Abstract
BackgroundRegulatory approval of next generation sequencing (NGS) by the FDA is advancing the use of genomic-based precision medicine for the therapeutic management of cancer as standard care. Recent FDA guidance for the classification of genomic variants based on clinical evidence to aid clinicians in understanding the actionability of identified variants provided by comprehensive NGS panels has also been set forth. In this retrospective analysis, we interpreted and applied the FDA variant classification guidance to comprehensive NGS testing performed for advanced cancer patients and assessed oncologist agreement with NGS test treatment recommendations.MethodsNGS comprehensive genomic profiling was performed in a CLIA certified lab (657 completed tests for 646 patients treated at Roswell Park Comprehensive Cancer Center) between June 2016 and June 2017. Physician treatment recommendations made within 120 days post-test were gathered from tested patients’ medical records and classified as targeted therapy, precision medicine clinical trial, immunotherapy, hormonal therapy, chemotherapy/radiation, surgery, transplant, or non-therapeutic (hospice, surveillance, or palliative care). Agreement between NGS test report targeted therapy recommendations based on the FDA variant classification and physician targeted therapy treatment recommendations were evaluated.ResultsExcluding variants contraindicating targeted therapy (i.e., KRAS or NRAS mutations), at least one variant with FDA level 1 companion diagnostic supporting evidence as the most actionable was identified in 14% of tests, with physicians most frequently recommending targeted therapy (48%) for patients with these results. This stands in contrast to physicians recommending targeted therapy based on test results with FDA level 2 (practice guideline) or FDA level 3 (clinical trial or off label) evidence as the most actionable result (11 and 4%, respectively).ConclusionsWe found an appropriate “dose-response” relationship between the strength of clinical evidence supporting biomarker-directed targeted therapy based on application of FDA guidance for NGS test variant classification, and subsequent treatment recommendations made by treating physicians. In view of recent changes at FDA, it is paramount to define regulatory grounds and medical policy coverage for NGS testing based on this guidance.
Highlights
Regulatory approval of generation sequencing (NGS) by the Food and Drug Administration (FDA) is advancing the use of genomicbased precision medicine for the therapeutic management of cancer as standard care
The Food and Drug Administration (FDA) has announced new mechanisms for regulatory approval of generation sequencing (NGS) [1]. This includes a new pathway for approval of next generation sequencing (NGS) tests for tumor profiling using the New York State Department of Health (NYSDOH) as a FDA third-party reviewer of in vitro diagnostics [2]
Repeat testing was mostly restricted to lung cancer patients with resistance to prior targeted therapies
Summary
Regulatory approval of generation sequencing (NGS) by the FDA is advancing the use of genomicbased precision medicine for the therapeutic management of cancer as standard care. Recent FDA guidance for the classification of genomic variants based on clinical evidence to aid clinicians in understanding the actionability of identified variants provided by comprehensive NGS panels has been set forth. In seeking FDA approval, NGS tests may include level 1 evidence claims for a specific drug based on support for the analytical validity of the test for each specific biomarker and a clinical study that establishes either the link between the result of that test and patient outcomes or the clinical concordance to a previously approved companion diagnostic. Level 3 variants are defined by FDA as informational or used to direct patients toward clinical trials Such claims are supported by analytical validation, principally through a representative approach when appropriate, and clinical or mechanistic rationale for inclusion in the panel, including peer-reviewed publications or in vitro preclinical models. While many groups have implemented other classification approaches for disease-biomarker-drug evidence associations, the FDA’s approach uniquely focuses on NGS and explicitly requires the analytical validity of the gene-variants tested
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