Patricia F. Fitzpatrick Dimond Ph.D. Technical Editor of Clinical OMICs President of BioInsight Communications

The White House Proposes Increased Funding For a National Precision Medicine Initiative

In his 2015 State of the Union address, President Obama stated his intention to fund a national Precision Medicine Initiative (PMI), defined by the NIH as an emerging approach for disease prevention and treatment that takes into account individual variations in genes, environment, and lifestyle.

The White House said that it will ask Congress for $215 million to fund the assembly of databases. Through the data, from over one million patients, scientists and researchers will be able to individualize care and generate the requisite scientific evidence to move the concept of precision medicine into clinical practice.

The initiative, in the near-term, focuses on cancer, with other disease areas included over the longer term. Of the $215 million, the White House proposed $70 million in increased funding for the NCI to advance the field of precision oncology.

Basically the initiative funds efforts to integrate and apply the explosion of molecular data on humans, particularly data associated with individual patients, and taps into opportunities to use it to improve health outcomes. The “time is right” for the initiative, NIH says, because of the sequencing of the human genome, improved technologies for biomedical analysis, and new tools for using large datasets.

The NCI launched its Precision Oncology Initiative to address two historical problems, as described by James H. Doroshow, M.D., deputy director for clinical and translational research at the NCI, at a June, 2015 presentation at a National Cancer Advisory Board and NCI Board of Scientific Advisors joint meeting. These, he said, are that cancer treatment for 70 years has relied on drugs “marginally more toxic” to malignant cells than to normal tissues, and that molecular markers to predict benefit or understand therapeutic resistance have “usually been lacking.” Dr. Doroshow said the proposed solution to these problems is to identify and target “molecular vulnerabilities” of various cancers.

NCI kicked off its program with four clinical trials in 2014: ALCHEMIST, a Phase III randomized trial for non-squamous, non-small cell lung cancer; Lung MAP, a Phase II and III randomized trial for second-line squamous lung cancer treatments; M-PACT, a pilot trial for refractory solid tumors; and an Exceptional Responders Initiative to study the less than 10% of patients who do well on otherwise failed-trial drugs.


The White House has proposed $70 million in increased funding for the National Cancer Institute to advance the field of precision oncology. [iStock/KatarzynaBialasiewicz]

Match Trials

In June at the American Society for Clinical Oncology (ASCO), the NCI announced its intention to initiate Molecular Analysis for Therapy Choice (MATCH) studies—clinical trials that analyze patients’ tumors to determine whether they contain genetic abnormalities for which a targeted drug exists (“actionable mutations”) and assign treatment based on the abnormality. MATCH, a Phase II trial aimed at testing targeted therapies against specific tumor alterations across tumor types, seeks to determine whether treating cancers according to their molecular abnormalities will show evidence of efficacy.

During the initial stage of enrollment, the researchers plan to screen biopsy samples from 3,000 individuals using a custom gene sequencing panel, the Oncomine Comprehensive Panel, developed for Thermo Fisher Scientific’s Ion Torrent PGM sequencing platform. As described by panel developer Daniel H. Hovelson and colleagues at The University of Michigan, Thermo Fisher Scientific, the Fred Hutchinson Cancer Institute, and the NCI in the April 2015 issue of Neoplasia, the panel is an integrative NGS-based assay coupled with an informatics pipeline that identifies relevant predefined variants.

The targeted sequencing assay includes 143 genes that were selected using the Oncomine Knowledgebase, reportedly the world’s largest collection of oncology data. The panel design enables simultaneous sequencing of a wide range of genetic alterations, including single nucleotide variants (SNV), small insertions and deletions (indels), copy number changes, and chromosomal translocations.

The MATCH trial will be open to the NCI-supported National Clinical Trial Network with more than 2,400 regional facilities across the country. Tumor samples will be sequenced using a standard protocol at the NCI Molecular Characterization Laboratory, the University of Texas MD Anderson Cancer Center, Massachusetts General Hospital, and Yale University.

Using the sequencing results, the study’s lead investigators will assign program participants, if eligible, to one of several trial arms based on the genetic alterations associated with their tumor, rather than their type of cancer or site of tumor origin. Multi-arm study designs like NCI-MATCH, investigators say, allow them to cast a wider net that encompasses relatively rare tumor mutations and helps drive the development of promising new therapies.

Patients can be considered for entering a second arm of MATCH if the first treatment they received in the trial fails. If genetic testing showed that the patient has a second abnormality targeted by a drug being studied in the trial, and an open slot in the sub-study testing that drug is available, the patient may be eligible for that sub-study. NCI program goals for 2015 and beyond include a significant expansion to include new trials, new agents, new genes, and new drug combinations.

