First Impressions of Leading the ECMC Combination Alliance

By Hazel Jones

Combination therapies are essential in cancer, starting back in 1940s with chemotherapy combinations and expanding today to chemotherapy, radiotherapy, targeted therapy, immunotherapy and novel agents, to enable us to beat cancer sooner. Clinical validation of a wide variety of mechanisms, such as immunotherapy (recognised as a leading medical breakthrough last year by Science magazine) means choosing combinations becomes ever more complex. The choice of combination extends from rationale design to serendipity and from large cell line panel screens to clinical initiatives such as our ECMC Combination Alliance. The benefit will be measured by step changes in patient care as combination therapy is tailored to the patients’ disease rather than added to current end stage treatment.

As combinations are now considered from the start of drug development, collaborations form an important role in clinical development, hence the expansion of the ECMC Combination Alliance. It is essential that UK academics gain access to the breadth and variety of molecules now entering development, to build translational research and maximise novel drug combinations. The ECMC Combinations Alliance is ideally placed to broker relationships between partners and offers UK early phase clinicians the opportunity to rationally design novel combination therapies.

Coming into the ECMC Combination Alliance in January, it’s great to see a strong foundation with 6 trials already running across the network; a further 7 are currently in set-up, and our first trial successfully completed and in closedown. The AZ support is going from strength to strength, with another EOI call, and workshop planned for 12-13th November 2014. A second partner, Lilly is currently investigating combination ideas for their hedgehog inhibitor LY9240680 and discussions are progressing with additional partners.  Now our focus must shift to expanding the current portfolio of combination studies, by increasing both the breadth of agents offered and number of partners involved. These partners may range from big Pharm, with multiple agents to offer, to biotech or academic projects looking to expand their patient populations. I invite you to email your suggestions to our mailbox or contact me directly.

Personally, following my 10-year experience in Cambridge Antibody Technology and then MedImmune I’d like to see some biotherapeutics brought into the Alliance. The Drug Development Office (DDO) has already demonstrated a track record with these agents (example - 6 antibody projects, 3 vaccine projects and 1 cell therapy project) and results across the sector are obvious from antibody blockbusters such as Avastin, Herceptin and Rituxan.  Investigating the next generation of biotherapeutics in novel combinations will maximise the potential for patient benefit.

Spending nearly 2 years in CRT Discovery Labs has highlighted to me the value of translating Cancer Research UK (CRUK) Drug Discovery projects to the clinic. Combination strategies must be investigated early in the drug discovery pipeline to maximise opportunities and provide strong rationale and preclinical evidence for further development. It has also given me insight into the CRUK and ECMC network, which provides a unique environment for understanding the biological pathways and clinical disease, and can be harnessed to investigate a broad range of combinations. Knowledge of the molecular characterisation is critical for understanding combinations in specific indications particularly as they become more subdivided. Ex vivo models, where patient material can be used for drug testing, can be utilised for wider screening of combinations. In addition, the extensive preclinical models, from patient derived xenografts to complex genetically engineered mouse models (GEMMs) allow us to build evidence of efficacy and validate biomarkers for clinical development. These models recapitulate many elements of clinical disease and provide confidence to progress novel agents to clinical investigation. The DDO recognises this critical step and has developed two methods for funding preclinical combinations:
- Preclinical combination funding to support final validation of novel combination strategies.
- RaDCom a consortium to expand radiotherapy combinations by delivering high quality preclinical efficacy data for specific radiotherapy-drug combinations to provide the necessary evidence base for early phase clinical trials.

Finally, FACING and DREAM have demonstrated successful delivery and interesting results, potentially changing treatment options for patients with oesophageal and colorectal cancer respectively. For me, true impact will be shown when the combinations progress later trials; either internally by the Partner or in continued collaboration with CRUK and NCRN. We’re currently focused on delivering the current trials and setting up further studies, thus expanding the number of patients receiving exciting and innovative combination therapies in the UK.