BATTLE trial personalises lung cancer therapy

Clinical trial acronyms are not chosen by chance, and are important in conveying a message to the participants, sponsors and public alike. The message conveyed by the first prospective, biopsy driven adaptive study in NSCLC, aptly named 'BATTLE' (Biomarker Integrated Approaches of Targeted therapy for Lung cancer Elimination) falls within the military rhetoric of cancer that characterizes the 101st AACR conference, and more in general cancer research in the west world.

The results of this first 'BATTLE' were enthusiastically presented by principal investigator Edward S. Kim (Director, Clinical Research Operations, Head and Neck Dept, Anderson Cancer Center, Houston) during the plenary session devoted to "Innovations in translational medicine".

According to Dr. Kim, the 'BATTLE' represents the first of a series of trials which should pave the way to personalised therapy in lung cancer. More realistically, the 'BATTLE' is one of the first examples of adaptive clinical trials. Personalised therapy in lung cancer seems to remains a longer term goal.

But what exactly are adaptive clinical trials? The term 'adaptive' is one of those words that have been very fashionable lately in the clinical research world, and it has been used to refer to many different things. As defined in a recent review by Orloff and coauthors (Orloff et al, Nat Rev Drug Disc 2009) adaptive clinical trials aim at increasing flexibility in the design of the trial, and at maximizing the use of accumulated knowledge. They use collected data to decide on how to modify aspects of the study mid-trial in a pre-planned manner, which must not undermine the validity of integrity of the study, such as: a) adjustments to sample size, b) allocation of treatment arms, c) inclusion and exclusion criteria, d) adjusting statistical hypothesis, and, e) combining trials or treatment phases, etc. Thanks to their 'learn as you go' approach, adaptive studies have the potential to result in more ethical treatment of patients within trials, as randomized patients are changed to the treatments which are most effective.

In the case of the 'BATTLE' trial (http://clinicaltrials.gov/ct2/show/NCT00409968), patients with chemorefractory metastatic NSCLC -in other words, with the worst possible prognosis- were stratified according to the presence of the (highest ranked) biomarker identified in a core needle biopsy: EGFR, KRAS, BRAF, or cyclin D. Primary endpoint was 8-week disease control (DC). Based on tumour biomarker analysis, patients were adaptively randomized under a Bayesian model into four treatment: erlotinib, sorafenib, vandetanib, or erlotinib + bexarotene. The primary 8-weed DC endpoint was shown to predict overall survival (median overall survival: 9 months).

What does Bayesian adaptive randomisation actually mean? Simply, that more patients are assigned to more effective therapies as the trial progresses and knowledge on how the arms are doing is accumulated. At the beginning of the trial, 97 patients were equally randomized, then as the trial progressed 157 more were adaptively randomized. The trial was activated in November 2006 and completed in October 2009.

The completion of this trial marks, in Kim's emphatic words, the first successful completion of a prospective biopsy-driven study in lung cancer, where patients are guided towards more effective personalized treatments based on their biomarker expression.

The second 'BATTLE' is already under way, and will involve no equal randomization step, but an initial biopsy will guide an adaptive randomization from the beginning, which will be followed by a second stage of more refined randomization.

Not only that, but 'BATTLE-3' has already taken root in the mind of the inventor; the ultimate 'BATTLE', which, according to Kim, will be a cancer prevention trial.

Dr. Kim concluded the talk by changing Hippocrates's oath: "Life is short, the art is long" to "Life is short, the art is the 'BATTLE'".