Researchers in the Netherlands presented preliminary results from a multiarm precision medicine trial at the recent ESMO 2017 Congress in Madrid, Spain. The trial, which matches patients with approved drugs based on mutations in their tumor and tissue type, has the potential to uncover treatment options for patients who have exhausted standard therapies, as well as those with rare cancers.

A precision medicine trial aimed at identifying patients with rare cancers or those who have exhausted standard treatment options suggests that drugs approved for specific types of cancer might work in other tumor types that harbor the same genetic mutations. Preliminary results from the trial were presented in September at the ESMO 2017 Congress, the annual meeting of the European Society for Medical Oncology, in Madrid, Spain.

Researchers with the Center for Personalized Cancer Treatment (CPCT), a network of more than 40 hospitals in the Netherlands, performed whole-genome sequencing on biopsies taken from about 2,000 patients with all types of metastatic cancer to create a database of genetic mutations that appear in multiple tumor types. The database is being used to inform enrollment in a multiarm trial that includes 19 different approved drugs.

To date, 70 patients have been enrolled out of more than 250 cases submitted for review. To be eligible for the trial, patients must have been diagnosed with solid tumors, lymphoma, or multiple myeloma, have exhausted standard treatment options, and have actionable tumor mutations—meaning that they can be targeted by one or more of the study drugs.


Emile Voest at the ESMO 2017 Congress

Efficacy is assessed in two stages, explained the trial's principal investigator Emile Voest, MD, PhD, medical director of the Netherlands Cancer Institute in Amsterdam. If at least one of the first eight patients with the same tumor type and genetic mutation responds to the treatment, that cohort is expanded to 24 patients to better understand the clinical benefit. If at least five patients in the larger cohort experience clinical benefit, researchers deem use of the agent a success. (Clinical benefit is defined as complete remission, partial response where the tumor shrinks by more than 50%, or stable disease for at least 16 weeks.)

So far, there has been a clinical benefit of 38% across all tumor types and drugs, he said. Researchers expect the trial to continue indefinitely and to add at least two more drugs over the next few months, he adds.

The study design is somewhat similar to other large so-called basket trials, such as the NCI-Molecular Analysis for Therapy Choice (NCI-MATCH) trial that was launched in the United States in 2015. However, the two efforts take slightly different approaches, said Voest.

For example, in contrast to NCI-MATCH, CPCT's Drug Rediscovery Protocol uses tissue type as well as genetic profile to assign patients to treatment arms, he said. In addition, the CPCT trial does not include experimental agents whereas NCI-MATCH tests approved therapies and drugs that have shown efficacy in late-stage clinical trials.

“This is a unique design in that we focus on approved drugs and try to maximally utilize these agents,” said Voest. “We create cohorts based on profile and tissue type because we know that the tissue background of tumors is extremely important, and we share data on small cohorts with other trials so we can increase numbers in rare indications.”

Catherine Pickworth, PhD, of Cancer Research UK in London, noted that the CPCT trial involves sequencing the whole genome rather than a panel of select genes. “The wide scope of this trial allows researchers to study both common and rarer genetic mistakes,” she said. “This could reveal new ways to use existing treatments, which is particularly exciting for people with rare cancers where fewer treatments are known to work.” –Janet Colwell

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