Medical World News: Precision Medicine in Oncology

Roxana Dronca, MD

Expression of the apoptosis regulator protein BIM could help predict response to PD-1 blockade in patients with melanoma, according to a study presented at the AACR International Cancer Immunotherapy Conference.

Despite promising results, immuno-oncology agents, particularly the PD-1 and PD-L1 agents, have not had much success with a predictive biomarker. Results have been mixed with correlating PD-L1 expression with treatment response. One study, presented at the 2015 ASCO Annual Meeting found that mismatch repair deficient tumors were more receptive to PD-1 inhibition with pembrolizumab.

In the early phase study, response was evaluated in 38 patients with metastatic melanoma being treated with pembrolizumab through a series of blood samples that were assayed by flow cytometry. Blood samples were collected and every 3 months after treatment.

Patients with high-levels of BIM expression on their T-cells responded to treatment while those who had relatively lower expression of the protein did not respond, as measured by RECIST 1.1 complete response, partial response, or stable disease after 4 cycles of treatment. Responders also had increased expression of soluble PD-L1 in their blood prior to treatment.

“The discovery of biomarkers of sensitivity are vital not only for informing clinical decisions, but also to help identify which patients with melanoma, and possibly other malignancies, who are most likely to benefit from PD-1 blockade,” said lead author of the abstract Roxana Dronca, MD, a hematologist at Mayo Clinic. “This will allow us to expose fewer patients to inadequate treatments, and their associated toxicities and costs.”

FDA Scrutinizes Pathway Genomics' Direct-to-Consumer Genetic Test

A major advantage of the method used is the use of circulating peripheral blood cells, which will avoid repeated tissue biopsies for the patient.The direct-to-consumer (DTC) screening test CancerIntercept Detect has not undergone proper regulatory clearance as a “device” and could therefore harm public health, according to a letter issued by the FDA to the manufacturer of the test, Pathway Genomics.

In the letter, which was addressed to the CEO of Pathway Genomics, Jim Plante, the FDA stated that under the DTC model, the company is shipping blood collection tubes—classified as a medical device—for use with CancerIntercept Detect without having submitted the tubes for FDA approval, clearance, or listing. The letter also cited the lack of clinical validation for this particular test as a screening tool for early detection of cancer in high-risk individuals.

The FDA expressed a desire to discuss a validation strategy with Pathway Genomics, which was founded just 7 years ago, for the test and to evaluate data on clinical sensitivity and specificity.

This is not the first time that Pathway Genomics has received pushback from the FDA. In 2010, a similar letter was sent to the company demanding justification for why their spit kit, which they had planned to market in collaboration with Walgreens, had not been FDA approved.

The DTC genetic testing industry has experienced a lot of turbulence, with 23andMe being a prime example. In 2013, the FDA prevented 23andMe from selling tests that detected disease risks; however, earlier this year, the company’s DTC test to screen for carriers of Bloom Syndrome was granted clearance.

Working Group Announces Precision Medicine Initiative Blueprint

According to the company's website, CancerIntercept Detect has been developed for individuals who are at risk for known hereditary cancer, have a family history of cancer, whose lifestyle choices may increase their risk for cancer, or who may have had environmental exposure to cancer causing agents. The company claims to have a College of American Pathologists and Clinical Laboratory Improvement Amendments accreditation.The Precision Medicine Initiative (PMI) Working Group has created an action plan that could help propel President Obama’s vision to better integrate personalized medicine in healthcare, Francis Collins, MD, PhD, announced in a conference call.

“We now have a design plan and it's time to move forward,” said Collins, the director of the National Institutes of Health (NIH). A nationwide search will be initiated for a leader for the project, he said—in the interim, Josephine Briggs, MD, director of the National Center for Complementary and Integrative Health, will serve as the acting director.

The working committee convened by the NIH brought together a diverse group of experts from across the healthcare spectrum, which included academic research centers, philanthropic organizations, patient advocacy, as well as the pharmaceutical industry. The committee held several workshops to gain additional expert as well as public insight and to shape their thoughts on several important issues.

According to the summary statement in the report, the PMI Cohort Program (PMI-CP) is planning to build a cohort of at least one million Americans. The working group has provided detailed guidance on 6 main topics in its report: cohort assembly, participant engagement, data, biobanking, policy, and governance. The report also provides direction for an optimal design of the PMI cohort, including:

• The development of quantitative estimates of risk for a range of diseases by integrating environmental exposures, genetic factors, and gene-environment interactions
• Identifying determinants of individual variation in efficacy and safety of commonly-used therapeutics
• Developing biomarkers to assess risk of common diseases
• Use of mobile health technologies to correlate activity, physiologic measures, and environmental exposures with health outcomes
• Determine health impact of heterozygous or loss-of-function mutations
• Developing new disease classification or relationships
• Empower participants with enough information/data to better manage their health
• Create platforms to enable trials of targeted therapy.

During the call, Collins discussed plans to start recruitment of study volunteers next year. Initial genetic testing will only include genotyping (which would cost $30 to $40 per person) rather than whole genomic sequencing, which is the ultimate goal.

President Obama’s request for $130 million for the study portion of the project is still under consideration with the lawmakers. Enrollees would include new volunteers who wish to participate and those who have already enrolled in large study cohorts through their health plans, such as Geisinger Health System, Kaiser Permanente, Mayo Clinic, and Marshfield Clinic.