About the Winther clinical Trial

OmiCure's approach to use RNA was tested and validated through the Winther clinical trial The results of this trial were published in Nature Medicine (link to Nature publication) in April 2019. Here is a brief summary of the trial.
For the first time in the clinic, the WINTHER trial applied transcriptomics (RNA expression testing) to tailor precision medicine in oncology to a greater number of patients based on the increased expression of RNA in tumors compared to normal tissues.

There are now numerous approved drugs affecting the molecular pathway frequently aberrant in tumors, and hundreds of novel targeted drugs, including immune-checkpoint modulators, are in clinical development. Not unexpectedly, meta-analyses demonstrate that biomarker-driven trials have better outcome than trials lacking biomarkers. Some of the most rapid advances have been achieved with investigation of DNA structural abnormalities.

 

Precision medicine focuses on DNA abnormalities, but not all tumors have tractable genomic alterations. 

Unfortunately, not all patients’ tumors have pharmacologically tractable DNA alterations. Thus, extending the application of precision medicine requires a deeper understanding of cancer biology.

 

Hence, we initiated an international trial WINTHER  that prospectively navigated patients to therapy according to either DNA-guided next-generation sequencing (NGS) or transcriptional (RNA) analysis that specifically compared tumor to matched normal tissue.

The WINTHER trial navigated patients to therapy on the basis of fresh biopsy DNA sequencing (arm A; 236 gene panel) or RNA expression (arm B; comparing tumor to normal). The most common diagnoses were colon, head and neck, and lung cancers.

The strategy employed in WINTHER resulted in a higher proportion of patients treated than in many precision medicine trials. Previous studies have identified potential treatments for between 5% and 25 % of patients based on DNA profiling alone, our findings represent an important step toward delivering on the true promise of precision medicine in oncology

L. Schilsky, Chairman WIN Consortium and Chief Medical Officer of ASCO.

The WINTHER protocol was conducted under the auspices of the Worldwide Innovative Network (WIN) for personalized cancer medicine (WIN Consortium) and included investigators from five countries in North America, Europe and the Middle East: Vall d’Hebron Institute of Oncology - VHIO (Spain), Chaim Sheba Medical Center (Israel) (Dr. Raanan Berger), Gustave Roussy (France) (Pr. Jean-Charles Soria), Centre Léon Bérard (France) (Dr. Pierre Saintigny), Segal Cancer Centre, McGill University (Canada) (Dr. Wilson H. Miller), UT MD Anderson Cancer Center (USA) (Jordi Rodon and Apostolia-Maria Tsimberidou) and University of California San Diego, Moores Cancer Center (USA).

To translate RNA investigations into therapeutic decisions for the physicians, a novel strategy and algorithm were developed by Ariana Pharma, based on three pillars: 

  • (1) dual biopsies, enabling differential gene expression and microRNA profile assessment in tumor versus matched normal organ tissues so as to discard most genetic variability between individuals 

  • (2) a knowledge database that included standard-of-care and investigational drug information; and 

  • (3) an innovative algorithm that enabled linking the patients’ RNA information to the knowledge database and provided a ranked drug list for each patient

Most previous studies of genome-guided therapy have been hindered by low matching rates, often in the range of ~10–25%. Our study suggests that incorporating transcriptomic analysis could attenuate this problem to some extent.

Assessing RNA is an important adjunct to DNA profiling for determining precision treatments. WINTHER rings in a new era for personalized medicine in oncology

Josep Tabernero, Vice-Chairman WIN Consortium, Director VHIO and President ESMO

This approach enables to witness several cases of exceptional responses.

One of these cases is the following.

 

A 69-year-old woman with a refractory gastrointestinal neuroendocrine small gut tumor and peritoneal metastasis underwent debulking surgery and received lanreotide (a long-acting somatostatin analog) for residual disease (April 2011 to June 2012). She then developed bowel obstruction (due to peritoneal progression), which required surgery. The somatostatin analog continued until April 2014, when progression to the liver occurred. Axitinib (on a clinical trial) was given for 10 months before progression.

 

In April 2015, she enrolled in the WINTHER trial. The NGS showed no DNA alterations; however, transcriptomics (RNA) revealed elevated expression of AKT2 and AKT3, and she was successfully treated with the mechanistic target of rapamycin (mTOR) inhibitor everolimus, resulting in disease stability ongoing at almost 3 yr. 

This response is of interest for several reasons: 

  • (1) effective therapy was based on transcriptomics; and 

  • (2) mTOR inhibitors as single agents (in contrast to their use in combinations) are rarely effective when matched to DNA alterations, presumably because of frequent genomic co-alterations. 

This patient started everolimus treatment in May 2015; in 2016, both the FDA and the EMEA approved everolimus for this indication according to studies showing improved outcome with a median PFS of ~11 months. The PFS is considerably longer in this patient, perhaps because she had transcriptomic indicators of phosphatidylinositol-3-OH kinase (PI3K) pathway component overexpression. As noted above, at the date of start of some of these treatments, they were exploratory and used off-label, but their approval at a later stage pointed to the pertinence of the WINTHER predictive tools and therapeutic choices.