Mefatinib as first-line treatment of patients with advanced EGFR-mutant non-small-cell lung cancer: a phase Ib/II efficacy and biomarker study

  • Signal Transduct Target Ther. 2021 Nov 1;6(1):374. doi: 10.1038/s41392-021-00773-3.
Pingli Wang  #  1 ,  Yuping Li  #  2 ,  Dongqing Lv  #  3 ,  Lingge Yang  4 ,  Liren Ding  1 ,  Jianya Zhou  5 ,  Wei Hong  6 ,  Youfei Chen  1 ,  Dongqing Zhang  2 ,  Susu He  3 ,  Jianying Zhou  7 ,  Kai Wang  8  9
Affiliations
  • 1. Department of Respiratory and Critical Care Medicine, The Second Affiliated Hospital of Zhejiang University School of Medicine, Hangzhou, China.
  • 2. Department of Respiratory and Critical Care Medicine, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, China.
  • 3. Department of Respiratory Medicine, Taizhou Hospital of Zhejiang Province Affiliated to Wenzhou Medical University, Linhai, China.
  • 4. Department of Respiratory and Critical Care Medicine, The Fourth Affiliated Hospital of Zhejiang University School of Medicine, Yiwu, China.
  • 5. Department of Respiratory Diseases, Thoracic Disease Diagnosis and Treatment Center, The First Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou, China.
  • 6. Department of Oncology and Chemotherapy, Zhejiang Cancer Hospital, Hangzhou, China.
  • 7. Department of Respiratory Diseases, Thoracic Disease Diagnosis and Treatment Center, The First Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou, China. [email protected].
  • 8. Department of Respiratory and Critical Care Medicine, The Second Affiliated Hospital of Zhejiang University School of Medicine, Hangzhou, China. [email protected].
  • 9. Department of Respiratory and Critical Care Medicine, The Fourth Affiliated Hospital of Zhejiang University School of Medicine, Yiwu, China. [email protected].
  • # Contributed equally.
PMID: 34719670 DOI: 10.1038/s41392-021-00773-3
Abstract

EGFR inhibitors have revolutionized the treatment of advanced non-small-cell lung Cancer (NSCLC). Mefatinib is a novel, bioavailable, second-generation, irreversible pan-EGFR inhibitor. This phase Ib/II open-label, single-arm, multi-center study investigated the efficacy, safety, biomarker, and resistance mechanisms of mefatinib in the first-line treatment of patients with advanced EGFR-mutant NSCLC. This study included 106 patients with EGFR-mutant stage IIIB-IV NSCLC who received first-line mefatinib at a daily dose of either 60 mg (n = 51) or 80 mg (n = 55). The primary endpoint was progression-free survival (PFS). Secondary endpoints were overall response rate (ORR), disease control rate (DCR), overall survival (OS), and safety. The cohort achieved an ORR of 84.9% and DCR of 97.2%. The median PFS was 15.4 months and the median OS was 31.6 months. Brain metastasis was detected in 29% of patients (n = 31) at diagnosis and demonstrated an ORR of 87.1%, PFS of 12.8 months, and OS of 25.2 months. Adverse events primarily involved skin and gastrointestinal toxicities, which were well-tolerated and manageable. Analyses of mutation profiles were performed using targeted Sequencing of plasma samples at baseline, first follow-up 6 weeks from starting mefatinib therapy (F1), and at progression. Patients with concurrent TP53 mutations had comparable PFS as wild-type TP53 (14.0 vs 15.4 months; p = 0.315). Furthermore, circulating tumor DNA clearance was associated with longer PFS (p = 0.040) and OS (p = 0.002). EGFR T790M was the predominant molecular mechanism of mefatinib resistance (42.1%, 16/38). First-line mefatinib provides durable PFS and an acceptable toxicity profile in patients with advanced EGFR-mutant NSCLC.

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