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Predicting treatment response in leiomyosarcoma, liposarcoma
Aberrations in oncogenic pathways and immune modulation influence treatment response in patients with metastatic leiomyosarcoma or liposarcoma, based on an analysis of whole-exome sequencing of tumor samples from patients in a completed phase 3 randomized trial comparing trabectedin and dacarbazine.
In that trial, trabectedin benefit was mostly seen in patients with leiomyosarcoma, as well as in patients with myxoid/round cell sarcomas, and less so in those with dedifferentiated and pleomorphic liposarcomas.
Gurpreet Kapoor, PhD, of LabConnect, Seattle, and colleagues examined aberrations in oncogenic pathways (DNA damage response, PI3K, MDM2-p53) and in immune modulation and then correlated the genomic aberrations with prospective data on clinical outcomes in the trial.
For the study, presented at the annual meeting of the American Society of Clinical Oncology in Chicago, archival tumor samples were collected from 456 of the 518 patients; 180 had uterine leiomyosarcomas, 149 had nonuterine leiomyosarcomas, 66 had dedifferentiated liposarcomas, 46 had myxoid liposarcomas, and 15 had pleomorphic liposarcomas.
Peripheral blood samples from a subset of 346 patients were also analyzed as matched normal to filter noise from nonpathogenic variants in the whole-exome sequencing.
Consistent with sarcoma data from The Cancer Genome Atlas, frequent homozygous gene deletions with relatively low mutational load were noted in these leiomyosarcoma and liposarcoma samples. TP53 and RB1 alterations were more frequent in leiomyosarcomas than in liposarcomas and were not associated with clinical outcomes. Analyses of 103 DNA damage-response genes found somatic alterations exceeded 20% across subtypes and correlated with improved progression-free survival in only uterine leiomyosarcomas (hazard ratio, 0.63; P = .03).
Genomic alterations in PI3K pathway genes were noted in 30% of myxoid liposarcomas and were associated with a worse rate of progression-free survival (HR, 3.0; P = .045).
A trend towards better overall survival was noted in dedifferentiated liposarcoma patients with MDM2 amplification as compared with normal MDM2 copy number.
Certain subtype-specific genomic aberrations in immune modulation pathways were associated with worse clinical outcomes in patients with uterine leiomyosarcoma or dedifferentiated liposarcoma. Alterations in immune suppressors were associated with improved clinical outcomes in nonuterine leiomyosarcomas and alterations in lipid metabolism were associated with improved clinical outcomes in dedifferentiated liposarcomas.
The invited discussant for the study, Mark Andrew Dickson, MD, of Memorial Sloan Kettering Cancer Center, New York, noted that “the real take-home here is that the TMBs (tumor mutation burdens) are relatively low across all of the L-type sarcomas.
“The pattern and prevalence of genomic aberrations that we’re seeing in this cohort of patients prospectively analyzed on a clinical trial are consistent with prior reports. ... including CDK4 and MDM2 in dedifferentiated liposarcoma, PI3-kinase in some myxoid/round cells, p53 in leiomyosarcoma and liposarcoma, and so on.”
Generally, tumor mutation burden is low in L-type sarcomas, and there are some intriguing associations with benefit to therapies, such as PI3-kinase pathway and potential resistance to trabectedin and high tumor mutation burden and potential sensitivity to trabectedin, that need to be explored and validated in another larger cohort, he said.
“I also am increasingly coming to terms with the fact that the tumors like leiomyosarcoma, which have low tumor mutation burden, and which so far have proven fairly immune to immunotherapy, based on all of the negative PD-1 data that we’ve seen, and that also have recurrent, relatively unactionable mutations, like p53 and Rb, remain very difficult to treat,” Dr. Dickson concluded.
SOURCE: Kapoor G et al. ASCO 2018, Abstract 11513.
Aberrations in oncogenic pathways and immune modulation influence treatment response in patients with metastatic leiomyosarcoma or liposarcoma, based on an analysis of whole-exome sequencing of tumor samples from patients in a completed phase 3 randomized trial comparing trabectedin and dacarbazine.
