Opinion
VIEWPOINT
Gideon M. Blumenthal, MD Center for Drug Evaluation and Research, US Food and Drug Administration, Silver Spring, Maryland. Elizabeth Mansfield, PhD Center for Devices and Radiologic Health, US Food and Drug Administration, Silver Spring, Maryland. Richard Pazdur, MD Center for Drug Evaluation and Research, US Food and Drug Administration, Silver Spring, Maryland.
Corresponding Author: Gideon M. Blumenthal, MD, Center for Drug Evaluation and Research, US Food and Drug Administration, 10903 New Hampshire Ave, Silver Spring, MD 20903 (gideon [email protected] .gov). jamaoncology.com
Next-Generation Sequencing in Oncology in the Era of Precision Medicine Through the rapid acceleration of our understanding of the underlying genetic and molecular underpinnings of malignancy, in the past 5 years there has been an explosion in the development and approval of highly effective targeted therapies and immunotherapies in oncology, several with contemporaneous approvals of companion diagnostics. In 2014, of the 41 new molecular entities approved by the US Food and Drug Administration (FDA) Center for Drug Evaluation and Research, 9 were for oncologic indications, and 5 of these were designated as breakthrough therapies.1 In addition, there are now 22 in vitro diagnostics approved by the FDA Center for Diagnostic and Radiologic Health as companion diagnostics for various targeted therapies in oncology.2
The Promise of Next-Generation Sequencing As the field of oncology drug development continues to evolve, regulatory pathways to develop novel and innovative anticancer drugs and diagnostics must adapt. The FDA is applying novel regulatory approaches in adoption of next-generation sequencing (NGS) as a companion diagnostic test, as well as for other purposes, for oncology drug development and clinical practice. Nextgeneration sequencing is a technology of highthroughput, massively parallel DNA sequencing where thousands of variants (somatic or germline) from hundreds of genes can be identified in a single test. With this technology, the conventional paradigm of a single drug being developed with a single companion diagnostic test measuring variants in a single gene will soon evolve to one of multiple drugs being developed and used in the clinic using a single NGS test as the companion diagnostic. This NGS multiplex paradigm has many advantages over the current single-drug, single–genetic test model. For patients and physicians, a comprehensive tumor genetic profile will address issues of tissue scarcity in metastatic specimens, reduce morbidity from repeat biopsy, and eventually could lower cost (both from fewer procedures and fewer independent tests sent out by the pathologist). For patients with advanced non–smallcell lung cancer (NSCLC) of adenocarcinoma histology, the current standard of care is to test for sensitizing EGFR mutations and ALK rearrangements to guide treatment decisions with targeted kinase inhibitors (eg, erlotinib, afatinib, and gefitinib for EGFR mutations, crizotinib for ALK rearrangements).3 In the foreseeable future, advanced NSCLC tumor specimens will likely be tested not only for EGFR mutations and ALK rearrangements but also for actionable mutations in other oncogenic drivers to help guide treatment decisions, and comprehensive NGS panel testing may become a standard practice.
For researchers and drug and diagnostic developers, interrogating hundreds of genes and thousands of tumor variants simultaneously with one test could improve our understanding of the complex interactions between overlapping genomic aberrations in a tumor. This enhanced understanding of tumor biology and therapeutic resistance could eventually lead to the development of more effective combinatorial approaches, which will likely be necessary to optimize efficacy in many advanced cancers. In addition, multiplexed screening tests could enhance detection of rare variants to guide patients toward master protocols, such as the National Cancer Institute–Molecular Analysis for Therapy Choice (NCI-MATCH), the Lung-MAP, and other trials designed to enhance the efficiency of drug development, lower drug development costs, and accelerate development timelines. Finding patients whose tumors harbor lowfrequency variants (eg,
VIEWPOINT
Gideon M. Blumenthal, MD Center for Drug Evaluation and Research, US Food and Drug Administration, Silver Spring, Maryland. Elizabeth Mansfield, PhD Center for Devices and Radiologic Health, US Food and Drug Administration, Silver Spring, Maryland. Richard Pazdur, MD Center for Drug Evaluation and Research, US Food and Drug Administration, Silver Spring, Maryland.
Corresponding Author: Gideon M. Blumenthal, MD, Center for Drug Evaluation and Research, US Food and Drug Administration, 10903 New Hampshire Ave, Silver Spring, MD 20903 (gideon [email protected] .gov). jamaoncology.com
Next-Generation Sequencing in Oncology in the Era of Precision Medicine Through the rapid acceleration of our understanding of the underlying genetic and molecular underpinnings of malignancy, in the past 5 years there has been an explosion in the development and approval of highly effective targeted therapies and immunotherapies in oncology, several with contemporaneous approvals of companion diagnostics. In 2014, of the 41 new molecular entities approved by the US Food and Drug Administration (FDA) Center for Drug Evaluation and Research, 9 were for oncologic indications, and 5 of these were designated as breakthrough therapies.1 In addition, there are now 22 in vitro diagnostics approved by the FDA Center for Diagnostic and Radiologic Health as companion diagnostics for various targeted therapies in oncology.2
The Promise of Next-Generation Sequencing As the field of oncology drug development continues to evolve, regulatory pathways to develop novel and innovative anticancer drugs and diagnostics must adapt. The FDA is applying novel regulatory approaches in adoption of next-generation sequencing (NGS) as a companion diagnostic test, as well as for other purposes, for oncology drug development and clinical practice. Nextgeneration sequencing is a technology of highthroughput, massively parallel DNA sequencing where thousands of variants (somatic or germline) from hundreds of genes can be identified in a single test. With this technology, the conventional paradigm of a single drug being developed with a single companion diagnostic test measuring variants in a single gene will soon evolve to one of multiple drugs being developed and used in the clinic using a single NGS test as the companion diagnostic. This NGS multiplex paradigm has many advantages over the current single-drug, single–genetic test model. For patients and physicians, a comprehensive tumor genetic profile will address issues of tissue scarcity in metastatic specimens, reduce morbidity from repeat biopsy, and eventually could lower cost (both from fewer procedures and fewer independent tests sent out by the pathologist). For patients with advanced non–smallcell lung cancer (NSCLC) of adenocarcinoma histology, the current standard of care is to test for sensitizing EGFR mutations and ALK rearrangements to guide treatment decisions with targeted kinase inhibitors (eg, erlotinib, afatinib, and gefitinib for EGFR mutations, crizotinib for ALK rearrangements).3 In the foreseeable future, advanced NSCLC tumor specimens will likely be tested not only for EGFR mutations and ALK rearrangements but also for actionable mutations in other oncogenic drivers to help guide treatment decisions, and comprehensive NGS panel testing may become a standard practice.
For researchers and drug and diagnostic developers, interrogating hundreds of genes and thousands of tumor variants simultaneously with one test could improve our understanding of the complex interactions between overlapping genomic aberrations in a tumor. This enhanced understanding of tumor biology and therapeutic resistance could eventually lead to the development of more effective combinatorial approaches, which will likely be necessary to optimize efficacy in many advanced cancers. In addition, multiplexed screening tests could enhance detection of rare variants to guide patients toward master protocols, such as the National Cancer Institute–Molecular Analysis for Therapy Choice (NCI-MATCH), the Lung-MAP, and other trials designed to enhance the efficiency of drug development, lower drug development costs, and accelerate development timelines. Finding patients whose tumors harbor lowfrequency variants (eg,
