BOSTON — The investigational drug AZD9291, a third-generation EGFR inhibitor, showed promise in preclinical studies and provides hope for patients with advanced lung cancers that have become resistant to existing EGFR inhibitors, according to results presented here at the AACR-NCI-EORTC International Conference on Molecular Targets and Cancer Therapeutics, held Oct. 19-23.
Mutations in the growth factor gene EGFR are present in about 10 to 15 percent of patients with the most common form of lung cancer, non-small cell lung cancer (NSCLC). Most NSCLCs harboring these EGFR mutations, called activating mutations, respond to the EGFR inhibitor drugs erlotinib and gefitinib. A majority of such cancers, however, develop resistance to these drugs within about nine to 11 months. In many cases, this is due to the cancer cells acquiring a second mutation called EGFR T790M, also known as the "resistance mutation."
"There are no approved therapies to treat lung cancer patients who develop the second mutation in the EGFR that stops the currently available medicines from working," said Susan Galbraith, M.D., Ph.D., head of the Oncology Innovative Medicines Unit at AstraZeneca. "The innovative breakthrough was finding a series of molecules that could target both the activating and resistance mutant forms of EGFR more potently than normal EGFR, which led to development of the new EGFR kinase inhibitor, AZD9291.
"AZD9291 is highly active in preclinical models and is well tolerated in animal models. It inhibits both activating and resistant EGFR mutations while sparing the normal form of EGFR that is present in normal skin and gut cells, thereby reducing the side effects encountered with currently available medicines," she added.
The AstraZeneca scientists first showed that AZD9291 potently inhibited lung cancer cells with mutant EGFR, grown in lab dishes. They then tested the drug on mice bearing lung tumors with activating mutations and mice bearing lung tumors with resistance mutations. AZD9291 showed substantial tumor shrinkage in both groups of mice after 14 days of treatment. After 40 days, the researchers found no visible tumors in these mice, and this effect was sustained for more than 100 days. They also observed similar tumor shrinkage in mice that were genetically modified to develop tumors bearing both the activating and resistance mutations.
When the investigators analyzed blood samples collected from the treated mice, they identified a breakdown product of the parent compound AZD9291, which they called AZ5104, circulating in blood in addition to AZD9291. They then found that AZ5104 is also a potent inhibitor of activating and resistance EGFR mutations, and speculated that this may contribute to the efficacy seen after dosing with AZD9291.
Using data from blood analyses of mice, the researchers then developed a mathematical model to evaluate the dynamics of conversion of AZD9291 to AZ5104 and cumulative tumor-inhibitory effects. These experiments helped them determine the potentially effective doses of AZD9291 for patients with NSCLC harboring both activating and resistance EGFR mutations.
"Findings from preclinical studies have recently been translated to the clinic, where the drug has already demonstrated tumor shrinkage in patients and has been well tolerated, with low rates of side effects," said Galbraith. "The degree of response to treatment with AZD9291 in such a short period of time is very exciting. This new drug has the potential to provide new treatment options for patients in this setting."
Galbraith is an employee of AstraZeneca, which sponsored this study.
The 2013 International Conference on Molecular Targets and Cancer Therapeutics is being co-hosted by the American Association for Cancer Research (AACR), the National Cancer Institute (NCI), and the European Organisation for Research and Treatment of Cancer (EORTC).
This research will be presented at a press conference entitled "Emerging Therapeutics" during the AACR-NCI-EORTC International Conference on Molecular Targets and Cancer Therapeutics on Sunday, Oct. 20 at 10 a.m. ET in room 202 of the Hynes Convention Center in Boston, Mass. Reporters who cannot attend in person may call in using the following numbers:
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Abstract Number: A109
Presenter: Susan Galbraith, M.D., Ph.D.
