Neoadjuvant sintilimab plus chemotherapy in EGFR-mutant NSCLC: Phase 2 trial interim results (NEOTIDE/CTONG2104)

Summary

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.

Graphical abstract

Highlights

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  Neoadjuvant sintilimab and chemotherapy are clinically feasible in EGFR-mutant NSCLC

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  The treatment regimen is well tolerated, with comparable surgical outcome

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  Baseline genomic features and dynamic MRD help identify potential beneficiaries

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  CXCL13 ⁺Tex/CCR8 ⁺Treg cell phenotype predicts efficacy of pre- and post-immunotherapy

Abstract

Zhang et al. demonstrate the acceptable clinical feasibility and safety of neoadjuvant sintilimab and chemotherapy in patients with EGFR-mutant localized NSCLC. They highlight that the baseline genomic features and dynamic MRD detection help identify responders and illustrate that the CXCL13 ⁺ Tex/CCR8 ⁺ Treg cell infiltrating phenotype is correlated with diverse immune statuses and clinical efficacy of immunotherapy.