AZD9291 (or osimertinib), an investigational third generation tyrosine kinase inhibitor, demonstrated 60%+ and 75% objective response rates (ORR: complete response + partial response) in pre-treated patients with NSCLC carrying EGFR T790M resistance mutation and in treatment-naïve patients, according to findings of 3 papers presented in the World Conference on Lung Cancer (WCLC) 2015.1-3
EGFR T790M mutation and treatment resistance
Certain activating mutations in tyrosine kinase domain of epidermal growth factor receptor (EGFR) gene, i.e., del exon 19, makes them the “Achilles Heels” of the deadly advanced NSCLC. Blocking the EGFR signaling with tyrosine kinase inhibitor (TKI) monotherapy has become the standard of care in those diagnosed with EGFR mutation (EGFRm) because of significantly improved PFS plus favourable tolerability comparing with doublet chemotherapy. However, despite initial response, progressive disease develops in majority of these patients within 1-2 years.
The most common mechanism of resistance due to treatment with EGFR TKIs, such as gefitinib, erlotinib, is the emergence of T790M (theronine being replaced with methionine) mutation that leads to enhanced affinity for ATP, thereby significantly reducing the effectiveness of these drugs as reversible competitive inhibitor of ATP binding site4 and rendering disease progression. This “top-up” mutation accounts for approximately 60% patients acquiring resistance. Second generation TKIs, i.e., afatinib as irreversible inhibitor that was effective in preclinical model, failed to achieve clinical benefits in patients harbouring T790M mutation, probably owing to inability to inhibit this EGFR mutant at clinical achievable dose.
Third generation TKIs have been developed on this background with the aim to overcoming sensitizing mutations and resistant T790M mutation.
The new study data
Data in the first-line setting (AURA firstline cohort) demonstrated that in 60 patients who received AZD9291 once daily 72% (95% CI: 58%-82%) were progression free (PFS) at month 12. Confirmed overall response rate (ORR) was 75% (95%CI: 62%-85%). The longest duration of response (DoR) was ongoing at month18.2
“While the data are still preliminary, these latest results from the AURA trial first-line cohort further reinforce the potential of AZD9291 in treatment-naïve EGFRm advanced NSCLC patients,” said Professor Suresh Ramalingam, presenting author of the AURA trial first-line cohort data and Chief of Thoracic Oncology and Director of Medical Oncology, Emory University School of Medicine, Atlanta, USA.
Data on two AURA phase II studies (AURA extension1 and AURA23) in previously treated patients with EGFR T790M mutation were consistent. While still preliminary, these studies showed an efficacy and tolerability profile for AZD9291 consistent with previously reported data. In AURA extension (n=201), ORR was 61% (95%CI: 54%-68%); median DoR and median PFS were not calculable (NC). Consistent results were observed in AURA2 (n=210), ORR was 71% (95%CI: 64%-77%); median DoR was 7.8 months (95%CI: 7.1m to not reached) and median PFS was 8.6 months (95%CI: 8.3m-9.7m).
The positive results of two phase II trial on pretreated patients will be confirmed in an ongoing AURA3 trial that compares AZD9291 with platinum-based doublet chemotherapy in patients with EGFRm- and T790M-positive advanced NSCLC who have disease progression after prior TKI. The planned enrollment is 410 and primary endpoint analysis available on April 2016, Dr. Tetsuya Mitsudomi, MD, lead author of AURA2 study and chief of thoracic surgery at Aichi Cancer Center Hospital in Nagoya, Japan, added
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The safety profile of AZD9291 was consistent with the earlier reports. In the AURA first line cohort, and phase II AURA extension / AURA2 pre-treated cohorts, the most common adverse events across various dosages were rash and diarrhea. Events rate were higher in first-line cohort than the pre-treated cohorts (refer to table).
Hyperglycemia, interstitial lung disease and QT prolongation were in line with data previously presented.
Dr. Martin Reck, MD, PhD, from the Department of Thoracic Oncology at the Lung Clinic Grosshansdorf, Germany, who was the discussant of these 3 papers at the WCLC conference, was glad to note the results of these trials, “We have seen confirmed efficacy in pretreated patients”. And tolerability wise, “due to the mechanism of these drugs, these compounds seem to be very well tolerated, so we typically do not see the side effects of the first-generation TKIs”.
As for using in the first-line setting, despite the initial positive data seen in the AURA first-line cohort, the phase III FLAURA trial will give more definitive answer, he cautioned, because in the AURA pre-treated cohort, “there are questions about efficacy in T790M-negative patients”. The response rate was 20-30% comparing to over 60% in T70M-postive patients.
Despite the initial positive data of AZD9291 in first-line and pretreated settings with T790M mutation, questions remained, said Professor Pasi Jänne, MD, PhD, director of the Lower Center for Thoracic Oncology at the Dana-Farber Cancer Institute, Boston, Massachusetts, and an investigator of several AZD9291 clinical trials: “Conceptually, what we all struggle with is, should we develop the sequential model — start with one inhibitor, develop resistance, and move on to another?”, “Or should we put our best weapon first?”
Given the heterogeneous nature of advanced cancer, Professor Jänne believed it’s hard to get cures with single agents, “but maybe we will with combinations or series of combinations”. The perceived better tolerability profile seen in patients treated with AZD9291 comparing with that of erlotinib or afatinib may make it easier to be used as part of the combination regimens. “There are already ongoing phase I study looking into that”, he added.