The US Food and Drug Administration ( FDA ) has approved Tagrisso ( Osimertinib ) for the 1st-line treatment of patients with metastatic non-small cell lung cancer ( NSCLC ) whose tumours have epidermal growth factor receptor ( EGFR ) mutations ( exon 19 deletions or exon 21 L858R mutations ), as detected by an FDA-approved test.
The approval is based on results from the phase III FLAURA trial, which were presented at the European Society of Medical Oncology 2017 Congress and published in the New England Journal of Medicine.
The FLAURA trial compared Osimertinib to current 1st-line EGFR tyrosine kinase inhibitors ( TKIs ), Erlotinib or Gefitinib, in previously-untreated patients with locally-advanced or metastatic EGFR-mutated ( EGFRm ) NSCLC.
Osimertinib met the primary endpoint of progression-free survival ( PFS ).
PFS results with Osimertinib were consistent across all pre-specified patient subgroups, including in patients with or without central nervous system ( CNS ) metastases.
Overall survival data were not mature at the time of the final PFS analysis.
Osimertinib extended progression-free survival compared with standard EGFR TKI therapy ( 18.9 months vs. 10.2 months; HR 0.46; 95% CI, 0.37-0.57 ).
Researchers observed these results across patient subgroups, including those with or without central nervous system metastases.
Safety data for Osimertinib in the FLAURA trial were in line with those observed in prior clinical trials.
Osimertinib was generally well tolerated, with grade 3 or higher adverse events ( AEs ) occurring in 34% of patients taking Osimertinib and 45% in the comparator arm.
The most common adverse reactions ( greater than or equal to 20% ) in patients treated with Osimertinib were diarrhoea ( 58% ), rash ( 58% ), dry skin ( 36% ), nail toxicity ( 35% ), stomatitis ( 29% ), fatigue ( 21% ) and decreased appetite ( 20% ).
In the US, Tagrisso is already approved for the 2nd-line treatment of patients with metastatic EGFRm NSCLC, whose disease has progressed on or after a 1st-line EGFR-TKI therapy and who have developed the secondary T790M mutation, as detected by an FDA-approved test.
In 2017, Tagrisso was granted Breakthrough Therapy and Priority Review designations by the US FDA in the 1st-line treatment setting.
Osimertinib is a third-generation, irreversible EGFR-TKI designed to inhibit both EGFR-sensitising and EGFR T790M-resistance mutations, with clinical activity against CNS metastases.
The FLAURA trial assessed the efficacy and safety of Osimertinib 80mg once daily versus standard-of-care EGFR-TKIs ( either Erlotinib [ 150mg orally, once daily ] or Gefitinib [ 250mg orally, once daily ] ) in previously-untreated patients with locally-advanced or metastatic EGFRm NSCLC.
The trial was double-blinded and randomised, with 556 patients across 29 countries.
Lung cancer is the leading cause of cancer death among both men and women, accounting for about one-fifth of all cancer deaths, more than breast, prostate and colorectal cancers combined. Approximately 10-15% of patients in the US and Europe, and 30-40% of patients in Asia have EGFRm NSCLC. These patients are particularly sensitive to treatment with EGFR-TKIs, which block the cell-signalling pathways that drive the growth of tumour cells.
Tumours almost always develop resistance to EGFR-TKI treatment, however, leading to disease progression.
Approximately half of patients develop resistance to approved EGFR-TKIs such as Gefitinib, Erlotinib and Afatinib due to the EGFR T790M resistance mutation.
There is also a need for medicines with improved CNS efficacy, since approximately 25% of patients with EGFRm NSCLC have brain metastases at diagnosis, increasing to approximately 40% within two years of diagnosis. ( Xagena )
Source: AstraZeneca, 2018