Anhui Provincial Cancer Hospital

This prospective, single-center clinical trial will enroll 30 treatment-naïve patients with locally advanced, resectable stage II-IIIA non-small cell lung cancer (NSCLC) to receive neoadjuvant Shenqi Fuzheng Injection (SFI) in combination with a PD-1 inhibitor and platinum-based chemotherapy. The primary endpoint is the pathological complete response (pCR) rate, while secondary endpoints include the major pathological response (MPR) rate and event-free survival (EFS). Furthermore, single-cell and spatial transcriptomics will be employed to dynamically track alterations in the immune regulatory network within the tumor microenvironment (TME) pre- and post-SFI administration. This approach aims to elucidate how SFI remodels the TME immune landscape and to uncover its potential advantages in improving clinical outcomes. Additionally, we will investigate the synergistic effects of SFI combined with PD-1 blockade and platinum-based chemotherapy, with the ultimate goal of advancing the integration of traditional Chinese medicine into the therapeutic paradigm for resectable NSCLC.

**Brief Summary (English)**
The goal of this clinical trial is to learn if a risk-adaptive consolidation therapy, guided by cerebrospinal fluid (CSF) circulating tumor DNA (ctDNA) clearance kinetics after induction intrathecal pemetrexed, can improve intracranial progression-free survival (iPFS) compared to standard intrathecal pemetrexed consolidation in patients with leptomeningeal metastasis (LM) from EGFR-mutant non-small cell lung cancer (NSCLC) that has progressed on third-generation EGFR-TKIs. It will also learn about the safety and tolerability of proton craniospinal irradiation (pCSI) in this setting.
The main questions it aims to answer are:
* Does risk-adaptive consolidation therapy (pCSI with or without concurrent low-dose intrathecal pemetrexed) prolong iPFS compared to standard intrathecal pemetrexed consolidation?
* What medical problems do participants have when receiving pCSI or intrathecal pemetrexed?
Researchers will compare the experimental arm (risk-adaptive consolidation: pCSI for intermediate-risk, or pCSI with concurrent low-dose intrathecal pemetrexed for high-risk patients) to the control arm (standard intrathecal pemetrexed consolidation) to see if the adaptive strategy improves survival outcomes.
Participants will:
* Receive induction intrathecal pemetrexed (40 mg, biw, q3w for 2 cycles) via Ommaya reservoir.
* Undergo CSF collection at baseline and after induction for ctDNA (maxVAF) analysis to determine risk stratification (low, intermediate, high).
* If stratified as intermediate or high risk, be randomly assigned to either standard intrathecal pemetrexed consolidation or risk-adaptive consolidation (pCSI 30 GyE/10f for intermediate-risk; pCSI 30 GyE/10f with concurrent intrathecal pemetrexed 30 mg on d1, d8 for high-risk).
* Receive maintenance intrathecal pemetrexed (40 mg, q4w) until intracranial progression.
* Undergo regular efficacy assessments (contrast-enhanced MRI of brain and whole spine) every 8 weeks, and complete neurocognitive and quality-of-life questionnaires.