Title: AZD9291: an irreversible, potent and selective third generation tyrosine kinase inhibitor (TKI) targeting EGFR activating (EGFRm+) and resistance (T790M) mutations in advanced lung adenocarcinoma
Authors: Darren Cross1, Sue Ashton1, Caroline Nebhan2, Cath Eberlein1, M. Raymond V. Finlay1, Gareth Hughes1, Vivien Jacobs1, Martine Mellor1, Monica Red Brewer2, Catherine Meador2, Jonathon Orme1, Paula Spitzler2, Steve Powell1, Amar Rahi1, Paula Taylor1, Richard A. Ward1, Paula Daunt1, Anne Galer1, Teresa Klinowska1, Graham Richmond1, William Pao2. 1AstraZeneca, Macclesfield, United Kingdom; 2Department of Medicine/Division of Hematology-Oncology, Vanderbilt University, Nashville, TN
The first generation EGFR TKIs gefitinib and erlotinib provide significant clinical benefit in patients with advanced lung adenocarcinoma harbouring activating EGFR mutants (EGFRm+), but patients will ultimately develop disease progression due to acquired resistance. Acquisition of the EGFR T790M mutation is the most common mechanism of drug resistance, detected in more than 50% of gefitinib/erlotinib resistant patients. Current therapeutic strategies are limited for advanced lung adenocarcinoma patients with EGFR T790M (EGFRm+/T790M), so this remains a key area of unmet need.
AZD9291 (structure to be disclosed at meeting) is an oral, irreversible, third generation, selective inhibitor of both EGFR activating (EGFRm+) and resistance (EGFRm+/T790M) mutations. The mechanistic and functional activity of AZD9291 was characterised in vitro and in vivo across a number of cell lines harbouring various EGFR-mutations or wild type EGFR. Presented data shows AZD9291 potently inhibits EGFR phosphorylation in EGFRm+ (e.g. PC9; <25nM) and EGFRm+/T790M (e.g. H1975; <25nM) cell lines in vitro, whilst demonstrating much less activity against wild-type EGFR lines (e.g. LoVo; >500nM). Consistently, AZD9291 showed significantly more potent inhibition of proliferation in mutant EGFR cell lines compared to wild-type in vitro. In addition, AZD9291 administered once daily orally at 5mg/kg caused profound regression of tumours across EGFRm+ (PC9; 178% growth inhibition) and EGFRm+/T790M (H1975; 119% growth inhibition) tumour models in vivo, after 14 days dosing. Furthermore 5mg/kg AZD9291 was sufficient to cause significant shrinkage of EGFRm+ and EGFRm+/T790M transgenic mouse lung tumours. Tumour growth inhibition was associated with profound inhibition of EGFR phosphorylation and key downstream signaling pathways such as AKT and ERK. Chronic long-term treatment of PC9 and H1975 xenograft tumours with AZD9291 led to a complete and sustained macroscopic response, with no visible tumours after 40 days dosing, and being maintained beyond 100 days. Furthermore, pre-clinical data also indicates that AZD9291 could target tumours that have acquired resistance to the more recently identified HER2-amplification mechanism, thus potentially extending its benefit in TKI resistant patients.
Taken together, preclinical data demonstrates that AZD9291 is a potent and effective inhibitor of both EGFR activating (EGFRm+) and resistance (EGFRm+/T790M) mutations whilst sparing wild-type EGFR. These data support the further clinical investigation of AZD9291 in advanced EGFR mutant lung adenocarcinoma.
Abstract Number: B94
Presenter: Susan Galbraith, M.D., Ph.D.
