- Over 80% of patients progression free at 9 months in the first-line treatment of advanced non-small cell lung cancer
CHICAGO, May 31, 2015 /PRNewswire/ -- AstraZeneca today announced preliminary efficacy and safety data for AZD9291 in the first-line treatment of epidermal growth factor receptor mutation positive (EGFRm) advanced non-small cell lung cancer (NSCLC). Data showed that 81% (95% confidence interval (CI) 68% to 89%) of patients on a once daily dose of AZD9291 were progression free at 9 months; overall response rate was 73% (95% CI 60% to 84%). The longest duration of response was ongoing at 13.8 months at the time of data cutoff.
The data from the first-line expansion cohorts of the AURA Phase I study were presented at the annual meeting of the American Society of Clinical Oncology in Chicago. The first-line cohorts included 60 patients with EGFRm advanced NSCLC who received AZD9291 80mg or 160mg once daily. The data are not fully mature with an approximate 11 month median follow up in the 80mg cohort, and an approximate 8.5 month median follow up in the 160mg cohort. The most common adverse events in both cohorts included rash (Grade 3: 0% at 80mg, 3% at 160mg) and diarrhoea (Grade 3: 0% at 80mg, 7% at 160mg).
"These preliminary data demonstrate the potential of AZD9291 in treatment-naïve advanced NSCLC patients with EGFR mutation. These promising results with AZD9291 will be studied further by the ongoing Phase III FLAURA trial in the first-line setting," said Professor Suresh S. Ramalingam, Chief of Medical Oncology, Emory University School of Medicine, Atlanta, GA, USA, who presented the AURA first-line data and is lead principal investigator for the FLAURA study.
The first-line data from the AURA study build on findings presented in April at the European Lung Cancer Congress (ELCC). Data presented at ELCC showed that previously treated patients with EGFRm advanced NSCLC who also have the T790M resistance mutation achieved a median progression-free survival (PFS) of 13.5 months (95% CI 8.3 months to not calculable) on AZD9291 80mg once daily, based on 38% of patients having tumour progression. Patients with EGFRm NSCLC are particularly sensitive to treatment with currently available EGFR tyrosine kinase inhibitors (TKIs). However, tumours almost always develop resistance to treatment, leading to disease progression. In approximately two thirds of patients treated with the approved EGFR-TKIs, gefitinib or erlotinib, this resistance is caused by the secondary T790M mutation.
Antoine Yver, Head of Oncology, Global Medicines Development, said: "The promising response to first-line treatment with AZD9291 builds on the encouraging efficacy already seen in patients with EGFRm advanced NSCLC who have the T790M resistance mutation, and whose disease has progressed following previous treatment with first-generation EGFR tyrosine kinase inhibitors. We have just been granted accelerated assessment for our upcoming regulatory submission for AZD9291 in Europe. We remain confident that AZD9291 has the potential to deliver early and durable efficacy by targeting both activating and resistance EGFR mutations."
AZD9291 is being investigated across different lines of therapy, both as monotherapy and in combination with other small molecule and immuno-oncology investigational medicines, to understand its potential benefit for overcoming newly identified forms of resistance for a broader range of patients. The ongoing TATTON study will investigate the combination of MEDI4736 (anti-PD-L1 immune checkpoint inhibitor), selumetinib (MEK inhibitor), or savolitinib (MET inhibitor; AZD6094) in lung cancer. Data presented at ASCO from the TATTON study showed that AZD9291 has a tolerable safety profile, supporting its investigation in potentially synergistic combinations with other molecules. A Phase III study (CAURAL) investigating AZD9291 in combination with MEDI4736 as a potential second-line treatment for EGFRm NSCLC patients with the T790M resistance mutation is also planned to start later this year, as part of AstraZeneca's combination-focused development strategy.
An expanded access programme (EAP) for AZD9291 for patients with advanced or metastatic EGFRm, T790M NSCLC has also been initiated in the US. Healthcare professionals based in the US seeking more information about the AZD9291 EAP can call 1-800-236-9933. Further information on the EAP is available at www.clinicaltrials.gov (ClinicalTrials.gov identifier: NCT02451852). Additional access programmes will be opened outside of the US shortly and details will be released when information becomes available.
AZD9291 and MEDI4736 are investigational products and are not approved for any indication in any market by any regulatory authority.
 Ramalingam SS, et al. AZD9291, A mutant-selective EGFR inhibitor, as first-line treatment for EGFR mutation-positive advanced non-small cell lung cancer (NSCLC): Results from a phase 1 expansion cohort. J Clin Oncol 2015; 33 (suppl; abstr 8000). Data on file [Atlas ID: 787,626.011].
 Ramalingam SS, et al. A randomized, Phase III study (FLAURA) of AZD9291, a novel EGFR-TKI, versus gefitinib or erlotinib in treatment-naïve patients with advanced non-small cell lung cancer and an EGFR-sensitizing mutation. J Clin Oncol 2015; 33 (suppl; abstr TPS8102).
 Jänne PA, et al. A Phase I study of AZD9291 in patients with EGFR-TKI-resistant advanced NSCLC – updated progression-free survival and duration of response data Ann Oncol 2015; 26(Suppl 1): i60, abs LBA3.
