Afatinib as Neoadjuvant Treatment for Stage III EGFR-Mutant Non-Small Cell Lung Cancer (TEAM-LungMate 004): A Prospective, Single-Arm, Phase II Study

Afatinib is a second-generation EGFR tyrosine kinase inhibitor recommended as the first-line treatment for patients with advanced EGFR mutant non-small cell lung cancer (NSCLC). The feasibility of neoadjuvant Afatinib for stage III EGFR mutant NSCLC was assessed in this phase II clinical trial.
Afatinib as Neoadjuvant Treatment for Stage III EGFR-Mutant Non-Small Cell Lung Cancer (TEAM-LungMate 004): A Prospective, Single-Arm, Phase II Study
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Non-small cell lung cancer (NSCLC) accounts for 85% of lung cancer cases1A higher proportion of NSCLC patients have epidermal growth factor receptor (EGFR) mutations, particularly among women, never smokers, East Asians, and those with adenocarcinoma2, 3EGFR tyrosine kinase inhibitors (EGFR-TKIs) have been recommended as the first-line treatment for advanced EGFR-mutant NSCLC patients (NSCLCm)4While, there are few clinical trials on the efficacy and safety of neoadjuvant EGFR-TKI treatment for locally advanced NSCLCmThis phase II clinical trial (TEAM-LungMate 004) assessed the feasibility of neoadjuvant Afatinib (a second-generation EGFR-TKI) for stage III NSCLCm. In addition, this study investigated the molecular characteristics that are associated with the efficacy of Afatinib, as well as explored the dynamic changes of tumor microenvironment induced by Afatinib.
Study Design
Treatment naive NSCLCm with stage III, older than 18 years, with an Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1, were enrolled in this study. Participants received 8 to 16 weeks administration of neoadjuvant Afatinib (Giotrif ®, Boehringer-Ingelheim Pharma GmbH, Ingelheim, Germany) therapy (NAT) (oral Afatinib 40mg, once-daily). Radical surgery should be performed within 3 weeks after Afatinib discontinuation for operable patients. Otherwise, patients who were still evaluated as inoperable after NAT will be withdrawn from the study and treated by MDT.The primary endpoint was objective response rate (ORR) accessed by the RECIST criteria. The secondary endpoints were major pathologic response (MPR) rate, pathologic complete response (pCR) rate, the complete resection (R0) rate, event-free survival (EFS), progression-free survival (PSF), disease-free survival (DFS), overall survival (OS) and treatment related adverse events (TRAEs).
Baseline Characteristics
Between July 2020 and February 2022, a total of 47 eligible NSCLCm in stage III were enrolled in this study. The majority of participants were female, never-smokers. The number of patients harbored Ex19Del mutation and L858R mutation was 28 and 16, respectively. Additionally, 3 participants had uncommon EGFR mutations. Besides, there were 26, 18, and 3 patients with stage IIIA, IIIB, and IIIc, respectively.
Efficacy

The ORR, was 70.2% (95% CI: 56.5%-84.0%) met the pre-specified primary endpoint. There were 33 patients received surgery after neoadjuvant treatment. The MPR, pCR, pathological downstaging, and R0 rates were 9.1%, 3.0%, 57.6%, and 87.9%, respectively.

Safety

All participants (100%) experienced TRAEs, but no grade 5 TRAEs were observed. Grade 3/4 TRAEs occurred in 3 patients (6.4%), including diarrhea, interstitial pneumonia, and hepatic impairment, respectively. Discontinuation of Afatinib was observed in only one patient due to grade 4 diarrhea. The most common TRAEs during NAT were diarrhea (78.7%), rash (78.7%). Surgery-related complications occurred in 4 patients, including prolonged air leakage (9.1%) and bronchopleural fistula (3.0%). No surgery-related death occurred within 90 days postoperatively.

Efficacy Associated Molecular Characteristics for Afatinib

Based on baseline tumor samples, Cytokine-Inducible SH2-Containing Protein (CISH)5-7 exhibited higher expression in responsive tumor samples compared to non-responsive samples at baseline (10 responsive samples vs 7 non-responsive samples, p = 0.007), the similar trend was confirmed in the CISH immunohistochemical (IHC) score (6 responsive samples vs 6 non-responsive samples, p = 0.100). CISH expression at baseline performed well in predicting positive response for Afatinib, as evidenced by RNA-seq and IHC score (AUC) = 0.918 and 0.792, respectively).
Anti-tumor Immunity Activation by Afatinib

By IHC score, the expression of programmed cell death 1 ligand 1 (PD-L1)  in primary tumor after NAT was significantly higher than those in baseline (p = 0.013), and this trend was validated in the evaluation of 5 paired samples before and after Afatinib treatment. By RNA-seq, “T cell receptor signaling” pathway was significantly enriched in responsive tumor samples, indicating T-cell activation and CD8+ T-cells infiltration after Afatinib treatment in responsive patients. Additionally, an increasing tendency of B-cellwas observed after Afatinib treatment drainage lymph node samples in responsive patients. Finally, the changes in the tumor microenvironment (TME) between different response groups after Afatinib treatment were observed. Several immune cells including T-cells, cytotoxic lymphocytes, B-cells, and NK cells were higher in responders.

Afatinib as a single-agent neoadjuvant therapy for stage III EGFR-mutant NSCLC offers a favorable objective tumor response and has an acceptable toxicity profile in clinical practice. Dynamic changes in TME are observed, particularly in responders, which may have implications for identifying predictive markers for EGFR-TKI treatment and guiding the future clinical trials.

1.    Goldstraw P, et al. The IASLC Lung Cancer Staging Project: Proposals for Revision of the TNM Stage Groupings in the Forthcoming (Eighth) Edition of the TNM Classification for Lung Cancer. J Thorac Oncol 11, 39-51 (2016).

2.    Zhao Y, et al. Efficacy and safety of first line treatments for patients with advanced epidermal growth factor receptor mutated, non-small cell lung cancer: systematic review and network meta-analysis. BMJ 367, l5460 (2019).

3.    Mitsudomi T, Suda K, Yatabe Y. Surgery for NSCLC in the era of personalized medicine. Nat Rev Clin Oncol 10, 235-244 (2013).

4.    Greenhalgh J, et al. First-line treatment of advanced epidermal growth factor receptor (EGFR) mutation positive non-squamous non-small cell lung cancer. The Cochrane database of systematic reviews 3, CD010383 (2021).

5.  Li S, et al. Cytokine-induced Src homology 2 protein (CIS) promotes T cell receptor-mediated proliferation and prolongs survival of activated T cells. J Exp Med 191, 985-994 (2000).

6.  Boudin L, et al. CISH Expression Is Associated with Metastasis-Free Interval in Triple-Negative Breast Cancer and Refines the Prognostic Value of PDL1 Expression. Cancers (Basel) 14,  (2022).

7.  Miah M, Yoon C, Kim J, Jang J, Seong Y, Bae Y. CISH is induced during DC development and regulates DC-mediated CTL activation. European journal of immunology 42, 58-68 (2012).

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