The European Commission has granted marketing authorisation for Tagrisso ( Osimertinib ), a third-generation, irreversible EGFR-TKI, as monotherapy for the 1st-line treatment of adult patients with locally-advanced or metastatic non-small cell lung cancer ( NSCLC ) with activating epidermal growth factor receptor ( EGFR ) mutations.
The approval is based on results from the phase III FLAURA trial published in the New England Journal of Medicine ( NEJM ).
The FLAURA trial is changing medical practice in the 1st-line treatment of EGFR-mutated NSCLC. The progression-free survival benefit seen in the trial is unprecedented for patients with an EGFR mutation, and this benefit was consistent across all subgroups including in patients with or without central nervous system metastases. Further, the preliminary overall survival data, while not statistically significant at the time of the interim analysis, is promising, with a 37% reduction in the risk of death.
In the FLAURA trial, 556 treatment-naïve patients with EGFR-positive locally advanced or metastatic NSCLC were randomly assigned to Osimertinib ( n = 279 ) or a standard TKI ( Erlotinib or Gefitinib; n = 277 ).
Patients with CNS metastases were allowed on the trial and all patients had exon 19 deletions or L858R mutations.
Daily oral therapy was given with 80 mg of Osimertinib, 250 mg of Gefitinib, or 150 mg of Erlotinib.
The objective response rate with Osimertinib was 80% compared with 76% for Erlotinib and Gefitinib ( odds ratio, OR=1.28, 95% CI, 0.85-1.93; P = 0.2335 ).
The median duration of response with Osimertinib was 17.2 months versus 8.5 months in the comparator arm.
In patients with CNS metastases ( n = 116 ), the median progression-free survival ( PFS ) with Osimertinib was 15.2 months ( 95% CI, 12.1-24.4 ) compared with 9.6 months ( 95% CI, 7.0-12.4 ) with standard therapy ( hazard ratio, HR=0.47; 95% CI, 0.30-0.74; P = 0.0009 ).
In those without CNS involvement ( n=440 ), the median PFS was 19.1 months ( 95% CI, 15.2-23.5 ) and 10.9 months ( 95% CI, 9.6-12.3 ), for Osimertinib and the control arm, respectively ( HR=0.46; 95% CI, 0.36-0.59; P less than 0.0001 ).
Across all patients, CNS progression occurred in 6% treated with Osimertinib versus 15% for Erlotinib and Gefitinib.
Safety data for Osimertinib from the FLAURA, AURA3, AURA and AURA2 trials were evaluated. Osimertinib was well tolerated, with most adverse reactions grade 1 or 2 in severity.
In all patients, the most common adverse reactions were decreased leucocytes ( 68% [ 1.5% grade greater than or equal to 3 ] ), decreased lymphocytes ( 67% [ 7.2% grade greater than or equal to 3 ] ), decreased platelet count ( 54% [ 1.6% grade greater than or equal to 3 ] ), diarrhoea ( 49% [ 1.2% grade greater than or equal to 3 ] ), rash ( 47% [ 0.9% grade greater than or equal to 3 ] ), decreased neutrophils ( 35% [ 4.1% grade greater than or equal to 3 ] ), dry skin ( 33% [ 0.1% grade greater than or equal to 3 ] ), paronychia ( 31% [ 0.3% grade greater than or equal to 3 ] ), stomatitis ( 20% [ 0.2% grade greater than or equal to 3 ] ), and pruritus ( 17% [ 0.1% grade greater than or equal to 3 ] ).
In the European Union, Tagrisso is already indicated for the treatment of patients with locally-advanced or metastatic EGFR T790M mutation-positive NSCLC.
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 EGFR-mutated ( 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 )
Fonte: AstraZeneca, 2018