Neoadjuvant PD-1 Blockade Plus Platinum-based Chemotherapy for EGFR-mutant NSCLC (CTONG2104): An Interim Analysis
Introduction: Pathological response of neoadjuvant EGFR-TKIs in early-stage NSCLC is discounted and whether immunotherapy
plus chemotherapy yield greater efficacy for these patients remains unknown. Herein, we report an interim analysis of a phase 2
prospective trial (NCT05244213).
Methods: This is an open-label, phase 2 prospective trial with Simon two-stage design. 35 patients with stage IIB-IIIB (N2) and
EGFR mutation were estimated to enroll, and 3 cycles sintilimab plus chemotherapy would be provided followed by surgery
(Figure 1A). The primary endpoint was major pathological response (MPR). Longitudinal tumor-informed MRD, single-cell RNA/
whole exome/ transcriptome sequencing, dynamic flow cytometry and organoid-based experiments were performed.
Results: By March 17, 2023, 13 patients were consecutively enrolled and 10 patients had completed neoadjuvant treatment and
surgery. All patients completed 3 cycles neoadjuvant treatment and one patient had delayed surgery due to pneumothorax.
The confirmed ORR was 70% (7/10). While no pCR was observed, 30% patients achieved MPR which met the primary endpoint
for stage I in advance (Figure 1B). The N/N2 downstaging rate was 50%. For safety profile and surgical outcome, the most
commonly reported grade 3 or worse adverse event was neutropenia (20%) while others were mostly grade 1/2. All patients
were performed minimally invasive lobectomy and achieved R0 resection except for one with occult pleura metastasis.
Peripheral/hilar adhesion and intraoperative fibrosis was 50% and 40%, respectively. 20% patients had grade 2 postoperative
complications regarding Clavien Dindo. In terms of 20% cutoff for median residual viable tumors, significantly increased plasma
IL-8 was found in responder (p=0.05) while decreased in non-responders (p=0.03). Plasma CD69+CD4+/CD8+early activated
lymphocytes were notably elevated after neoadjuvant treatment in responders. Whole-exome sequencing of primary tumor
along with matched PBMC were sequenced and 50-gene assay MRD was established. Despite MRD was negative at 30-day
after surgery following neoadjuvant treatment for both responders and non-responders, deeper mean tumor molecules (MTM)
clearance after initial cycle of treatment was found in responders. By integrating single-cell RNA/TCR sequencing of this study
and a real-world cohort of EGFR-mutant NSCLCs treated with neoadjuvant immunotherapy plus chemotherapy, we identified
enriched TNFRSF4+activated Treg and remarkably TCR expansion of FOXP3+Treg in non-responders while predominant TCR
expansion of CXCL13+Tpex, ZNF683+CXCR6+Trm and FGFBP2+NK-like CD8T in responders.
Conclusions: Neoadjuvant sintilimab plus chemotherapy showed superior efficacy in localized EGFR-mutant NSCLC.
Longitudinal multi-omics analysis is required to tailor more optimal treatment modalities for localized EGFR-mutant NSCLC as
well as providing insight of combination strategies for advanced NSCLC.
