Combinations Alliance from an Industry Perspective
1AstraZeneca Oncology Innovative Medicines, Cambridge, UK
Recent drug development successes have lead to launches of targeted therapies with high response rates to monotherapy treatment for example EGFR inhibitors in the treatment of patients whose tumours have an activating EGFR mutation. However, emergence of resistance mechanisms and reactivation of pathway signaling in the targeted pathway limit the extent of cancer cel kill which can be achieved by monotherapy, so combinations are critical to further improve outcomes. Indeed, the history of cancer drug development shows substantial improvements in long-term patient outcomes have more frequently been built via combination regimens.
Thus early investment in understanding the potential for rational combinations with both currently available standard of care therapies and for novel-novel combinations is important. Access to the Combinations Alliance has enabled the more rapid assessment of such combinations in parallel with the initial development plan for Phase I and II stage development compounds. Examples include trials of AZD2014 (a dual TORC1/2 inhibitor) with weekly paclitaxel in the TAX-TORC study, which has tested different combination schedules and delivered early proof of principle in lung and ovarian cancer settings. Another example is the combination of AZD5363 (an AKT inhibitor) with olaparib (PARP inhibitor). Both examples illustrate the need for consideration of dose and schedule to optimise the safety and potential for efficacy by understanding the PK/PD relationship and the links to triggering cell death.
These examples will be discussed in the context of the value of such trials to broaden and enrich early development programs.