Erlotinib and trametinib in patients with EGFR-mutant lung adenocarcinoma and acquired resistance to a prior tyrosine kinase inhibitor Journal Article


Authors: Luo, J.; Makhnin, A.; Tobi, Y.; Ahn, L.; Hayes, S. A.; Iqbal, A.; Ng, K.; Arcila, M. E.; Riely, G. J.; Kris, M. G.; Yu, H. A.
Article Title: Erlotinib and trametinib in patients with EGFR-mutant lung adenocarcinoma and acquired resistance to a prior tyrosine kinase inhibitor
Abstract: PURPOSE Inhibition of the MEK/ERK pathway is critical for Bcl-2-like protein 11 (BIM)-mediated epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor (TKI)-induced apoptosis, and dysregulation of this pathway may be a mechanism of acquired resistance. Therefore, MEK inhibition with trametinib and an EGFR TKI may resensitize tumors with acquired resistance. Limited targeted therapies are available after progression on EGFR TKIs, and it is in this setting that we completed a phase I/II study of erlotinib and trametinib. METHODS Patients with metastatic EGFR-mutant lung adenocarcinoma and acquired resistance to an EGFR TKI received combination erlotinib 75 mg and trametinib 1.5 mg daily until progression or unacceptable side effects. The primary objective was objective response rate determined using RECIST version 1.1. RESULTS Twenty-three patients were accrued; patients had received a median of two lines of prior TKI therapy (61% prior osimertinib), and 48% had acquired EGFR T790M. We confirmed one partial response (1/23, 4%, 95% CI, 0 to 22). The median progression-free survival was 1.8 months, and the median overall survival was 21 months. Diarrhea (87%), acneiform rash (87%), and fatigue (52%) were the most common treatment-related adverse events. Two patients who had tumor shrinkage both harbored a BRAF fusion. CONCLUSION Addition of trametinib to erlotinib in the acquired resistance setting in an unselected population is not efficacious. Future studies should focus on targeted therapies in molecularly selected populations. Acquired BRAF fusions in patients with EGFR-sensitizing mutations may be a molecular subset where EGFR and MEK combination therapy could be studied further. © 2021 American Society of Clinical Oncology. All rights reserved.
Journal Title: JCO Precision Oncology
Volume: 5
ISSN: 2473-4284
Publisher: American Society of Clinical Oncology  
Date Published: 2021-01-01
Start Page: 55
End Page: 64
Language: English
DOI: 10.1200/po.20.00315
PROVIDER: scopus
PMCID: PMC8232136
PUBMED: 34250388
DOI/URL:
Notes: Article -- Export Date: 3 January 2022 -- Source: Scopus
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MSK Authors
  1. Kenneth K Ng
    58 Ng
  2. Helena Alexandra Yu
    288 Yu
  3. Gregory J Riely
    604 Riely
  4. Linda Su Hyun Ahn
    25 Ahn
  5. Maria Eugenia Arcila
    669 Arcila
  6. Mark Kris
    872 Kris
  7. Sara Anne Hayes
    33 Hayes
  8. Afsheen Naz Iqbal
    22 Iqbal
  9. Alex Makhnin
    20 Makhnin
  10. Jia Luo
    27 Luo
  11. Yosef Y Tobi
    6 Tobi