26 April 2016
The explosion of sequencing technologies such as next generation sequencing (NGS) means it is now possible to tailor individual cancer therapies based on patients' genetic make-up and tumour molecular profiling. The challenge lies in determining which genetic alterations are important in driving disease, so called ‘actionable mutations’.
Sequencing the entire genome or even a limited region reveals large numbers of alterations. Most are harmless, normal changes that do not promote the transformation of a normal cell to a cancer cell. Being able to sort out which changes are drivers in a cancer is a significant, but critical challenge in being able to guide therapy in clinical trials.
Our scientists at AstraZeneca are taking a leading position, defining a genetic classification strategy for how patients can be characterised at the molecular level, integrating knowledge from the drug’s mechanism of action combined with disease biology to help guide cancer therapy in early stage exploratory clinical trials. The article published in the May 2016 issue of Nature Reviews Cancer describes approaches taken by external groups alongside our own efforts to tackle this problem.
The approval of AstraZeneca’s poly-ADP ribose polymerase (PARP) inhibitor, represented the first example of using a genetic classification system rather than a pre-determined list of genetic changes to identify BRCA1 and BRCA2 mutant patients. Whilst this approach proved successful for a single-arm trial design, for complex multi-arm exploratory trials with genomically-driven patient selection, so-called umbrella or basket trials, a simpler approach is required.
Building on their knowledge, our team in Translational Sciences in Oncology iMed at AstraZeneca, has devised a framework to collate and categorise the evidence against each of the multitude of potential mutations which may be seen in cancer patients. By integrating genetic information with knowledge from the drugs mechanism of action we have defined ‘tiers of actionability’ to help determine which mutations may be drivers of the disease and targeted by novel cancer therapies.
This approach is now underpinning our design of our umbrella and basket trials, testing several drugs in parallel within the same trial, across many different patient populations based on the genetic makeup of their cancers. The genetic criteria for analysing NGS data has played an important role in our progress with the VIKTORY (gastric cancer) and SAFIR (lung and breast cancers) clinical programmes, both of which are recruiting successfully.
At AstraZeneca, we believe targeted therapies that address the underlying mechanisms of disease are the future of personalised healthcare treatments for cancer. The recent
advances in genomic analysis are helping us to refine and improve our ability to identify the right patients, for the right drug, at the right time.
About VIKTORY (gastric cancer)
VIKTORY: NCT02299648; The Screening Protocol for The VIKTORY Trial – Targeted Agent eValuation in gastrIc Cancer basKeT KORea studY: SMC-AZ GC Basket Trial Screening Protocol. The molecular screening protocol provides extensive tumour molecular characterisation to direct patients treatment in an open label, non-randomised Phase 2a multi-arm, multi-drug trial in gastric cancer (second-line) evaluating 6 AstraZeneca development compounds in combination with paclitaxel or docetaxel across 12 study arms based on tumour molecular characterisation.
About SAFIR (lung and breast cancers)
Lung Cancer: NCT02117167; Intergroup Trial UNICANCER UC 0105-1305/ IFCT 1301: SAFIR02_Lung – Evaluation of the Efficacy of High Throughput Genome Analysis as a Therapeutic Decision Tool for Patients With Metastatic Non-small Cell Lung Cancer. An open label, randomized Phase 2 trial using high throughput genome analysis to guide therapy, and to compare targeted treatment administered according to identified tumour molecular anomalies with standard treatment, and immunotherapy to maintenance therapy in patients without an actionable genomic alteration (or non-eligible). This study is evaluating 6 AstraZeneca development compounds against standard therapies.
Breast Cancer: NCT02299999; PERSONALIZED MEDICINE GROUP / UCBG UC-0105/1304: SAFIR02 Breast – Efficacy of Genome Analysis as a Therapeutic Decision Tool for Patients With Metastatic Breast Cancer. An open label, randomised Phase 2 trial using high throughput genome analysis to guide therapy, and to compare a targeted treatment administered according to the identified tumour molecular anomalies with maintenance chemotherapy, and immunotherapy with maintenance chemotherapy in patients without an actionable genomic alterations (or non-eligible). This study is evaluating 7 AstraZeneca development compounds against standard therapies.