Abstract
Tyrosine kinase inhibitors (TKIs) against the human epidermal growth factor receptor (EGFR) are now standard treatment in the clinic for patients with advanced EGFR mutant non-small-cell lung cancer (NSCLC). First-generation EGFR TKIs, binding competitively and reversibly to the ATP-binding site of the EGFR tyrosine kinase domain, have resulted in a significant improvement in outcome for NSCLC patients with activating EGFR mutations (L858R and Del19). However, after a median duration of response of ~12 months, all patients develop tumor resistance, and in over half of these patients this is due to the emergence of the EGFR T790M resistance mutation. The second-generation EGFR/HER TKIs were developed to treat resistant disease, targeting not only T790M but EGFR-activating mutations and wild-type EGFR. Although they exhibited promising anti-T790M activity in the laboratory, their clinical activity among T790M+ NSCLC was poor mainly because of dose-limiting toxicity due to simultaneous inhibition of wild-type EGFR. The third-generation EGFR TKIs selectively and irreversibly target EGFR T790M and activating EGFR mutations, showing promising efficacy in NSCLC resistant to the first- and second-generation EGFR TKIs. They also appear to have lower incidences of toxicity due to the limited inhibitory effect on wild-type EGFR. Currently, the first-generation gefitinib and erlotinib and second-generation afatinib have been approved for first-line treatment of metastatic NSCLC with activating EGFR mutations. Among the third-generation EGFR TKIs, osimertinib is today the only drug approved by the Food and Drug Administration and the European Medicines Agency to treat metastatic EGFR T790M NSCLC patients who have progressed on or after EGFR TKI therapy. In this review, we summarize the available post-progression therapies including third-generation EGFR inhibitors and combination treatment strategies for treating patients with NSCLC harboring EGFR mutations and address the known mechanisms of resistance.
Highlights
Over the past decade, scientific advances have progressively improved outcomes for patients diagnosed with lung cancers driven by target oncogene mutations
An unplanned pooled overall survival (OS) analysis of patients included in the LUX-Lung 3 or LUX-Lung 6 phase III trials demonstrated an OS benefit for afatinib compared to platinum-based chemotherapy in patients whose tumors harbor epidermal growth factor receptor (EGFR) Del19 mutations vs. EGFR L858R mutations: 27.3 vs. 24.3 months, respectively [hazard ratio (HR) 0.81; 95% confidence interval (CI), 0.66–0.99; p = 0.037] [14]
Three EGFR tyrosine kinase inhibitors (TKIs) are currently Food and Drug Administration (FDA) and European Medicines Agency (EMA) approved for first-line treatment of patients with sensitizing EGFR mutations in metastatic non-small-cell lung cancer (NSCLC)
Summary
Scientific advances have progressively improved outcomes for patients diagnosed with lung cancers driven by target oncogene mutations. Hoffmann-La Roche, Basel, Switzerland), and the second-generation TKI afatinib (Giotrif®, Boehringer Ingelheim, Ingelheim, Germany) have shown higher response rates (RRs), improving progression-free survival (PFS) and quality of life compared to standard platinum-based chemotherapy in patients with good performance status (0–2) whose tumors harbor an activating (sensitizing) EGFR mutation [6,7,8,9,10,11,12,13]. These data established EGFR TKIs as the treatment of choice for patients with newly diagnosed EGFR-mutant advanced NSCLC. On the basis of preclinical observations that afatinib plus cetuximab (an anti-EGFR monoclonal antibody) overcame T790M-mediated resistance [31], this combination was evaluated in a phase Ib trial enrolling 126 heavily pretreated patients with advanced EGFR-mutant NSCLC who had developed resistance
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