The 10-arm trial opened for enrollment in August, each arm enrolling adults 18 years of age and older with advanced solid tumors and lymphomas that are no longer responsive to treatment, or that never responded. A pediatric version of NCI-MATCH, which will be led by the Children’s Oncology Group, is still in development and is expected to launch in 2016.

Dr. Doroshow told GEN that while MATCH was launched in mid-August “I can guarantee you that we are counting on money from the Precision Medicine Initiative to perform the additional molecular characterization studies, including whole-exome sequencing, for all of the patient materials generated by this trial.

“Basically we have started to pay for biopsies and assign patients to specific therapies but all we have money for is to examine a targeted series of mutations. If we get the additional money in the 2016 budget, we can do the additional genomic investigations that will greatly enrich the value of the trial.”


Regulatory Umbrella

Dr. Doroshow distinguishes these trials from other individual cancer trials in that MATCH, he says, “Will serve as a regulatory umbrella under which we will have about 22 individual trials that match 22 different drugs or drug combinations to specific molecular alterations in tumors. The trials are agnostic as to the origin of the tumor.” A clinical trial like this, he adds, has never been done on this scale, spanning the entire country and involving many clinical trial sites.

Dr. Doroshow noted that it took the NCI a year and a half to negotiate with 20 companies who are contributing their compounds to this study. These compounds include Crizotinib (ALK rearrangement and ROS1 translocations), Dabrafenib and Trametinib (BRAFV600E or V600K mutations), and Afatinib (EGFR activating mutations), among others.

The NCI says the MATCH protocol design has a built-in review after 500 patients, a goal that was reached in late October. During a study-mandated pause in enrollment, the team will review data from the first 500 patients, and examine all of the processes that support the study. The study team will continue to add new treatment arms to the trial as planned, to improve the frequency of matching mutations to drugs.

“A study of this scale would not be feasible using the traditional one-sample, one-biomarker testing approach,” says Mark Stevenson, executive vp and president, life sciences solutions, for Thermo Fisher Scientific.

A key goal of the study as it is broadened includes the expansion and addition of Phase II trials to explore novel clinical signals, as Dr. Dorowshow explains, to understand the context in which the mutation/disease occur. As an example, “patients with breast cancer with the Her-2 neu amplification mutation are not eligible for the MATCH trial because that’s standard of care—we know Her-2 neu positive patients will respond to Herceptin. On the other hand, if we found a small number of colorectal cancer patients that had Her-2 amplification, treating those patients is clearly investigational, and we could give Herceptin treatment as part of the MATCH trial.”

And, he says, “It has become clear than certain diseases depend on certain molecular characteristics, for example, BRAF in melanoma.” This mutation also occurs less frequently than in cancers of the colon, rectum, ovary, and thyroid gland. Dysregulation of BRAF signaling is a key melanoma driver, with the BRAFV600 mutation occurring in approximately 50% of these cancers. In the mutational context, multiple targeted drugs produce remissions in a lot of patients, notes Dr. Doroshow, but “a lesser percentage of patients with colorectal cancer have the same mutation in the BRAF gene, but the drug doesn’t work nearly as well. Therefore, both mutational context and disease context matter in figuring out which targeted agent to use.”

It turns out, according to Dr. Doroshow, that in colorectal tumors the tumors can upregulate other genes to get around the mutation when you give a single gene inhibitor. “The resistance of colon cancer to BRAF inhibitors can be overcome by a combination of agents that hit the pathway in two different places. Melanomas don’t become resistant in that fashion.

“Even in the few years that BRAF inhibitors have been around, about a dozen mechanisms of resistance have been described in the literature.” These include development of additional resistance mutations in the BRAF gene itself, alterations in parallel signaling pathways required for tumor cell survival that obviate the need for the survival signal produced by the mutated gene product inhibited by a drug, and enhancement of the activity of the export pumps that rid the tumor cell of the gene-targeted therapies.

A critical goal of the Precision Oncology Initiative, according to the NCI, is to provide the foundation for a national cancer database integrating genomic information with clinical response and outcome to accelerate the understanding of cancer and how to improve its treatment. As Levi A. Garroway, M.D., Ph.D., of the Dana Darber Institute, noted in an overview in the Journal of Clinical Oncology, “Despite the hype, one presently cannot assert with confidence that genomics-driven medicine will win the day across all cancers. Nonetheless, the confluence of science, technology, and drug discovery has produced a tractable investigative path with a reasonable chance to improve the outcomes of many patients with cancer.”   








































This article was originally published in the January 2016 issue of Clinical OMICs. For more content like this and details on how to get a free subscription to this digital publication, go to www.clinicalomics.com.

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