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Neoadjuvant sintilimab plus chemotherapy in EGFR-mutant NSCLC: Phase 2 trial interim results (NEOTIDE/CTONG2104)
Chao Zhang1, Yu-Xuan Sun2, Ding-Cheng Yi2
1Department of Pulmonary Surgery, Guangdong Lung Cancer Institute, Guangdong Provincial People's Hospital (Guangdong Academy of Medical Sciences), Southern Medical University, Guangzhou, China; Guangdong Lung Cancer Institute, Guangdong Provincial People's Hospital (Guangdong Academy of Medical Sciences), Southern Medical University, Guangzhou, China; School of Medicine, South China University of Technology, Guangzhou, China.
Abstract:
The clinical efficacy of neoadjuvant immunotherapy plus chemotherapy remains elusive in localized epidermal growth factor receptor (EGFR)-mutant non-small cell lung cancer (NSCLC). Here, we report interim results of a Simon's two-stage design, phase 2 trial using neoadjuvant sintilimab with carboplatin and nab-paclitaxel in resectable EGFR-mutant NSCLC. All 18 patients undergo radical surgery, with one patient experiencing surgery delay. Fourteen patients exhibit confirmed radiological response, with 44% achieving major pathological response (MPR) and no pathological complete response (pCR). Similar genomic alterations are observed before and after treatment without influencing the efficacy of subsequent EGFR-tyrosine kinase inhibitors (TKIs) in vitro. Infiltration and T cell receptor (TCR) clonal expansion of CCR8+ regulatory T (Treg)hi/CXCL13+ exhausted T (Tex)lo cells define a subtype of EGFR-mutant NSCLC highly resistant to immunotherapy, with the phenotype potentially serving as a promising signature to predict immunotherapy efficacy. Informed circulating tumor DNA (ctDNA) detection in EGFR-mutant NSCLC could help identify patients nonresponsive to neoadjuvant immunochemotherapy. These findings provide supportive data for the utilization of neoadjuvant immunochemotherapy and insight into immune resistance in EGFR-mutant NSCLC.
Insights
Neoadjuvant immunotherapy combined with chemotherapy shows promise for EGFR-mutant non-small cell lung cancer (NSCLC). However, specific T-cell profiles indicate resistance, suggesting potential biomarkers for treatment response in NSCLC.
Area of Science:
- Oncology
- Immunology
- Genetics
Background:
- Neoadjuvant immunotherapy plus chemotherapy efficacy is unclear in EGFR-mutant non-small cell lung cancer (NSCLC).
- EGFR mutations are a key driver in NSCLC, influencing treatment strategies.
Purpose of the Study:
- To evaluate the clinical efficacy of neoadjuvant sintilimab with chemotherapy in resectable EGFR-mutant NSCLC.
- To identify biomarkers predicting response or resistance to neoadjuvant immunochemotherapy in NSCLC.
Main Methods:
- Phase 2 trial with Simon's two-stage design.
- Administered neoadjuvant sintilimab, carboplatin, and nab-paclitaxel.
- Assessed radiological and pathological responses, genomic alterations, and T-cell receptor (TCR) profiles.
Main Results:
- 14 out of 18 patients showed radiological response; 44% achieved major pathological response (MPR).
- Genomic alterations remained similar pre- and post-treatment.
- A specific T-cell phenotype (CCR8+ regulatory T/CXCL13+ exhausted T cells) correlated with immunotherapy resistance.
Conclusions:
- Neoadjuvant immunochemotherapy provides supportive data for EGFR-mutant NSCLC treatment.
- T-cell phenotypes and ctDNA detection may predict immunotherapy response and identify non-responders.
- Findings offer insights into immune resistance mechanisms in EGFR-mutant NSCLC.
