Non-small cell lung cancer (NSCLC) is the most common epithelial lung cancer accounting for approximately 80–85% of all lung cancers. Adenocarcinoma, the most frequent histological type, has a survival rate of approximately 4–6% at five years. Epidermal growth factor receptor (EGFR) mutations are found in 15–20% of adenocarcinomas. Osimertinib (Tagrisso®), an irreversible third-generation EGFR tyrosine kinase inhibitor (EGFR-TKI), prevents cell cycle progression by selectively targeting both EGFR-TKI-sensitising mutations and EGFRT790M resistance mutations, while sparing wild-type EGFR function. Following the phase III FLAURA trial in April 2018, osimertinib was approved by the US Food and Drug Administration (FDA) as first-line treatment for advanced NSCLC with EGFR Ex19del or L858R substitution mutations as detected by an FDA-approved test. While osimertinib is not approved in Europe for the first-line setting, the Committee for Medicinal Products for Human Use (CHMP) adopted a positive opinion recommending a change to the terms of the marketing authorisation of osimertinib in April 2018.

In the phase III, FLAURA study 556 patients with untreated advanced EGFR-mutated NSCLC were randomised 1:1 to osimertinib or standard of care (SoC) until disease progression or unacceptable toxicity. Compared with SoC EGFR-TKIs, osimertinib increased investigator-assessed median progression-free survival (PFS) by 8.7 months, and lowered the risk of disease progression or death by 54%. The PFS benefit was consistent across subgroups regardless of Asian or non-Asian race, Ex19del or L858R EGFR subtype, and presence or absence of central nervous system (CNS) metastases. Overall survival (OS) data were immature at interim analysis; however, 83% of osimertinib patients and 71% of SoC patients achieved 18-month survival. Grade ≥3 AEs were less common in the osimertinib group compared to SoC (34% versus 45%); however, decreased appetite (3%), pneumonia (2%), diarrhoea (2%), and prolonged QTc (2%) were most common. Cardiac and lung effects occurred more frequently in the osimertinib group than in the SoC group (10% and 4% versus 5% and 2%, respectively); notably cardiac failure (4%), prolonged QTc interval (10%), and interstitial lung disease (4%).

Overall, FLAURA is the first phase III, randomised, double-blind, comparative trial to demonstrate that osimertinib substantially increases PFS and lowers the risk of disease progression compared to first-generation EGFR-TKI as initial therapy for EGFR-mutated advanced NSCLC. The PFS benefit was consistent across subgroups. OS and QoL data are needed to confirm patients achieve a clinically relevant benefit over time despite favourable tolerability. Currently, the optimal therapeutic sequencing of different generations of EGFR-TKI remains unknown. However osimertinib holds efficacy for brain metastases which represent a significant clinical problem in patients treated with first and second generation EGFR-TKIs. Further analyses are necessary to fully characterise the resistance mechanisms to osimertinib for targeting by fourth-generation inhibitors. A new class of inhibitors, designed to target a triple mutation thought to confer resistance to fourth-generation EGFR-TKIs, is also under development.