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Netherlands Drug Repurposing, Tumor Profiling Trial Results Reported at ESMO

BARCELONA – Two genomics-centered trials in the Netherlands — the Center for Personalized Cancer Treatment (CPCT-02) and Drug Rediscovery Protocol (DRUP) — are demonstrating the potential for finding tumor genomic features that may guide treatment for advanced cancer patients, even as experts continue working on strategies for interpreting, evaluating, and communicating such findings in a clinical context.

During a session on the genomic characterization of cancer cells at the European Society for Medical Oncology Congress here yesterday, representatives from CPCT and DRUP provided updates on the Phase I trials, which are digging into genomic features influencing treatment response and molecularly guided off-label drug matching in advanced cancers, respectively.

After publishing some early results from CPCT-02 in the European Journal of Human Genetics in 2016, a representative from the Hartwig Medical Foundation offered an update on both CPCT-02 and DRUP at the Association for Molecular Pathology AMP Europe meeting in 2018.

At the time, the DRUP team reported results for more than 200 Dutch patients with advanced cancer. At ESMO this week, Emile Voest, a molecular oncology and immunology researcher affiliated with the Netherlands Cancer Institute, the Center for Personalized Cancer Treatment in Rotterdam, and the Oncode Institute, presented the latest DRUP data.

In particular, he illustrated some of the targetable alterations identified so far, and outlined the team's broader "adaptive precision oncology" protocol, which is designed to assess matched treatments in cases that have no standard of care treatment options available.

After doing whole-genome sequencing on a tumor biopsy samples and matched normal tissue, the investigators systematically search for approved drug targets, using partial response, complete response, or stable disease to evaluate clinical benefit. When no benefit is found, that treatment cohort is closed, Voest explained, and the search for targeted treatments continues.

In a paper published online today in Nature, Voest and his colleagues described results for a subset of 215 DRUP advanced cancer cases from more than 10 primary cancer types that were assessed with this approach. In 136 advanced cancer patients treated with targeted therapy and another 79 prescribed immunotherapy, they reported, 34 percent had a complete response, partial response, or stable disease reaching beyond about four months.

In that paper, Voest and co-authors noted DRUP "provides a framework through which patients with all types of tumors are able to acquire access to existing targeted therapies and immunotherapies, and in which treatment outcomes are monitored and publicly reported."

"The public availability of these data is especially relevant given recent concerns that the increasingly widespread use of genetic profiling could escalate the demand for off-lab treatment," they added, emphasizing that "the importance of publicly reporting negative results cannot be underestimated, as it prevents patient exposure to ineffective agents with all their accompanying toxicities and financial costs."

The DRUP investigators currently have access to more than two dozen drugs for the trial, Voest noted. Since September 2016, they have received more than 1,000 case submissions and narrowed in on 295 patients who were eligible for the study.

The group gleaned potentially clinically relevant new information for 85 percent of the cases that were successfully sequenced, though whole genome sequences could be attained for just 61 percent of the cases so far.

As part of the same session, Edwin Cuppen shared findings from the CPCT-02 trial, another non-randomized, prospective effort done through the Center for Personalized Cancer Treatment, including data outlined in a BioRxiv preprint last September.

Cuppen, a molecular medicine researcher at the University Medical Center Utrecht and director of the not-for-profit Hartwig Medical Foundation, noted that the CPCT-02 effort currently spans some 49 hospitals in the Netherlands, generating whole-genome tumor and matched normal sequence data for advanced cancer patients with an average turnaround time of 14 days.

From there, CPCT-02 investigators are profiling everything from single nucleotide variants or small insertions and deletions up to whole-genome duplications or complex structural variants to better understand metastatic disease across tumor types.

Newcastle University's Ruth Plummer, who was not involved in DRUP or CPCT-02, discussed the findings within the context of other early-stage, molecularly informed trials such as TAPUR, during her own presentation. She noted that many oncologists will likely need additional education and guidance to know when, and how, to use genomic data for their patients.

For his part, Vall d'Hebron Institute of Oncology investigator Joaquin Mateo highlighted efforts by ESMO's translational research and precision medicine working group to develop and bolster its "ESMO scale for clinical actionability of molecular targets" (ESCAT) guidelines.

The team published its initial framework for ranking potential precision medicine targets in the Annals of Oncology last year, describing half a dozen tiers for molecular targets, depending on their potential clinical benefit, level of evidence, and so on.

Citing cancer alteration interpretation guidelines from the Association for Molecular Pathology, American Society of Clinical Oncology, the College of American Pathologists and other organizations or centers, authors of that paper noted that many classifications "are only partially overlapping, with greatest overlap in the top tiers, and none of them have been broadly implemented in clinical practice."

The ESMO group is continuing to grapple with strategies for prioritizing genomic data on cancer patients and interpreting their clinical relevance, if any. Mateo also pointed to the need for "scalability" around genomics to reduce healthcare inequality and treatment disparities as much as possible by reaching community clinics outside of academic centers.