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WINTHER Trial Highlights Challenges, Potential of Transcriptomics for Precision Oncology

NEW YORK (GenomeWeb) – A newly published study has demonstrated the potential of using transcriptomics to help get cancer patients on treatments they're most likely to benefit from.

The study, called WINTHER, appears today in Nature Medicine and included RNA expression analysis in addition to genetic sequencing to match cancer patients to drugs. Despite demonstrating the promise of the approach, the study did not reach its primary endpoint as it had to deal with the same challenges that have plagued other precision oncology trials.

This is the first trial to match patients with solid tumors to treatments based on transcriptomics, noted Vladimir Lazar, an investigator on WINTHER and chief scientific and operating officer of the WIN Consortium, the body organizing the study. While the trial may not have reached its prespecified endpoint, "the lessons in this trial and results are very important," Lazar said, highlighting a post-hoc analysis that demonstrated the importance of defining the biology driving the tumor and interrogating that biology to "match" patients to treatments.

The study, led by Razelle Kurzrock from the University of California, San Diego Moores Cancer Center, involved 107 evaluable patients with a variety of cancers enrolled at four centers in Spain, Israel, France, and Canada. Of these patients, 69 individuals received treatments based on results following genetic sequencing using Foundation Medicine's FoundationOne test.

In most precision oncology studies, if patients don't match to targeted treatments based on genetic abnormalities, then they don't have any other options. However, in this study, there were 38 such patients who didn't have DNA alterations, but then received microarray-based RNA expression analysis of tumor and normal tissues and received treatments based on that information.

At the time WINTHER was designed "nobody felt that it was reasonable or ethical to start matching by RNA if the patients had a good DNA match," Kurzrock explained. "However — and here is the important thing — if there was no DNA match then we had an additional option."

Researchers evaluated outcomes by using each patient as his or her own control by comparing their progression-free survival in the present trial (PFS2) against the progression-free survival they experienced on the treatment they received prior to entering the trial (PFS1). Because these were heavily pretreated patients, the expectation would be that they would do worse with every subsequent therapy.

WINTHER investigators hoped to show a degree of improvement in patient outcomes in the trial based on matched therapy, and prespecified a PFS2 to PFS1 ratio of greater than 1.5 in 50 percent of patients in the DNA sequencing arm and in 40 percent of patients in the RNA expression analysis arm. The study failed to meet this prespecified endpoint, however, with 20 percent of patients in the DNA sequencing arm and 26 percent of patients in the RNA expression analysis arm exceeding that ratio.

The field of precision oncology, though relatively new, can now boast a number of advances with the recent approval of larotrectinib (Vitrakvi) for patients with NTRK gene fusions, and even a growing list of next-generation treatment options for when patients develop resistance to first generation targeted drugs, as in the case of EGFR inhibitors. "Even though there are many successes in precision oncology ... there are also limitations with some studies showing that many patients don't have durable responses," Kurzrock said. "Then, the question is, why is it that occurs?"

WINTHER, which had aimed to enroll 60 patients in the DNA sequencing arm and 140 patients in the RNA expression analysis arm, faced a number of challenges that may have impacted the results. In fact, the opposite happened, partly due to regulatory delays in the US. Additionally, the prespecified endpoint of PFS2/PFS1 greater than 1.5 was too ambitious, researchers acknowledged during a presentation last year at the American Society of Clinical Oncology's annual meeting.

According to Lazar, a PFS2/PFS1 ratio of greater than 1.3 is accepted in the field and would have pushed the proportion that met the prespecified endpoint in the overall trial from 22 percent to 25 percent. In all 107 patients, 11 percent experienced a complete or partial response, 15 percent had stable disease for six months or longer, and median overall survival was 5.9 months.

In a blinded post-hoc analysis, researchers developed a DNA and RNA matching score and assessed whether patients who received drugs that they were predicted to benefit from based on molecular profiling data fared better than those who didn't. "The matching score ... tries to reflect the degree to which patients were matched," Kurzrock said, noting that the researchers hypothesized that the degree to which a patient is matched to the therapy should make a difference. "And, indeed, that's what the paper shows." Multivariate analysis demonstrated that patients with an ECOG performance status of 0 and a high matching score had the longest overall survival compared to all other subgroups.

"The changes at the DNA level are not all the changes that occur in a cell," Kurzrock explained. "If there is a change at the DNA level but it is not reflected at the RNA level, then you don't have enough information ... The transcriptomics is going to give you more information about the underlying biology that can help you craft an appropriate therapy."

Additionally, tumors are complicated and typically have multiple changes at the DNA and RNA level that are helping them grow and spread. "Therefore, it makes sense that if there are many different drivers of the tumor and you're only addressing a small portion of the drivers then you may not get a great response, because the tumor has alternative mechanisms by which to grow," Kurzrock said.

In the WINTHER trial, patients had very advanced disease, with 26 percent receiving more than five prior treatments. And although around 300 patients consented to partake in the study, many ended up not getting on a treatment because the quality of their biopsies didn't allow for molecular assessments, they dropped out due to poor health status, or died.

"Most precision oncology studies have been plagued by patients enrolling very late ... and [this is] also reflected in WINTHER," Kurzrock said. "Doctors tend to enroll in these studies as a last-ditch [effort] right before hospice, and by that time, the patient is in bad shape and the tumor has evolved tremendously."

Even so, in WINTHER researchers were able to match 35 percent of consented patients to treatments based on DNA sequencing or RNA expression analysis. If the study had relied only on DNA information, the match rate would have been around 23 percent.

Moreover, despite not reaching the primary endpoint in WINTHER, there were suggestions that transcriptomics may better reflect tumor biology in some cases and therefore identify better targeted treatment "matches" than with DNA information. For example, the authors pointed out that the benefit rate in the RNA expression analysis arm was approximately 32 percent compared to 23 percent in the DNA sequencing arm, though this was not statistically significantly higher.

One of the exceptional responders in the study, a patient with refractory gastrointestinal neuroendocrine tumors, did not have any targetable DNA alterations, but transcriptomics revealed she had elevated expression of AKT2 and AKT3. She received the mTOR inhibitor everolimus (Afinitor), and experienced stable disease that's ongoing at nearly three years. The authors wrote this case is particularly notable since when patients are matched to mTOR inhibitors based on DNA alterations they rarely benefit likely due to the existence of other genomic alterations.

The study not only demonstrates the feasibility of incorporating transcriptomics into precision oncology trials, but also highlights the importance of collaboration among researchers across institutions and in different countries. Richard Schilsky, an author on the paper and chief medical officer of ASCO, noted that WINTHER dealt with its share of logistical challenges, for example, ensuring consistent standard operating procedures for tissue collection and handling across multiple centers in different countries and enabling investigators in different time zones to discuss treatment recommendations based on the -omics data.

"Since WINTHER did not test a specific treatment, there were also challenges in patient access to the recommended treatments and collecting consistent patient follow-up data," Schilsky said. In the study, of the 107 who received single or combination treatment with 159 drugs, 115 treatments were given off-label, 22 were prescribed on-label, and 22 were investigational agents.

Despite these challenges, investigators in the WIN Consortium also learned alot from WINTHER, and are now applying those lessons to the SPRING trial, he noted. "The model of global precision medicine trial is absolutely essential to test interventions in molecularly-defined rare patient populations," Schilsky said.

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