As Largest Precision Medicine Trial in Oncology Launches, Questions Remain for Industry

By Dr. David Hewitt, Vice President of Medical and Scientific Affairs

Over the last few days at ASCO, multiple studies have shown the remarkable potential of matching cancer therapeutics to specific gene mutations, demonstrating that we are truly entering an age of personalized medicine in oncology. Despite all of the promise, the conference discussions also covered many questions yet to be resolved – by academic centers and pharmaceutical companies, doctors, patients and those of us working in the lab.

“It would be great if you could match a mutation to a therapeutic, but we’re not there yet,” said Dr. Alan Venook in opening a session Monday morning on “New Diagnostics.”

Comprehensive genomic sequencing for individual patients will allow clinicians to better identify appropriate therapy and prognosis. They will provide oncologists with information on individual genomic abnormalities that can be linked to specific treatments, resistance mutations that would preclude some treatments, compensatory mutations that would counteract other mutations and passenger genes that may have no functional role in cancer, but could offer clues to prognosis.

Many challenges remain:

• The pace of discovery is white hot and the number of target genes to be analyzed increases with every discovery. All of this increases the complexity of interpreting an individual patient’s genomic profile and implications for treatment.
• Inconsistencies remain in the genomic tests themselves. Each genomic testing platform, whether commercially or institutionally developed, may analyze different sets of genes and may sequence either whole genes or only specific regions of genes. In addition, the ways results are presented differ by institution and genomic company, making it more difficult for clinicians to interpret and analyze the results. 
• Science has already demonstrated that mutations once thought to be specific for certain cancer types are in fact shared across multiple cancer types. The analysis of genomic tests already is increasing the use of some advanced therapies off-label, with implications for reimbursement. Out-of-pocket costs may be untenable in the age of six-figure targeted therapies.

Interpreting and applying the data remains in the hands of clinicians who increasingly will require the expertise of multidisciplinary institutional tumor boards consisting of oncologists, hematologists, pathologists, preclinical scientists, cytogeneticists, bioinformaticians, clinical pharmacists and genetic counselors to translate results and make decisions. Decisions on treatment plans also will incorporate supporting scientific literature for every genomic variant detected and treatment options.

To aid physicians and increase general knowledge, ASCO announced Monday its first-ever clinical trial, offering patients with advanced cancer access to molecularly-targeted cancer drugs. The trial will allow ASCO to gather “real world data on clinical outcomes to help learn the best uses of these drugs beyond the indications approved by the FDA.”

“Oncologists often use therapies approved for a specific cancer indication to treat people with other types of advanced cancer, but we rarely learn from that experience to benefit other patients,” said ASCO President Dr. Peter Paul Yu. The study will help gather effectiveness and side effects data for a wide range of uses of commercially available targeted therapies. 

The Targeted Agent and Profiling Utilization Registry (TAPUR) study hopes to help change this. ASCO will be working with patient advocacy organizations, five pharmaceutical companies and a network of research sites, including research networks that run trials for the National Cancer Institute.   The pharmaceutical manufacturers participating in the study include AstraZeneca, Bristol-Myers Squibb, Eli Lilly and Company, Genentech and Pfizer.

From a clinical development perspective, the evolution of genomic research in cancer leads to questions on how to design protocols that incorporate not just individual genomic sequencing but comprehensive genomic sequencing for a drug being studied. It is an issue that drug developers must address quickly because things are getting more complicated.

Genomic tests that previously looked at a single gene are now looking at multiple genes simultaneously. And once you begin studying multiple genes, you also must understand how to deal with issues like compensatory genes that may eliminate a patient from trial.

Accrual rates for studies may fall as the inclusion criteria become more complex with greater knowledge of a patient’s genetic profile. A handful of pharmaceutical companies have begun incorporating comprehensive genomic testing in studies, and it won’t be long before many more use genomic testing to profile patients entering trial.

A great many organizations are looking to increase our knowledge.

As part of the President’s Precision Medicine Initiative, The National Cancer Institute told conference attendees about the start next July of the largest and most rigorous precision oncology trial to be attempted in history. NCI-Match: Molecular Analysis for Therapy of Choice, is a foundational discovery treatment trial focused on molecular abnormalities rather than tumor origin.

It will be run through 2,400 sites nationwide to better understand the relative efficacy of the same therapy applied to different tumor types. The study will conduct broad-based genomic pre-screening to assign patients whose tumors harbor specific molecular abnormalities to relevant targeted treatment, regardless of tumor histology.

“The study has great relevance to how we proceed and build rational therapies,” said Dr. Keith Flaherty, Associate Professor, Department of Medicine, Harvard Medical School, noting that the study would launch with 10 treatment arms, but expand to more than 20 within months.

Overall, the conference has highlighted an almost overwhelming number of questions. But the energy and resources being devoted to research both here and abroad suggests that every step brings us closer to developing smarter drugs tailored to extending many millions of lives.

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