Two decades ago, lung cancer specialists had no targeted tools at their disposal to treat EGFR mutations, one of the most common drivers of non-small cell lung cancer (NSCLC). This began to change in the early 2000s with the Food and Drug Administration (FDA) approvals of the EGFR-directed tyrosine kinase inhibitors (TKIs) erlotinib (Tarceva) and gefitinib (Iressa).1,2 In 2013 and 2015 respectively, these first-generation TKIs were approved for the treatment of patients with metastatic NSCLC harboring EGFR exon 19 deletions or exon 21 L858R substitution mutations, which together represent the most common EGFR mutations.3,4 Erlotinib was specifically approved for use in patients receiving first-line, maintenance, or second- or later-line therapy after disease progression following at least one prior chemotherapy regimen; gefitinib was indicated for first-line use.1,2

Not long after erlotinib and gefitinib entered the EGFR-mutant NSCLC armamentarium, a second generation of TKIs tailored to this genetically specific population with metastatic disease arrived on the scene, including afatinib (Gilotrif) in 2013, and more recently, dacomitinib (Vizimpro) in 2018.5,6 These TKIs differed from their first-generation predecessors in that they irreversibly inhibited EGFR proteins, delivering higher efficacy with slightly increased toxicities such as diarrhea and rashes.7,8 However, patients’ tumors exposed to first- and/or second-generation TKIs ultimately develop resistance, most commonly with a T790M mutation, which affects the agents’ ability to bind to the EGFR binding site.

Fortunately, osimertinib (Tagrisso)—a TKI that selectively targets T790M and other mutated forms of EGFR—gained FDA approval in 2017 for the treatment of patients with metastatic, T790M-positive disease that progressed on or after an EGFR-directed TKI therapy.9 One year later, following positive results from the Phase 3 FLAURA trial (NCT02296125), this third-generation TKI was approved as an upfront treatment for patients with metastatic NSCLC whose tumors harbor EGFR exon 19 deletions or exon 21 L858R mutations.10,11

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Now, clinicians have 5 TKI monotherapies—as well as a recently approved anti-angiogenic-TKI combo—at their disposal, transforming the management of patients with metastatic, EGFR-mutated disease, said Edgardo S. Santos, MD, FACP, a clinical affiliate associate professor at Charles E. Schmidt College of Medicine at Florida Atlantic University in Boca Raton, Florida, and a medical oncologist and medical director of research services at Florida Precision Oncology in Aventura, Florida. “But [now] the question is, which one is better?”

Since its approval, osimertinib has quickly become the first-line agent of choice for this patient subgroup. This is based on favorable data from the phase 3 FLAURA trial (NCT02296125), in which investigators randomly assigned 556 patients with advanced NSCLC and an exon 19 or exon 21 L858R mutation to receive either osimertinib or one of 2 first-generation drugs. The median progression-free survival (PFS) was 18.9 months in the osimertinib group compared with 10.2 months with the other TKIs tested (erlotinib and gefitinib).10

Importantly, more recent data confirmed an overall survival (OS) benefit with osimertinib; the median OS with osimertinib was 38.6 months vs 31.8 months with first-generation EGFR TKIs.12  In addition, osimertinib “is very selective to the mutated receptor, and therefore has a better safety profile,” noted Suresh Ramalingam, MD, a professor in the department of hematology and medical oncology and the deputy director of the Winship Cancer Institute of Emory University in Atlanta, Georgia. Because osimertinib better penetrates the brain vs other EGFR-directed TKIs and has activity against brain metastases, experts in the field maintain that there is no question that osimertinib is the preferred agent for patients with brain masses.