Title: Discovery of and first disclosure of the clinical candidate AZD9291, a potent and selective third-generation EGFR inhibitor of both activating and T790M resistant mutations that spares the wild type form of the receptor
Authors: M. Raymond V. Finlay1, Mark Anderton1, Susan Ashton1, Peter G. Ballard1, Rob H. Bradbury1, Sam Butterworth1, Nicola Colclough1, Darren A.E. Cross1, Heather L. McFarland2, Martine J. Mellor1, Richard A. Ward1, Mike J. Waring1. 1AstraZeneca, Oncology Innovative Medicines, Macclesfield, Cheshire, SK10 4TG, United Kingdom; 2AstraZeneca, Global Medicines Development, Macclesfield, Cheshire, SK10 4TG, United Kingdom
Small molecule inhibitors of the epidermal growth factor receptor (EGFR) tyrosine kinase such as gefitinib and erlotinib have been employed successfully in the treatment of non-small cell lung cancer (NSCLC) patients harboring an activating mutation (EGFRm+). However, resistance to these inhibitors in the form of additional mutations in the kinase domain such as T790M is emerging as a growing clinical issue. This presentation will describe the discovery of AZD9291, an orally bioavailable, irreversible EGFR inhibitor of both the resistance (NCI-H1975, cell phosphorylation IC50 <0.025 μM) and activating mutations (PC9, cell phosphorylation IC50<0.025 μM) that also spares inhibition of the wild type form of the receptor (A431, cell phosphorylation IC50>0.5 μM). Wild type EGFR inhibition is believed to drive the observed dose limiting toxicities (such as skin rash and diarrhea) for these first generation therapies in the clinic. New data will be discussed for the first time including the medicinal chemistry program that led to the identification of AZD9291, details of significant in vivo oral activity in pre-clinical xenograft models (including tumor regression in the L858R/T790M double mutant setting at a dose of 5 mpk) and the first disclosure of the candidate drug structure. The pre-clinical findings from this work strongly supported selection of AZD9291 as a clinical candidate, and first dose in man was achieved with AZD9291 in March 2013.
Abstract Number: B212
Presenter: Susan Galbraith, M.D., Ph.D.
Title: Integrating the pre-clinical pharmacokinetic, pharmacodynamics, and efficacy data for AZD9291, an oral, irreversible inhibitor of EGFR activating (EGFRm+) and resistant (EGFRm+/T790M) mutations and an active metabolite to predict the human pharmacokinetics and potential efficacious dose in patients.
Authors: Peter Ballard1, Susan Ashton1, Darren Cross1, Richard Dimelow2, James Yates1. 1AstraZeneca, Macclesfield, Cheshire, United Kingdom; 2Wright-Dose, Altrincham, Cheshire, United Kingdom
Small molecule tyrosine kinase inhibitors gefitinib and erlotinib have demonstrated clinical benefit in advanced NSCLC patients with the EGFR activating mutation but ultimately disease progression develops due to resistant mutations. The most common resistant mutation is EGFR T790M and remains a key area of unmet need.
AZD9291 is an irreversible inhibitor of both the EGFR activating mutant (EGFRm+) and resistance mutation (EGFRm+/T790M), while maintaining a margin to wild type EGFR. AZD9291 has demonstrated impressive efficacy and regressions at low doses in mouse xenograft models for both activating (EGFRm+) and resistant (EGFRm+/T790M) mutant forms of EGFR (PC9 and H1975 cell lines). Analysis of plasma samples from these xenograft studies identified a des-methylated metabolite circulating in addition to AZD9291 with subsequent in vitro studies indicating the metabolite was around five fold more potent than AZD9291.
A program of mouse xenograft studies was undertaken to determine the tumor pEGFR pharmacodynamics (PD) and tumor growth inhibition (TGI) of AZD9291 and metabolite. Mathematical models incorporating an irreversible binding component have been developed to describe the contribution of AZD9291 and metabolite exposure to the pEGFR PD and TGI in the mouse (a PK/PD-TGI model). Pre-clinical drug metabolism and pharmacokinetic data were used to predict the human pharmacokinetics of AZD9291 and formation of the active metabolite. The predicted human exposures of both AZD9291 and metabolite were then used to drive the PK/PD-TGI model to simulate inhibition of pEGFR and inhibition of tumor growth. Assuming that human tumours and biomarkers behave in a similar way to those in mouse xenografts, these simulations suggest that a dose of 7-17 mg of AZD9291 once a day would be efficacious in patients with advanced NSCLC harboring the EGFR activating and T790M resistant mutations.
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