On March 28, 2017 AstraZeneca, along with its global biologics research and development arm, MedImmune, reported it will present the strength and depth of its translational science, which is expected to deliver the Company’s next wave of innovative oncology medicines, at the American Association for Cancer Research (AACR) (Free AACR Whitepaper) Annual Meeting in Washington DC, US, 1-5 April 2017 (Press release, AstraZeneca, MAR 28, 2017, View Source [SID1234518288]). Schedule your 30 min Free 1stOncology Demo! In addition to demonstrating a robust early oncology portfolio in DNA Damage Response (DDR) and Tumour Drivers and Resistance, AstraZeneca will highlight the continued progress being made in early Immuno-Oncology (IO) and Antibody-Drug Conjugate (ADC) science.
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Susan Galbraith, Senior Vice President, Head of Oncology, Innovative Medicines and Early Development (IMED) Biotech Unit, said: "The progress we will report at AACR (Free AACR Whitepaper) 2017 highlights the rapid growth of our highly-differentiated DNA Damage Response portfolio that targets a broad range of key molecular pathways. Presentations will also show our progress within Tumour Drivers and Resistance with the development of molecules targeting two key mechanisms that tumours use to resist cell death, namely MCL-1 and CDK9."
David Berman, Senior Vice President, Head of Oncology Innovative Medicines at MedImmune, added: "AACR 2017 is an exciting moment for our next-generation oncology portfolio, demonstrating how our broad biologics pipeline is targeting the multiple ways cancer evades the immune system. We will update on our scientific progress in cancer Immuno-Oncology, including predictive biomarkers of response to immune checkpoint inhibitors. We also look forward to presenting the first clinical trial results for our TLR 7/8 agonist, an important mechanism for immunologically-silent tumours, and to sharing updates from our Antibody-Drug Conjugate platform, a key pillar of AstraZeneca’s oncology strategy."
Shedding new light on Tumour Drivers and Resistance
AstraZeneca was a pioneer in the development of epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) for patients with non-small cell lung cancer (NSCLC) (Iressa, Tagrisso), and continues to work on the unmet needs of patients who fail to respond, or respond for limited periods, to these compounds. An expanding programme of tumour cell-death research is targeting upregulation of key proteins that cancer cells use to evade death, including myeloid cell leukaemia 1 (MCL-1) and cyclin-dependent kinase 9 (CDK9) and is leveraging the sophistication of macrocyles – larger, cyclic compounds – to address the complexity of protein interactions.
Presentations include:
AZD4205, a potent inhibitor of Janus kinase 1 (JAK1), part of the JAK1/signal transducer and activator of transcription (STAT) axis, which is understood to play an important role in tumour escape from EGFR-targeted treatment (oral presentation; Abstract #979)
The first preclinical data presented on AZD5991 demonstrating the tumour cell-killing potential of this potent, selective macrocylic inhibitor of MCL-1 in blood cancers (oral presentation; Abstract #DDT01)
AZD4205 combined with Tagrisso (osimertinib) in patients with EGFR mutation-positive NSCLC to reduce residual tumour burden and prolong the benefit of osimertinib (Abstract #4046)
Preclinical data supporting the potential of the CDK9 inhibitor, AZD5576, alone and in combination with AstraZeneca’s potentially best-in-class Bruton’s tyrosine kinase (BTK) inhibitor, acalabrutinib, in the treatment of non-Hodgkin lymphoma (Abstract #4295).
A leading DNA Damage Response (DDR) position
With one approved medicine and four candidates in clinical development, AstraZeneca is extending its leadership in medicines that target novel DDR deficiencies to selectively kill cancer cells, while minimising the impact on normal cells.
Four oral presentations will include the following data:
Phase I/II studies exploring the combination of Lynparza (olaparib) and temozolomide (an alkylating chemotherapy) in patients with small-cell lung cancer (SCLC) following failure of prior chemotherapy (Abstract #CT048), and
A Phase I study of Lynparza and the alpha-specific PI3-kinase inhibitor BYL719, in patients with recurrent ovarian and breast cancer (Abstract #CT008)
Preclinical data uncovering a novel role for the bromodomain protein, BRD4, in regulating DNA replication-stress response, and the potential of the combination of the BRD4 inhibitor, AZD5153, and the ATR inhibitor, AZD6738, in the sustained delay of tumour growth (Abstract #1026)
The European paediatric precision medicine programme in recurrent tumours showing first results from the MAPPYACTS molecular profiling trial aimed at increasing the number of targetable genomic alternations for DDR therapies (Abstract #CT004)
Preliminary results will also be reported from a Phase I dose-escalation study of the ataxia-telangiectasia and Rad3 related (ATR) inhibitor, AZD6738, in advanced solid tumours (PATRIOT Part A) (Abstract #CT084).
Immuno-Oncology (IO): Activating the immune system via multiple approaches
Presentations will illustrate the depth of AstraZeneca’s IO capabilities beyond its comprehensive late-stage portfolio.
Key presentations include:
Oral presentation of innovative computer modelling to identify tumour and immune cell interactions during disease progression to predict susceptibility to checkpoint inhibitors and other compounds (Abstract #975)
Phase I data on the Toll-like receptor 7/8 (TLR7/8) agonist MEDI9197 in solid tumours (Abstract #CT091) and preclinical data showing its anti-tumour activity in combination with PD-L1 or CTLA-4 checkpoint inhibitors (Abstract #4697)
Phase I/II data showing that high pre-treatment levels of interferon gamma gene signature are associated with greater benefit with durvalumab in patients with NSCLC and urothelial bladder cancer (Abstract #1773).
Antibody-Drug Conjugates: Sophisticated targeting of toxic payloads
AstraZeneca will share data demonstrating the potential of a range of ADCs in targeting cytotoxic treatments to tumour cells. These include preclinical data with toxic pyrrolobenzodiazepine (PBD) or tubulysin payloads in combination with multiple immunotherapies (Abstract #4596), and data on the potent anti-tumour activity of ADCT-401/MEDI3726 when targeting prostate-specific membrane antigen (PSMA) in prostate cancer models (Abstract #3111A).