In that trial, trabectedin benefit was mostly seen in patients with leiomyosarcoma, as well as in patients with myxoid/round cell sarcomas, and less so in those with dedifferentiated and pleomorphic liposarcomas.
Gurpreet Kapoor, PhD, of LabConnect, Seattle, and colleagues examined aberrations in oncogenic pathways (DNA damage response, PI3K, MDM2-p53) and in immune modulation and then correlated the genomic aberrations with prospective data on clinical outcomes in the trial.
For the study, presented at the annual meeting of the American Society of Clinical Oncology in Chicago, archival tumor samples were collected from 456 of the 518 patients; 180 had uterine leiomyosarcomas, 149 had nonuterine leiomyosarcomas, 66 had dedifferentiated liposarcomas, 46 had myxoid liposarcomas, and 15 had pleomorphic liposarcomas.
Peripheral blood samples from a subset of 346 patients were also analyzed as matched normal to filter noise from nonpathogenic variants in the whole-exome sequencing.
Consistent with sarcoma data from The Cancer Genome Atlas, frequent homozygous gene deletions with relatively low mutational load were noted in these leiomyosarcoma and liposarcoma samples. TP53 and RB1 alterations were more frequent in leiomyosarcomas than in liposarcomas and were not associated with clinical outcomes. Analyses of 103 DNA damage-response genes found somatic alterations exceeded 20% across subtypes and correlated with improved progression-free survival in only uterine leiomyosarcomas (hazard ratio, 0.63; P = .03).
Genomic alterations in PI3K pathway genes were noted in 30% of myxoid liposarcomas and were associated with a worse rate of progression-free survival (HR, 3.0; P = .045).
A trend towards better overall survival was noted in dedifferentiated liposarcoma patients with MDM2 amplification as compared with normal MDM2 copy number.
Certain subtype-specific genomic aberrations in immune modulation pathways were associated with worse clinical outcomes in patients with uterine leiomyosarcoma or dedifferentiated liposarcoma. Alterations in immune suppressors were associated with improved clinical outcomes in nonuterine leiomyosarcomas and alterations in lipid metabolism were associated with improved clinical outcomes in dedifferentiated liposarcomas.
The invited discussant for the study, Mark Andrew Dickson, MD, of Memorial Sloan Kettering Cancer Center, New York, noted that “the real take-home here is that the TMBs (tumor mutation burdens) are relatively low across all of the L-type sarcomas.
“The pattern and prevalence of genomic aberrations that we’re seeing in this cohort of patients prospectively analyzed on a clinical trial are consistent with prior reports. ... including CDK4 and MDM2 in dedifferentiated liposarcoma, PI3-kinase in some myxoid/round cells, p53 in leiomyosarcoma and liposarcoma, and so on.”
Generally, tumor mutation burden is low in L-type sarcomas, and there are some intriguing associations with benefit to therapies, such as PI3-kinase pathway and potential resistance to trabectedin and high tumor mutation burden and potential sensitivity to trabectedin, that need to be explored and validated in another larger cohort, he said.
“I also am increasingly coming to terms with the fact that the tumors like leiomyosarcoma, which have low tumor mutation burden, and which so far have proven fairly immune to immunotherapy, based on all of the negative PD-1 data that we’ve seen, and that also have recurrent, relatively unactionable mutations, like p53 and Rb, remain very difficult to treat,” Dr. Dickson concluded.
SOURCE: Kapoor G et al. ASCO 2018, Abstract 11513.
Aberrations in oncogenic pathways and immune modulation influence treatment response in patients with metastatic leiomyosarcoma or liposarcoma, based on an analysis of whole-exome sequencing of tumor samples from patients in a completed phase 3 randomized trial comparing trabectedin and dacarbazine.
In that trial, trabectedin benefit was mostly seen in patients with leiomyosarcoma, as well as in patients with myxoid/round cell sarcomas, and less so in those with dedifferentiated and pleomorphic liposarcomas.
