Lung cancer is the malignant tumor with the highest incidence rate in China, and EGFR is the most common driver gene for lung cancer.EGFR-TKI has become the first-line standard treatment for advanced EGFR-mutant NSCLC and the first choice for postoperative adjuvant therapy in locally advanced patients. However, the evidence for neoadjuvant EGFR-TKI-targeted therapy for locally advanced EGFR-mutant NSCLC is insufficient.

Recently, the TEAM-LungMate 004 clinical study initiated by the team of Prof. Jiang Geling and Prof. Zhang Peng from the Department of Thoracic Surgery, Shanghai Pulmonary Hospital, Tongji University, has published the latest results of "Neoadjuvant Afatinib for Stage III EGFR-Mutated NSCLC" in Nature Communications, an internationally recognized academic journal. Stage III EGFR-Mutant Non-Small Cell Lung Cancer: A Phase II Study". This is the first prospective clinical study of a second-generation EGFR-TKI for the neoadjuvant treatment of EGFR-mutant NSCLC, filling a gap in the field of neoadjuvant therapy. It also reveals the biological characteristics of EGFR-TKI-targeted therapy-sensitive population for the first time through the multi-omics analysis of tumor tissue samples, and explores the impact of EGFR-TKI-targeted therapy on the tumor immune microenvironment of patients. This study provides new ideas and solutions for the treatment of patients with locally advanced NSCLC with EGFR mutations.

Study Design

TEAM-LungMate 004 is a single-center, single-arm, open-label, prospective, phase II clinical study in which a total of 47 subjects with EGFR-mutant stage III primary NSCLC were screened between July 20, 2020 and February 10, 2022 and treated with afatinib maleate tablets (Giotrif ? , Boehringer-Ingelheim Pharma GmbH, Ingelheim, Germany) for 8 to 16 weeks of neoadjuvant induction therapy, and subjects evaluated as resectable were treated surgically and conversely continued with targeted therapy. The primary study endpoint of the study was objective remission rate (ORR).

Results

The ORR after neoadjuvant therapy was 70.2% in all subjects (Figure 1), which met the prespecified primary study endpoint. This was a significant advantage over the historical data of patients treated with first-generation EGFR-TKI1 , while the objective remission rate of neoadjuvant targeted therapy with second-generation EGFR-TKI was close to that of third-generation EGFR-TKI.2 During the neoadjuvant treatment period, the incidence of grade 3-4 adverse events was low (3/47, 6.4%) and no grade 5 adverse events occurred, resulting in a manageable safety profile of the treatment.

Figure 1: Objective remission rate after neoadjuvant therapy

Thirty-six subjects were evaluated as operable after neoadjuvant therapy, of whom 33 completed neoadjuvant therapy combined with pneumonectomy. No conditions leading to delayed surgery or increased surgical complications were identified after neoadjuvant targeted therapy. Of all 33 patients who underwent surgery, the major pathologic remission (MPR) rate was 9.1% and the pathologic complete remission (pCR) rate was 3.0%, similar to previous data published for neoadjuvant therapy with first- and third-generation EGFR-TKIs. Follow-up data showed that subjects treated with afatinib neoadjuvant therapy had a 1-year survival rate of 100%, a 2-year survival rate of nearly 90%, and a 2-year progression-free survival rate of 76.6%.

Biomarker Exploration

   The study collected pre- and post-treatment tumor as well as metastatic lymph node samples for Bulk RNA sequencing. Analysis of differential gene expression comparing treatment responders and non-responders revealed that patients responding to afatinib had high expression of CISH at baseline and that patients with high CISH expression had longer event-free survival (Figure 2). In addition, the authors found significantly different changes in the tumor microenvironment before and after treatment in responders and nonresponders. Responders exhibited features of immune activation after treatment: increased infiltration of T cells and B cells in the tumor and metastatic lymph nodes, respectively. In contrast, non-responders exhibited upregulation of VEGFB expression and epithelial-mesenchymal transition (EMT) signaling.

Figure 2: Bulk RNA sequencing analysis identifies response markers as well as tumor microenvironment characteristics

Significance of the study

This study confirms the promise of applying the regimen of neoadjuvant targeted therapy with afatinib in locally advanced EGFR-mutant NSCLC. Against the backdrop of the challenge of resistance to targeted therapies that has yet to be conquered, the opportunity to renew third-generation EGFR-TKI therapy is preserved for patients while ensuring that neoadjuvant therapy is safe and efficient. By analyzing the tumor tissue samples of subjects before and after treatment, we identified that CISH can predict the therapeutic effect of afatinib, and revealed the characteristics of the tumor immune microenvironment in the targeted therapy-sensitive population, which provides an important theoretical basis for precision targeted therapy, targeted combined anti-angiogenic therapy, and targeted sequential immunotherapy.

Link to original article：https://www.nature.com/articles/s41467-023-40349-z