Next-GenerationEGFRTyrosine Kinase Inhibitors for TreatingEGFR-Mutant Lung Cancer beyond First Line.
Tyrosine kinase inhibitors (TKIs) against the human epidermal growth factor receptor (EGFR) are now standard treatment in the clinic for patients with advancedEGFRmutant non-small-cell lung cancer (NSCLC). First-generationEGFRTKIs, binding competitively and reversibly to the ATP-binding site of theEGFRtyrosine kinase domain, have resulted in a significant improvement in outcome for NSCLC patients with activatingEGFRmutations (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 theEGFRT790M resistance mutation. The second-generationEGFR/HERTKIs were developed to treat resistant disease, targeting not only T790M butEGFR-activating mutations and wild-typeEGFR. 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-typeEGFR. The third-generationEGFRTKIs selectively and irreversibly targetEGFRT790M and activatingEGFRmutations, showing promising efficacy in NSCLC resistant to the first- and second-generationEGFRTKIs. They also appear to have lower incidences of toxicity due to the limited inhibitory effect on wild-typeEGFR. Currently, the first-generation gefitinib and erlotinib and second-generation afatinib have been approved for first-line treatment of metastatic NSCLC with activatingEGFRmutations. Among the third-generationEGFRTKIs, osimertinib is today the only drug approved by the Food and Drug Administration and the European Medicines Agency to treat metastaticEGFRT790M NSCLC patients who have progressed on or afterEGFRTKI therapy. In this review, we summarize the available post-progression therapies including third-generationEGFRinhibitors and combination treatment strategies for treating patients with NSCLC harboringEGFRmutations and address the known mechanisms of resistance.
Department Medical Oncology, Gustave Roussy , Villejuif , France.
Ivana
I
Sullivan
Department Medical Oncology, Gustave Roussy , Villejuif , France.
David
D
Planchard
EGFR; NSCLC; T790M; brain metastasis; osimertinib; third generation