Interim WINTHER study findings provide lessons for future research

Jean-Charles Soria – Institut Gustave Roussy, Villejuif, France

What is the rationale for conducting the WINTHER study?

WINTHER is a second generation precision medicine trial. It’s sponsored by the WIN Consortium, Worldwide Innovative Networking consortium, and it aims at providing biology guided therapy which is based on two pillars: the classical one, structural DNA changes, and the more innovative one which is transcriptomic guidance of rational therapy for patients who do not have an actionable structural change.

How is WINTHER different to other trials?

Most of the other molecular triage trials will focus on analysing the tumour, either from an archive material or from an all-purpose biopsy. Those trials are usually going to evaluate only structural DNA changes and that represents 40-60% of the patients meaning that for half of the patients there is no biology guided therapy. WINTHER tries to compensate for this limitation of structural DNA changes by branching on the design of the trial a second biopsy which is a biopsy on the normal tissue. This dual biopsy, normal plus tumour tissue, allows to deliver a therapy that is guided, either by the structural DNA changes or the transcriptomic changes.

What have been some of the key stages of the trial to date?

WINTHER is an ambitious and complex trial and the most challenging steps have been the implementation of the trial. The trial was designed in 2012 and the trial became a clinical reality in April 2013. We underestimated the variability of behaviour of the different regulatory agencies because this trial encompassed recruiting centres in Spain, Vall d’Hebron Institute of Oncology, in Israel Chaim Sheba, in France Gustave Roussy, in Canada Segal Cancer Center but also in the USA with MD Anderson and the University of California San Diego. While in France the timeline from conception to recruitment of the first patient was 19 months in the United States 56 months down the line they have not yet recruited a patient and the reason is mainly related to the FDA evaluation of the trial. The FDA requested this trial to be evaluated as an investigational device and then it mandated that all the analysis on DNA or RNA would be performed in CLIA certified labs.

How has the challenge of recruitment been addressed?

This has been addressed by the fact that recruitment had to increase in the sites that were open to enrolment, mostly Europe, Israel and Canada, that have recruited 250 patients. Between April 2013 and April 2015 250 patients have been recruited.

What were the interim results of WINTHER you presented at the meeting?

This trial, because of its nature, because it mandates a dual biopsy and it mandates that the threshold of tumour cells in the tumour biopsy is 60%, has faced a significant number of failures in terms of patients who consent then get a tumour biopsy with a threshold of cells that is below 60%. Or if they succeed in the tumour biopsy they may not get the appropriate normal biopsy. Or even if they succeed the tumour biopsy, the normal biopsy, the 60% threshold, they might still fail because the quality of RNA and DNA is not good enough. So this is a learning process in which failure rates were initially 70% and are now down to 30%, a learning experience, an important learning process for intervention and radiology, for pathology, for biology and for clinicians in an ambitious trial.

Have there been any other challenges for conducting the trial?

The other challenge from WINTHER is that the targeted therapies, so standard therapies, that will be defined according to WINTHER algorithms were not provided in the trial. So access to these therapies was a challenge for some participating sites. Some sites who had a very large panel of phase I trials will have limited problems to access these innovative therapies but sites where there was a very limited portfolio of clinical trials will need to pay out of pocket many of these compounds and this encompasses a significant burden for WIN as a consortium to compensate for those costs.

What can be learned for future studies?

WINTHER is a trial still ongoing, we are still recruiting. As I said, 250 patients are on board out of which 100 have a treatment decision. We need to keep the recruitment. The lesson from WINTHER is probably that we need to be able to find the technology that allows for analysis of the tumour not on fresh frozen material, which is pretty challenging, if FFT could be analysed it would be better. The second main lesson is that we need to negotiate with the pharma companies up-front access to the targeted therapies to match the specific defaults in the tumour with the ad hoc pharmaceutical compounds that will leverage this structural transcriptomic fragility in the tumour.