy (SBRT)
RadiationSBRT at 8 Gy per fraction for 3 fractions to the primary lung tumor and selected lymph node regions.
Radical Lung Cancer Surgery
Procedure/SurgeryParticipants considered operable after neoadjuvant therapy are intended to undergo radical lung cancer surgery.
Stereotactic Body Radiotherapy (SBRT)
RadiationParticipants considered inoperable after neoadjuvant therapy are intended to continue SBRT at radical dose assessed by department of radiotherapy.
Complete Response (CR) Rate in Phase 2
The percentage of participants in the Phase 2 operable cohort who achieve a CR according to RECIST v1.1, at the protocol-specified preoperative tumor assessment. A CR is defined as the disappearance of all target lesions. Any pathological lymph nodes must have a reduction in the short axis to less than 10 mm. Participants who discontinue treatment, experience disease progression, become unable to undergo the planned response assessment, or have no evaluable post-baseline tumor assessment will be classified as not having achieved a CR.
Incidence of Grade 3 or Higher Treatment-Related Adverse Events (TRAE) in Phase 1
The percentage of participants in the Phase 1 dose-escalation cohort who experience at least one Grade 3 or higher TRAE during the safety assessment period. Adverse events will be graded according to the CTCAE 5.0. The relationship of each adverse event (AE) to oral paclitaxel solution, the anti-PD-1 antibody, radiotherapy, or the combination regimen will be assessed by the investigator.
CR Rate in Phase 1
The percentage of participants in the Phase 1 dose-escalation cohort who achieve a CR according toRECIST v1.1. A CR is defined as the disappearance of all target lesions, with any pathological lymph nodes having a reduction in the short axis to less than 10 mm.
Two-Year Event-Free Survival (EFS) Rate
The percentage of participants in the Phase 1/2 who remain alive and event-free at 2 years after first dose up. An event is defined as any of the following: Disease progression that precludes planned curative-intent treatment; Local, regional, or distant disease progression or recurrence; Death from any cause. Participants without an event will be censored at the date of their last adequate disease assessment.
Two-Year Overall Survival (OS) Rate
The percentage of participants in the Phase 2 who are alive at 2 years after first dose. Participants who are alive or whose survival status is unknown at the data cutoff will be censored at the date they were last known to be alive.
Incidence of AE
The percentage of participants in Phase 2 who experience treatment-emergent adverse events (TEAE), TRAE, Grade 3 or higher AE, serious adverse events (SAE), immune-related adverse events(irAE), or radiation-related AE. Adverse events will be graded according to CTCAE 5.0. Postoperative complications occurring during the protocol-specified postoperative safety period will also be summarized.
Change From Baseline in Circulating Tumor DNA (ctDNA)
Changes in ctDNA levels and molecular residual disease status will be evaluated from baseline to protocol-specified post-treatment and follow-up assessments. The association between ctDNA clearance or persistence and CR, EFS, and OS will be explored separately in Phase 2 Cohorts A and B.
Change From Baseline in PD-L1 Expression
Changes in tumor PD-L1 expression from baseline to the available post-treatment tissue assessment will be evaluated using the protocol-specified immunohistochemical assay. The association between baseline or post-treatment PD-L1 expression and CR will be explored separately in Phase 2 Cohorts A and B.
Change From Baseline in Tumor and Peripheral Immune Cell Subsets
Changes in protocol-specified tumor-infiltrating and peripheral immune cell subsets will be evaluated from baseline to post-treatment assessments. Exploratory analyses will assess the association between changes in immune cell subsets and CR, EFS, and OS separately in Phase 2 Cohorts A and B.
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