Precision Medicine Trials for Cancer: A New Era

December 10, 2015, by Jeff Abrams, M.D., and Nita Seibel, M.D.

The following is the latest in a series of posts from senior NCI scientists and leaders on NCI’s Annual Plan and Budget Proposal for Fiscal Year 2017, which was officially submitted to the President on September 17, 2015. The proposal provides an overview of NCI’s priorities and key initiatives and the institute’s funding request for the President to consider in formulating his own Fiscal Year (FY) 2017 budget proposal.

In this post, Jeff Abrams, M.D., and Nita Seibel, M.D., of NCI's Division of Cancer Treatment and Diagnosis, discuss how precision medicine is influencing the design and conduct of NCI-supported clinical trials.

Conventional cancer clinical trials have produced some remarkable results over the past decades, leading to progress against diseases like Hodgkin lymphoma, which was a nearly fatal cancer in adolescents and young adults a half century ago, and breast cancer, which mainly affects adults.

However, those trials often required the recruitment of thousands of participants, took up to a decade to complete, and cost hundreds of millions of dollars per trial. Today, with significant advances in genomics, imaging, bioinformatics, and related disciplines, we are designing smaller, quicker, and smarter trials that incorporate the principal tenets of precision medicine.

In the past 2 years, NCI has launched a series of precision medicine trials, including two lung cancer trials, Lung-MAP and ALCHEMIST, and NCI-MATCH, which is enrolling patients 18 years of age or older with many cancer types, including rare cancers. In 2016, NCI plans to launch a pediatric version of MATCH. All three trials aptly illustrate how precision medicine is influencing how we conduct cancer research.

For example, they all include an initial screening step to determine which mutation (or mutations) may be driving an individual patient’s cancer. Next-generation genomic sequencing and analysis is then performed to determine if a patient’s tumor has one or more mutations that align with approved or investigational targeted therapies.

This screening step is extremely important because it will be used to determine patient treatment assignment. For example, the screening arm of ALCHEMIST, which is enrolling patients with early-stage non-small cell lung cancer that has been treated surgically, will screen 6,000 to 8,000 patients to determine whether their tumors have mutations in the ALK or EGFR genes. Patients with ALK mutations will be assigned to a clinical trial testing an ALK inhibitor, and those with EGFR mutations will be assigned to a clinical trial testing an EGFR inhibitor.

NCI-MATCH also requires a fresh biopsy sample of patients' tumors, which helps to ensure that the sequencing results more accurately reflect the tumor characteristics after exposure to standard treatment, in contrast to samples taken before treatment was given.

In addition, because NCI-MATCH has already enrolled nearly 800 patients in just a few months, new enrollments have been halted temporarily while study leaders analyze results from these initial patients. This “pause” in the trial will allow more mutations and targeted drugs to be added to the trial when it reopens, which will allow NCI-MATCH to address a wider variety of cancer types.

Precision medicine trials can also be more nimble than most conventional trials. Both Lung-MAP and ALCHEMIST, for instance, are being amended to include new treatment arms that will assign patients whose tumors lack a mutation to receive immunotherapy drugs.

These precision medicine trials present physicians and patients with new issues to consider regarding genetic testing in general. Patients participating in NCI-MATCH and Lung-MAP will be surveyed about their knowledge and preferences regarding genetic testing. It will be important to determine how well patients understand the difference between germline mutations (mutations that can be transmitted to children) and somatic mutations (mutations that are specific to the tumor and are not transmissible to children).

We are also making important strides toward applying precision medicine in pediatric trials. The NCI Pediatric MATCH trial will be conducted nationwide and led by NCI and the Children’s Oncology Group (COG). Pediatric MATCH will provide a tremendous opportunity to test molecularly targeted therapies in children and adolescents with recurrent or treatment-resistant solid tumors (including lymphomas)—patients who usually have few other treatment options.

Although Pediatric MATCH will be similar to the adult version of NCI-MATCH in design, there will be some differences. The genetic landscape of childhood cancer is far less complex than that of tumors that occur in adults. Childhood tumors contain far fewer genetic mutations than adult tumors, and many mutations that are seen in adult cancers are not detected in pediatric cancers. Therefore, the types of agents included in Pediatric MATCH may differ from those in the adult NCI-MATCH. When interesting results are seen with an agent in Pediatric MATCH, that agent can go on to other trials for its further development.

It’s important to stress that not every cancer clinical trial will require such large-scale changes. Large conventional trials still have a valuable role to play, for example, for head-to-head comparisons of therapies with proven efficacy against a specific cancer or cancer subtype, or for testing combinations of therapies.

We are already seeing precision medicine trials offer increased flexibility and efficiency, with the potential to more rapidly influence patient care. And as we learn more about how to optimally conduct these trials, our belief is that we will see even more rapid advances in the coming years.

Social Media Event

We encourage you to leave a comment below with your thoughts and questions about precision oncology trials. We also encourage you to read the Annual Plan and Budget Proposal and the remaining blog posts in this series.

And on January 5 at 1:00 p.m. ET, please join us for a Google Hangout about precision medicine in NCI’s National Clinical Trials Network, using the hashtag #CancerGenomics. You can find more details on our social media events page.

NCI FY 2017 Annual Plan & Budget Proposal Blog Series

January 13: Cancer Prevention: The Best Defense