 Yu H, et al. Analysis of Tumor Specimens at the Time of Acquired Resistance to EGFR-TKI Therapy in 155 Patients with EGFR-Mutant Lung Cancers. Clin Cancer Res 2013:19:2240-7.
 Oxnard GR, et al. Preliminary results of TATTON, a multi-arm phase Ib trial of AZD9291 combined with MEDI4736, AZD6094 or selumetinib in EGFR-mutant lung cancer. J Clin Oncol 2015; 33 (suppl; abstr 2509).
 Cross DA, et al. AZD9291, an irreversible EGFR TKI, overcomes T790M-mediated resistance to EGFR inhibitors in lung cancer. Cancer Discov 2014;4:1046-61.
 Szumera-CieÄ‡kiewicz A, et al. EGFR mutation testing on cytological and histological samples in non-small cell lung cancer: a Polish, single institution study and systematic review of European incidence. Int J Clin Exp Pathol 2013;6:2800-12.
 Ellison G, et al. EGFR mutation testing in lung cancer: a review of available methods and their use for analysis of tumour tissue and cytology samples. J Clin Pathol 2013;66:79-89.
 Sharma SV, et al. Epidermal growth factor receptor mutations in lung cancer. Nat Rev Cancer 2007;7:169-81.
 Mok TS, et al. Gefitinib or Carboplatin-Paclitaxel in Pulmonary Adenocarcinoma. N Engl J Med 2009;361:947-57.
 Rosell R, et al. Erlotinib versus standard chemotherapy as first-line treatment for European patients with advanced EGFR mutation-positive non-small-cell lung cancer (EURTAC): a multicentre, open-label, randomised phase 3 trial. Lancet Oncol 2012;13:239–46.
NOTES TO EDITORS
AZD9291 is an investigational, highly selective, irreversible inhibitor of both activating sensitising EGFRm and the resistance mutation, T790M, while sparing the activity of wild type EGFR.
Patients who have the EGFRm form of NSCLC, which occurs in 10-15 percent of NSCLC patients in Europe and 30-40 percent of NSCLC patients in Asia, are particularly sensitive to treatment with currently available EGFR TKIs, which block the cell signalling pathways that drive the growth of tumour cells.[9-11] However, tumours almost always develop resistance to treatment, leading to disease progression. In approximately two thirds of patients treated with the approved EGFR-TKIs, gefitinib or erlotinib, this resistance is caused by the secondary mutation, T790M. Currently, no targeted therapies are approved for the treatment of tumours with this resistance mutation.
AZD9291 has been granted Breakthrough Therapy designation, Orphan Drug and Fast Track status by the US Food and Drug Administration (FDA).
About the AURA First-Line Cohort
Sixty treatment-naïve patients with EGFRm advanced NSCLC were enrolled to receive AZD9291 80mg or 160mg once daily (sequential cohorts). At the 15 April 2015 data cut-off, 48 out of 60 patients remained on study treatment across the 80mg and 160mg cohorts. Final data are expected August 2015.
Of grade ≥3 adverse events (AEs), one patient reported nausea in the 80mg cohort, and six patients in the 160mg reported rash (1), diarrhoea (2), stomatitis (1) or paronychia (2).
As of April 7, 2015, of more than 1100 patients across all studies dosed with AZD9291, interstitial lung disease (ILD) grouped term events were reported in approximately 2.6% of patients (31 events): seven Grade 1, seven Grade 2, 16 Grade ≥3; one currently ungraded. Of these, a total of three patients are reported to have died due to ILD (Grade 5).
FLAURA is a Phase III, double blind, randomised study which is comparing the efficacy and safety of AZD9291 80mg per day and standard of care (SoC) EGFR-TKI treatment with gefitinib 250mg per day or erlotinib 150mg per day in treatment-naïve patients with locally advanced or metastatic EGFRm NSCLC. The primary objective is to compare PFS for AZD9291 with SoC EGFR-TKI, and a key secondary objective is PFS in patients with the T790M resistance mutation.
TATTON is a multi-arm Phase Ib trial investigating AZD9291 80mg in combination with MEDI4736 (anti-PD-L1 mAb), savolitinib (MET inhibitor; AZD6094) or selumetinib (MEK1/2 inhibitor; AZD6244, ARRY-142886) in patients with advanced EGFR mutant lung cancer that has progressed on previous EGFR TKI treatment. As of 30 April 2015, 71 patients had been enrolled on combination therapy, and doses of selumetinib and savolitinib were escalated to their Phase II monotherapy doses while doses of MEDI4736 were escalated to its Phase III monotherapy dose. The most common adverse events (AEs) included diarrhoea, vomiting, anaemia, constipation, cough and nausea with AZD9291+MEDI4736; diarrhoea, nausea and fatigue with AZD9291+selumetinib; and vomiting, nausea and rash with AZD9291+savolitinib.
About AstraZeneca in Oncology
Oncology is a therapeutic area in which AstraZeneca has deep-rooted heritage. It will be potentially transformational for the company's future, becoming the sixth growth platform. Our vision is to help patients by redefining the cancer treatment paradigm and one day eliminate cancer as cause of death. By 2020, we are aiming to bring six new cancer medicines to patients.
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