Gene |
Genetic Alterations |
Tumor Type |
Targeted Agent |
Receptor Tyrosine Kinase ALK |
Mutation , CNV |
Anaplastic Large Cell Lymphoma |
Crizotinib |
FGFR1 |
Translocation |
CML , Myelodysplastic Disorders |
Imatinib Methylase |
FGFR3 |
Translocation , Mutation |
Multiple Myeloma |
PKC412 , BIBF-1120 |
FLT3 |
CNV |
AML |
Lestaurtinib , XL999 |
PDGFRB |
Translocation , Mutation |
CML |
Sunitinib , Sorafenib ,
Imatinib , Nilotinib
|
Non-Receptor Tyrosine Kinase ABL |
Translocation ( BCR-ABL ) |
CML , AML |
Dasatinib , Nilotinib ,
Bosutinib
|
JAK |
Mutation ( V617F ) Translocation |
CML , Myeloproliferative Disorders |
Lestaurtinib , INCB018424 |
ERK1 / 2 |
Mutation |
Mantle Cell Lymphoma , CLL |
Ibrutinib |
Serine-Threonin Kinase Aurora A and B Kinase |
CNV |
Leukemia |
MK5108 |
BRAFV600E |
Mutation |
LCH , ECD , Hairy Cell Leukemia |
Vemurafenib ( PLX4032 ) |
Polio-Like Kinase |
Mutation |
Lymphoma |
B12356 |
Non-Kinase Targets PARP |
Mutation , CNV |
Advanced Hematologic Malignancies ,
CLL , Mantle Cell Lymphoma
|
BMN 673 |
Antibodies CD20 |
Hodgkin Lymphoma |
Rituximab |
|
CD52 |
B-Cell Chronic Lymphocytic Lymphoma |
Alemtuzumab |
|
CD20 |
Non-Hodgkin Lymphoma |
Ibritumomab Tiuxetan |
|
Apoptotic Agents Proton Pump Inhibitors |
Multiple Myeloma , Mantle Cell Lymphoma , Peripheral T-Cell Lymphoma |
Bortezomib , Pralatrexate |
|
some physiologic feature that indicates that someone should be treated or will benefit from treatment .”
Most companion diagnostics for guiding blood cancer treatment are categorized as class II or III in the FDA ’ s approval process , Dr . Cesano explained , based on the level of control necessary to assure the safety and effectiveness of the devices and the risk they pose to the patient and / or user . Class II devices are generally prognostic and are not related to a particular therapeutic drug or agent . “ The results tell you , in general , whether this patient ’ s disease is going to have a good outcome – is it an aggressive disease or a more indolent disease ? With a class II test , you have to provide analytic and clinical validation .”
Class III devices , on the other hand , are predictive tests that act as “ the gatekeeper for the use of a drug ,” she said . These tests require a Premarket Approval Application ( PMA ) to the FDA and must meet analytic and clinical validity standards and demonstrate clinical utility . “ If a class III assay is not analytically and clinically robust , there is a greater chance of false-positive or false-negative results , which can have serious consequences for the patient , either because they don ’ t receive the appropriate treatment or they undergo unnecessary treatment ,” Dr . Cesano explained .
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The Next Generation of Companion Diagnostics
Over time , the FDA has approved companion diagnostics under a “ one indication , one treatment ” paradigm , although , according to Dr . Mansfield , that happened more by default than design . “ The one test , one drug situation occurred because that is the way the products were brought to us ; it is not a requirement .”
But the advent of next-generation sequencing ( NGS ) in genomics is changing that approval pathway . NGS , also known as high-throughput sequencing , sequences millions of small fragments of DNA in parallel . Clinicians then use bioinformatics analyses to “ piece together ” the fragments by mapping the individual reads to the human reference genome . Each of the 3 billion bases in the human genome is sequenced multiple times , providing insight into unexpected DNA variations . NGS can be used to sequence entire genomes or targeted to specific areas of interest , including coding a whole exome ( 22,000 coding genes ) or a specific number of individual genes . 6
“ NGS will allow for multiple tests to be done on a single sample ,” Dr . Mansfield pointed out . “ We are looking at possible approval of an NGS test that can produce many different diagnostic claims . The complication with this is that more data will need to be generated to determine that the
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test works . It will take us more time to review , but we think that patients will benefit from having to only undergo one test , rather than multiple tests , to guide their treatment .”
Rather than a “ one test , one drug ” scenario , NGS will deliver biomarkers that may not yet have a companion diagnostic available . Once a drug comes along that uses that biomarker , the companion diagnostic can be developed based on NGS data , she explained .
NGS is also expected to strengthen the working relationship between diagnostics developers and therapeutics developers . “ The challenge is that you have to get a company to sign a collaborative agreement to invest in the companion diagnostic and the drug at the same time ,” Dr . Cesano said . “ Unfortunately , the pharmaceutical companies tend to approach the diagnostics companies toward the end of the process – at the end of the phase II stage for the drug – and say , ‘ We want to start phase III testing next month , so we ’ ll need a companion assay .’ That ’ s very late .”
Ideally , a companion diagnostic assay would be used during the phase II trial of the drug to determine clinical validity , and then in phase III to determine clinical utility , she added . “ However , that means that investigators need a fully validated assay available by phase III of a clinical trial – that takes time .”
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• PDGFRB FISH for Gleevec Eligibility in Myelodysplastic Syndrome / Myeloproliferative Disease ( MDS / MPD ) and imatinib : This in vitro diagnostic test detects PDGFRB gene rearrangement from fresh bone marrow samples of patients with MDS / MPD to select patients for whom imatinib treatment is being considered .
The FDA ’ s Center for Devices and Radiological Health has also approved a number of nucleic acid-based tests for hematologic indications , including :
• Acute myeloid leukemia : Vysis D7S486 / CEP 7 FISH Probe Kit and Vysis EGR 1 FISH Probe Kit
• B-cell chronic lymphocytic leukemia : Vysis CLL FISH Probe Kit and CEP 12 SpectrumOrange Direct Labeled Chromosome Enumeration DNA Probe
Source : U . S . Food and Drug Administration . “ List of Cleared or Approved Companion Diagnostic Devices ( In Vitro and Imaging Tools ).” Accessed June 27 , 2016 from http :// www . fda . gov / MedicalDevices / ProductsandMedicalProcedures / InVitroDiagnostics / ucm301431 . htm .
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