Meeting the challenges of clinical trial design in cancer

Despite continuing advances in medicine and drug development technology, it remains very difficult for new cancer drugs to gain regulatory approval.

The reason behind this is partly due to the stringent standards set by the EMA and the FDA, but is also a direct result of the particular challenges that face clinical trialists working in cancer indications. Specifically, approvals of new agents are hindered by reliance of regulatory agencies on overall survival as a license-enabling endpoint, which often requires clinical trials with a large number of patients and an extensive follow-up. Surrogate endpoints, such as disease-free survival (DFS) and progression- free survival (PFS) are gaining traction, particularly in solid tumours. In hepatic cellular carcinoma and gastrointestinal stromal tumours, tumour response is under scrutiny as there is a realization that the traditional RECIST criteria, which require tumour shrinkage to classify a response, do not account for tumour stasis and/or necrosis, both of which are clinically meaningful and indicate drug activity. In other indications, biomarkers are a topic of intense study, with prostate-specific antigen losing relevance for some of the newer prostate cancer therapies, and hENT1 emerging as the first marker identified for pancreatic cancer (Abstract 709P, Poster session II, Sunday 30 September).

At this year’s ESMO, presentations and posters throughout the programme showcased the ingenuity and perseverance of the European clinical community in efforts to advance the study of anticancer agents.

Dr/Professor Arif Manji from The Hospital for Sick Children, Toronto, Canada, described the increased use of expanded cohort Phase 1 studies to gain additional clinical experience at recommended Phase 2 drug doses (abstract 455P). Dr Emilio Bria from Azienda Ospedaliera Universitaria Integrata Verona, Verona, Italy, presented results of a treatment interaction analysis based on data from randomized controlled trials in order to calculate the benefits (pathological complete response rates) versus potential harms (cardiotoxicity) associated with combining anthracyclines with anti-human epidermal growth factor receptor 2 (HER2) agents in women with breast cancer (abstract 322PD).

In other poster presentations, Dr Takanori Tanase from Taiho Pharmaceutical, Tokyo, Japan explored the relevance of PFS in colorectal cancer and commented on the importance of timing of imaging assessments (abstract 1378P); and Dr Chantal Dreyer from Hopital Beaujon, Clichy, France, evaluated the use of Choi criteria, already used for GIST, as an alternative to RECIST in patients with well differentiated pancreatic neuroendocrine tumours (PNET) treated with sunitinib or everolimus (abstract 1163P).

On Saturday, Professor Shukui Qin from the People's Liberation Army, Nanjing Bayi Hospital, China, and Professor Martine Piccart from Institut Jules Bordet and the Université Libre de Bruxelles, Brussels, Belgium, chaired the ESMO-CSCO Joint Symposium session session on the future of clinical trial design in cancer, where the faculty presented on a range of topics, including biopsy sample banks and biomarker-driven trials in breast cancer and non-small-cell lung cancer, with insights and experience provided by both Eastern and Western cancer centres involved in large clinical trials.

Professor Piccart described the long and expensive procedure associated with the development of new drugs, with only ~5% obtaining license approval, and the resulting delay in the availability of effective therapies to patients. “What is more frustrating is that after such a process we still have only a crude idea of the subsets of patients who will ‘truly’ benefit from a given agent”, Professor Piccart said. Commenting on the future of clinical trial design, Professor Piccart underscored the need to adopt innovative strategies to accelerate drug development in a more efficient and targeted way. In breast cancer, Professor Piccart described data from the Neoadjuvant Lapatinib and/or Trastuzumab Treatment Optimisation (NeoALTTO), and the Adjuvant Lapatinib And/Or Trastuzumab Treatment Optimisation (ALTTO) studies to illustrate how neoadjuvant trials could represent a smart, fast and cheap model for obtaining regulatory approval of effective agents.