AstraZeneca presented data from the AURA3 trial that data is supportive of Tagrisso (osimertinib) potentially becoming the new standard of care for 2nd-line treatment of patients with epidermal growth factor receptor (EGFR) T790M mutation-positive locally-advanced or metastatic non-small cell lung cancer (NSCLC). The first randomised phase III data showed that Tagrisso 2nd-line therapy improved progression-free survival (PFS) by 5.7 months compared with standard platinum-based doublet chemotherapy (Hazard Ratio [HR]=0.3). The results were presented at the 17th World Conference on Lung Cancer (WCLC) in Vienna, Austria, hosted by the International Association for the Study of Lung Cancer, and published simultaneously online in The New England Journal of Medicine.
Sean Bohen, executive vice president, global medicines development and chief medical officer at AstraZeneca, said: “The confirmatory phase III data suggest the potential for Tagrisso to replace chemotherapy as the standard of care for patients who have progressed following EGFR tyrosine kinase inhibitor treatment. As lung cancer is the most common type of cancer to spread to the brain, it is also encouraging to see the activity of Tagrisso in patients with central nervous system metastases whose prognosis is often particularly poor.”
AURA3 data showed Tagrisso offered a statistically-significant improvement in PFS versus standard platinum-based doublet chemotherapy (10.1 months vs 4.4 months, hazard ratio [HR] 0.30; 95% confidence interval (CI):0.23, 0.41; p<0.001). In the 34% of patients with central nervous system (CNS) metastases at baseline, PFS was also significantly greater with Tagrisso than with platinum-based doublet chemotherapy (8.5 months vs 4.2 months, HR 0.32; 95% CI: 0.21, 0.49).
Dr. Vassiliki A Papadimitrakopoulou, from the University of Texas MD Anderson Cancer Center, Houston, Texas, USA, said: “The results of AURA3 are not only statistically significant, but clinically meaningful because it is the first time a targeted medicine like Tagrisso has shown improvement in progression-free survival over standard platinum-pemetrexed chemotherapy. It’s very rewarding to be able to give this type of news to patients, as it highlights the major advances we are making in targeted lung cancer treatments.”
Professor Tony Mok, from the Chinese University of Hong Kong, Hong Kong said: “The superiority of Tagrisso in progression free survival and response rate over platinum-pemetrexed chemotherapy suggests we may be moving towards a new standard of care for patients with resistance to EGFR TKI. With the publication of the AURA3 data, clinicians should perform T790M mutation testing to ensure Tagrisso be given to patients who are most likely to benefit.”
The AURA3 safety data for Tagrisso were in line with previous experience. Grade =3 drug-related adverse events (AEs) were reported in 6% of patients (n=16) treated with Tagrisso and 34% (n=46) treated with platinum-based doublet chemotherapy. The most common drug-related AEs in the Tagrisso group, were diarrhoea (29% overall; 1% Grade =3) and rash (28% overall; <1% Grade =3) and, in the chemotherapy group, they were nausea (47% overall; 3% Grade =3) and decreased appetite (32% overall; 3% Grade =3).
The data for AURA3 are consistent with those previously presented in the Phase II trials, AURA2 and AURA extension. This consistency extends to testing of tissue and plasma samples for the detection of the EGFR T790M resistance mutation. In AURA3, approximately half of patients with T790M in tumour tissue also had the T790M mutation detected in plasma. Clinical benefits were reported with Tagrisso compared to platinum-based doublet chemotherapy, irrespective of whether the T790M mutation was identified by plasma ctDNA or tissue testing. When feasible, tissue testing is recommended for patients with a negative plasma T790M test.
Tagrisso was granted accelerated approval by the US Food and Drug Administration (FDA) in November 2015 for the treatment of patients with metastatic EGFR T790M mutation-positive NSCLC, as detected by an FDA-approved test, who have progressed on or after EGFR TKI therapy. In the EU, Tagrisso was granted conditional marketing authorisation for adult patients with locally advanced or metastatic EGFR T790M NSCLC, irrespective of previous EGFR-TKI treatment by the European Medicines Agency (EMA) in February 2016.
In addition, Tagrisso received approval in Japan in March 2016 for the treatment of patients with EGFR T790M mutation-positive inoperable or recurrent NSCLC that is resistant to EGFR TKI therapy, and it is currently under fast track review in China, where nearly half of lung cancer patients are thought to have the EGFR mutation.
AURA3 compared the efficacy and safety of Tagrisso<> 80mg once daily and platinum-based doublet chemotherapy (platinum-pemetrexed) in 419 patients with EGFR T790M mutation-positive, locally-advanced or metastatic NSCLC whose disease had progressed on or after treatment with a previous EGFR tyrosine kinase inhibitor (TKI). The trial was carried out in more than 130 locations worldwide, including the USA, Canada, Europe, China, Japan, Korea, Taiwan and Australia.
The primary endpoint of the trial was PFS, and secondary endpoints included overall survival (OS), overall response rate (ORR), duration of response (DoR), disease control rate (DCR), safety and measures of health-related quality of life (HRQoL).
Tagrisso (osimertinib, AZD9291) 80mg once daily tablet is approved in the US, EU, Japan, Canada, Switzerland, Israel, Mexico, Australia and a number of other countries as the first treatment for patients with locally-advanced or metastatic EGFR T790M mutation-positive NSCLC. Tagrisso is also approved in South Korea in the same indication. Eligibility for treatment with Tagrisso is dependent on confirmation that the EGFR T790M mutation is present in the tumour.
Tagrisso has one of the fastest development programmes, from start of clinical trials to approval in just over two and a half years. Tagrisso is as an irreversible EGFR inhibitor, born out of scientific exploration and engineered to combat the mechanism of resistance by targeting the T790M resistance mutation. Tagrisso is also investigated in the adjuvant and metastatic first-line settings, including in patients with and without brain metastases, in leptomeningeal disease, and in combination with other treatments.