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18 to 22 April 2015.
Data being presented at the AACR annual meeting include:
Detail on three molecular subtypes of acquired resistance to AZD9291, AstraZeneca’s investigational medicine for patients with advanced non-small cell lung cancer, identified through cutting-edge plasma next generation sequencing (rapid whole genome sequencing of tumour DNA from blood samples) [Late breaker 123]. Data will highlight the need for combination therapies to effectively prevent or treat resistance and demonstrate the potential of the combination of AZD9291 with AstraZeneca’s investigational, highly potent and selective c-MET inhibitor, savolitinib (AZD6094, volitinib) [Abs761], as a therapeutic solution to these resistance mechanisms.
The medicinal chemistry behind the discovery of AZD9496, AstraZeneca’s novel, oral selective oestrogen receptor down-regulator (SERD), currently in Phase I development for patients with oestrogen receptor positive (ER+) breast cancer. The oral pharmacokinetic properties of AZD9496 will also be presented [Abs3650], demonstrating the significant pre-clinical tumour efficacy that supported its advance into clinical trials.
The PI3K/ AKT/ mTOR cellular pathway, which regulates cell growth and survival, is the most commonly mutated pathway in cancer. Data will be presented on compounds within AstraZeneca’s pipeline that inhibit key enzymes (kinases) on this pathway, including:
AZD2014 is a novel dual m-TORC1 and m-TORC2 inhibitor, currently in Phase II development in solid tumours. Preclinical data will be presented supporting the combination of AZD2014 with paclitaxel (chemotherapy) in solid tumours including ovarian and lung cancer [AbsCT138]. Phase I data will also be presented on the combination of AZD2014 with AstraZeneca’s treatment for advanced breast cancer, Faslodex (fulvestrant), in patients with ER+ advanced metastatic breast cancer [AbsCT233], demonstrating the advantage of intermittent versus continuous infusion of AZD2014 to avoid toxicity and give a favourable adverse event profile.
AZD8186 is a potent, oral inhibitor of PI3K isoforms beta and delta, currently in Phase I development in solid tumours. Clinical data will be presented from a dosing and safety study in PTEN deficient tumours carried out in collaboration with a number of partners including the Princess Margaret Cancer Centre, Toronto, The Royal Marsden Hospital, London and the Dana Farber Cancer Institute, Boston [AbsCT329]. PTEN is a natural inhibitor of the PI3K/ AKT/ mTOR pathway. Loss of PTEN, which is implicated in the development of a large number of cancers, can confer dependency on the PI3K beta form of PI3K.
AZD5363 is an inhibitor of three different forms of the AKT protein, currently in Phase II development in breast cancer. Phase I/II data will be presented on the combination of AZD5363 with paclitaxel [AbsCT331] in advanced or metastatic breast cancer, with cutting edge circulating tumour DNA analysis used as a surrogate for response and resistance. Phase I data will also be presented on AZD5363 in combination with Lynparza (olaparib) for advanced BRCA mutated cancer patients in a study designed to optimise drug exposures, minimise pharmacokinetic variability and reduce patient numbers needed for study [AbsCT323].
First generation compounds targeting the PI3K/AKT/mTOR pathway have experienced toxicity issues resulting in adverse events such as rash, diarrhoea and hyperglycaemia. Data from preclinical studies will also be presented at the AACR meeting demonstrating the potential of combinations of inhibitors across the pathway (AZD8186 with inhibitors of PI3K and mTOR) as an approach to achieve comprehensive PI3K pathway suppression in a range of PTEN protein deficient tumours [Abs4696], while limiting potential adverse events.
Pre-clinical data will also be presented on AZD8835, an inhibitor of both PI3Kalpha and PI3Kdelta in Phase I development in solid tumours, examining whether intermittent dosing can avoid adverse effects and overcome resistance [Abs2830; 2665].
DNA damage repair
AstraZeneca has one of the most extensive portfolios in the area of DNA damage repair, including the recently approved Lynparza (olaparib). Scientists from the UK Institute of Cancer Research, leading the TOPARP Phase II study (Trial of Olaparib in Patients with Advanced Castration Resistant Prostate Cancer) will present data in an oral late breaker session demonstrating the potential to identify biomarkers for patients who will respond well to olaparib through next generation sequencing of tumour biopsies [AbsCT322].
Susan Galbraith, Head of the Oncology Innovative Medicines Unit at AstraZeneca, said: “The extensive range of work we are presenting this year illustrates the pace of acceleration of our early-to-mid-stage pipeline, and its sharp focus on the science. For example, the PI3Kinase pathway is the most commonly mutated pathway in cancer. Our strategy is to develop highly specific inhibitors to the different PI3K isotypes and use them in intermittent dosing schedules which address the issue of pathway. Because we have compounds which work at each step of this pathway, we are able to use them in combinations which overcome elements of resistance and improve the risk benefit profile and efficacy compared with monotherapy for the benefit of patients. We are also presenting a number of examples of combinations across our portfolio, which is an important part of our strategy to develop more efficacious treatments for cancer.”
Immunotherapy
Immuno-oncology is a promising therapeutic approach that harnesses the patient’s own immune system to help fight cancer. AstraZeneca’s strategy is to develop novel combinations that target each of the escape mechanisms used by tumour cells to evade the immune system. Across preclinical and clinical development, the company’s robust immuno-oncology pipeline contains molecules that enhance antigen presentation to initiate an immune response to the tumour; molecules to enhance tumour destruction by T-cells (immune cells) and enhance immune cell memory; and compounds that target the tumour microenvironment.
At AACR AstraZeneca will describe molecules within its immuno-oncology pipeline that stimulate the OX40 receptor, which plays a key role in the survival and homeostasis of effector and memory T-cells, and cause T-cell activation, survival, proliferation and cytokine (small proteins that act as chemical ‘messengers’ between cells) release, all of which may help destroy cancer cells. Preclinical data will be presented to show that OX40 ligand fusion proteins, such as MEDI6383, induce potent T-cell proliferation, overcome regulatory T-cell suppression and promote anti-tumour activity in preclinical models as a single agent or in combination [Abs4275].
Yong-Jun Liu, M.D., Ph.D., Head of Research at MedImmune said: “Our comprehensive immuno-oncology pipeline allows us to address multiple immune pathways to explore the most effective treatment options for patients in an accelerated way. OX40 is one of the most exciting T-cell co-stimulatory receptors, critical for T-cell activation, expansion, effector T-cell function and T-cell memory maintenance. In addition, OX40 has the ability to block the function of both inducible and natural regulatory T-cells. We believe that the combination of OX40 agonists with checkpoint blockers and other co-stimulatory molecules and cytokines that target antigen presenting cells, innate immune cells and the cancer microenvironment will be key to achieving more successful cancer immunotherapy".
Antibody drug conjugates
Antibody-drug conjugates (ADCs) are anticancer drugs which combine the specificity of antibodies with the potent cancer cell killing properties of novel ‘warheads’. The antibody selectively targets cancer cells to deliver tumour-destroying warhead chemicals which are internalised into the cancer cell, avoiding damage to healthy tissue. MedImmune scientists will describe generation of a potent, novel antibody-drug conjugate that induces long-term tumour regression and has anticancer stem cell activity [Abs948]. However, resistance to ADCs can develop through a number of mechanisms, one of which is the increased expression of molecular ‘pumps’ inside the cancer cell, such as P-glycoprotein (P-gp), which pump the anti-cancer drug out before it can have an effect. Data will be presented at the AACR meeting showing how ADCs with different warheads (pyrrolobenzodiazepine dimer and tubulysin) are active in tumours with P-gp resistance [Abs3601]. |
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