Dual Inhibition of EGFR with Afatinib and Cetuximab in Kinase Inhibitor-Resistant EGFR-Mutant Lung Cancer with and without T790M Mutations

Yelena Y. Janjigian*, Egbert F. Smit, Harry J. M. Groen, Leora Horn, Scott Gettinger, D. Ross Camidge, Gregory J. Riely, Bushi Wang, Yali Fu, Vikram K. Chand, Vincent A. Miller, William Pao

*Corresponding author for this work

    Research output: Contribution to journalArticleAcademicpeer-review

    283 Citations (Scopus)

    Abstract

    EGFR-mutant lung cancers responsive to reversible EGFR inhibitors (gefitinib/erlotinib) develop acquired resistance, mediated by second-site EGFR T790M mutation in >50% of cases. Preclinically, afatinib (irreversible ErbB family blocker) plus cetuximab (anti-EGFR monoclonal antibody) overcomes T790M-mediated resistance. This phase lb study combining afatinib and cetuximab enrolled heavily pretreated patients with advanced EGFR-mutant lung cancer and acquired resistance to erlotinib/gefitinib. Patients provided post-acquired-resistance tumor samples for profiling EGFR mutations. Among 126 patients, objective response rate (overall 29%) was comparable in T790M-positive and T790M-negative tumors (32% vs. 25%; P = 0.341). Median progression-free survival was 4.7 months (95% confidence interval, 4.3-6.4), and the median duration of confirmed objective response was 5.7 months (range, 1.8-24.4). Therapy-related grade 3/4 adverse events occurred in 44%/2% of patients. Afatinib-cetuximab demonstrated robust clinical activity and a manageable safety profile in EGFR-mutant lung cancers with acquired resistance to gefitinibor erlotinib, both with and without T790M mutations, warranting further investigation.

    SIGNIFICANCE: This article reports the results of a trial combining afatinib and cetuximab in patients with acquired resistance and details the first clinical proof-of-concept for the preclinical hypothesis that a significant proportion of tumors in patients with acquired resistance to gefitinib/erlotinib remain dependent on EGFR signaling for survival. (C) 2014 AACR.

    Original languageEnglish
    Pages (from-to)1036-1045
    Number of pages10
    JournalCancer discovery
    Volume4
    Issue number9
    DOIs
    Publication statusPublished - Sep-2014

    Keywords

    • GROWTH-FACTOR RECEPTOR
    • PHASE-II TRIAL
    • ACQUIRED-RESISTANCE
    • MONOCLONAL-ANTIBODY
    • 1ST-LINE TREATMENT
    • OPEN-LABEL
    • GEFITINIB
    • ERLOTINIB
    • CHEMOTHERAPY
    • AMPLIFICATION

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