Personalizing cancer treatment by matching precision drugs with targetable driver mutations is at the heart of modern oncology. The strategy has sparked an explosion in the identification of genetic alterations linked with cancer’s growth and in research aimed at determining how the activity these glitches stimulate can be prevented or reversed.
To have the best likelihood of finding precision treatments for patients after molecular testing, physicians need a way to review all known actionable mutations, and that was the impetus for OncoKB, a new database of somatic genetic variants developed at Memorial Sloan Kettering (MSK). In October 2021, OncoKB (the “KB” in its name stands for “knowledge base”) became the first such database to receive partial recognition from the U.S. Food and Drug Administration (FDA), deeming it a scientifically valid tool for interpreting the usefulness of tumor mutations as predictors of drug response.1
Molecular geneticist Debyani Chakravarty, PhD, co-led the development of OncoKB at the Henry and Marie-Josée Kravis Center for Molecular Oncology (CMO) at MSK with Nikolaus Schultz, PhD, CMO’s Head of Knowledge Systems; and David Solit, MD, CMO’s Director and the database’s lead scientist. Dr. Chakravarty is also an assistant member of the Molecular Diagnostics Service in the Department of Pathology and Laboratory Medicine at the institution.
Dr. Chakravarty recently spoke with the ILCN about the project.
ILCN: How did OncoKB come into being?
Dr. Chakravarty: OncoKB came into being with the recognition that in the past two decades, the number of molecular alterations in the cancer genome that could guide cancer-specific treatment strategies had accumulated into the hundreds. When we began developing OncoKB, there were literally hundreds of molecular markers specified in FDA drug labels or in clinical trial eligibility criteria and we knew that number was going to continue to grow. Previously, we were asking clinical oncologists to memorize the association of one molecular biomarker with a single targeted therapy in a single cancer indication. Now however, not only have the number of molecular alterations increased enormously, but the same molecular event could arise in multiple different cancers, and we know that each cancer has unique therapeutic implications. That’s why we created OncoKB, a clinical decision support system to help clinicians make genomically informed clinical decisions.
Q: Is OncoKB the only database of its kind?
A: No, there are several academic and commercial cancer mutation knowledge bases that emerged around the same time.
The first cancer mutation knowledge base created in 2014 and currently available via Vanderbilt University is MyCancerGenome. Then there is the publicly available CIViC offered through Washington University in St Louis. MD Anderson has a precision oncology decision support system and so on.
Q: What differentiates OncoKB from other genetic variant databases?
A: Well, the first and key differentiator of OncoKB is our content. OncoKB codifies the clinical expertise of MSK’s clinical oncologists and molecular pathologists with respect to tumor type specific cancer mutations. We have a clinical advisory committee—the Clinical Genomics Annotation Committee (CGAC)—comprised of the clinical leadership of MSK, disease-management chiefs, and physician scientists who are well-versed in both the clinical management and scientific underpinnings of the disease. Our team actively communicates with CGAC on an ongoing basis which provides oversight and content suggestions for OncoKB. A second differentiator is OncoKB’s nimble software infrastructure that allows its content to be seamlessly delivered to multiple outputs, such as medical sequencing reports, onto our publicly available website, or to other websites such as the cBioPortal. And lastly, OncoKB is the first somatic cancer precision oncology database to be recognized by the FDA2. This regulatory recognition adds a stamp of credibility to our database’s content and the processes we have in place regarding curation and database operation.
Q: What should other centers with databases know about the FDA’s recognition process?
A: The FDA announced a regulatory approach for the use of human genetic variant databases back in April 2018 to help ensure that the information that annotates clinical sequencing reports is “accurate, reliable, and clinically meaningful.” Specifically, FDA-recognized databases such as OncoKB are considered by the agency as containing valid scientific evidence that may be used to streamline the next generation sequencing (NGS)-based tumor profiling test development. Additionally, the FDA ensures that an FDA-recognized database is transparent about its processes of variant curation and interpretation and the evidence it cites to support the final variant classifications.
Any knowledge base may apply for recognition with the FDA and each database’s journey to FDA-recognition is unique. We began liaising with the FDA in August of 2018, and it was a 3-year process to receive recognition. Our application process was very open and collaborative with the agency, and it resulted in our comprehensively defining and documenting all our processes.
We applied through the Q-Submission Program, which is similar to the application process that a next-generation test developer makes for a companion diagnostic, however the content of our application is very different. We got a response with several recommendations, which we addressed.
Q: Please explain what you mean when you say that the FDA has given partial recognition to the database.
A: The FDA recognition of OncoKB includes clinically actionable variants that map to an FDA level of evidence, the processes of variant curation, and policies regarding database oversight, personnel training and transparency of data sources and operations. However, the FDA partial recognition of OncoKB does not pertain to the mapping of variants to specific targeted therapies and cannot currently be used for reimbursement purposes.
Q: How do you expect OncoKB to contribute to the therapeutic approval process?
A: OncoKB does not directly contribute to the approval of a therapy by the FDA. OncoKB monitors the emerging clinical data and keeps a close eye on those tumor biomarkers and associated targeted agents that have shown promising clinical data in the clinical trial space. In some cases, certain investigational targeted agents included in OncoKB and associated with a level of evidence offers a preview of the targeted drugs that may be promoted to standard of care (i.e. by their approval by the FDA).
Q: How do you envision the database’s audience?
A: When we started OncoKB, our intended audience was cancer researchers, clinical oncologists, and molecular pathologists. The FDA recognition, however, now includes a fourth audience group: next-generation test developers that often use knowledge bases as a reference when developing a tumor-profiling companion diagnostic to determine which genes and mutations to include in their tests.
Q: How should OncoKB be used?
A: OncoKB is a clinical-decision support system and a reference tool about the cancer type specific clinical implications associated with mutations found in cancer. OncoKB can be used in the academic space, for researchers and physician scientists exploring the different functions of cancer-associated genes and their mutations. OncoKB can also provide information for tumor NGS test sequencing reports, but this information should be interpreted by a molecular pathologist or clinical oncologist. Specifically, OncoKB can be used in the point-of-care setting to interpret the clinical implications of a patient’s sequencing results. It can also be used in the setting of a molecular tumor board where medical professionals from different disciplines consult about the molecular sequencing results of a series of patients. Lastly, NGS test developers can use OncoKB as a reference source of clinical validity when deciding which genes to include in their panels.
Q: Any final words about the impact of OncoKB?
A: At the end of the day, it’s all about the patients and how tools like OncoKB may make their journey with cancer easier. That is the intent with which OncoKB was initially developed. The mission of OncoKB is to equip clinical oncologists and molecular pathologists with the most accurate and up-to-date information they need to provide treatment options for their patients.
References:
- 1. MSKCC.org. A Milestone for Precision Oncology: FDA Gives Green Light to MSK’s Genetic Database. Published Nov. 24, 2021. Accessed Jan. 1, 2022.
- 2. FDA.gov. Updated Oct. 7, 2021. Accessed Jan. 1, 2022. FDA Recognition of Public Human Genetic Variant Databases.