Gurpreet Kapoor, PhD, of LabConnect, Seattle, and colleagues examined aberrations in oncogenic pathways (DNA damage response, PI3K, MDM2-p53) and in immune modulation and then correlated the genomic aberrations with prospective data on clinical outcomes in the trial.
For the study, presented at the annual meeting of the American Society of Clinical Oncology in Chicago, archival tumor samples were collected from 456 of the 518 patients; 180 had uterine leiomyosarcomas, 149 had nonuterine leiomyosarcomas, 66 had dedifferentiated liposarcomas, 46 had myxoid liposarcomas, and 15 had pleomorphic liposarcomas.
Peripheral blood samples from a subset of 346 patients were also analyzed as matched normal to filter noise from nonpathogenic variants in the whole-exome sequencing.
Consistent with sarcoma data from The Cancer Genome Atlas, frequent homozygous gene deletions with relatively low mutational load were noted in these leiomyosarcoma and liposarcoma samples. TP53 and RB1 alterations were more frequent in leiomyosarcomas than in liposarcomas and were not associated with clinical outcomes. Analyses of 103 DNA damage-response genes found somatic alterations exceeded 20% across subtypes and correlated with improved progression-free survival in only uterine leiomyosarcomas (hazard ratio, 0.63; P = .03).
Genomic alterations in PI3K pathway genes were noted in 30% of myxoid liposarcomas and were associated with a worse rate of progression-free survival (HR, 3.0; P = .045).
A trend towards better overall survival was noted in dedifferentiated liposarcoma patients with MDM2 amplification as compared with normal MDM2 copy number.
Certain subtype-specific genomic aberrations in immune modulation pathways were associated with worse clinical outcomes in patients with uterine leiomyosarcoma or dedifferentiated liposarcoma. Alterations in immune suppressors were associated with improved clinical outcomes in nonuterine leiomyosarcomas and alterations in lipid metabolism were associated with improved clinical outcomes in dedifferentiated liposarcomas.
The invited discussant for the study, Mark Andrew Dickson, MD, of Memorial Sloan Kettering Cancer Center, New York, noted that “the real take-home here is that the TMBs (tumor mutation burdens) are relatively low across all of the L-type sarcomas.
“The pattern and prevalence of genomic aberrations that we’re seeing in this cohort of patients prospectively analyzed on a clinical trial are consistent with prior reports. ... including CDK4 and MDM2 in dedifferentiated liposarcoma, PI3-kinase in some myxoid/round cells, p53 in leiomyosarcoma and liposarcoma, and so on.”
Generally, tumor mutation burden is low in L-type sarcomas, and there are some intriguing associations with benefit to therapies, such as PI3-kinase pathway and potential resistance to trabectedin and high tumor mutation burden and potential sensitivity to trabectedin, that need to be explored and validated in another larger cohort, he said.
“I also am increasingly coming to terms with the fact that the tumors like leiomyosarcoma, which have low tumor mutation burden, and which so far have proven fairly immune to immunotherapy, based on all of the negative PD-1 data that we’ve seen, and that also have recurrent, relatively unactionable mutations, like p53 and Rb, remain very difficult to treat,” Dr. Dickson concluded.
SOURCE: Kapoor G et al. ASCO 2018, Abstract 11513.
REPORTING FROM ASCO 2018
Key clinical point: Aberrations in oncogenic pathways and immune modulation influence treatment response in patients with metastatic leiomyosarcoma or liposarcoma.
Major finding: Genomic alterations in PI3K pathway genes were noted in 30% of myxoid liposarcomas and were associated with a worse rate of progression-free survival (HR, 3.0; P = .045).
Study details: Archival tumor samples were collected from 456 of the 518 patients; 180 had uterine leiomyosarcomas, 149 had nonuterine leiomyosarcomas, 66 had dedifferentiated liposarcomas, 46 had myxoid liposarcomas, and 15 had pleomorphic liposarcomas in the completed phase 3 randomized trial comparing trabectedin and dacarbazine.
Disclosures: Dr. Kapoor is employed by LabConnect, Seattle. Research funding was supplied by Janssen Research & Development.
Source: Kapoor G et al. ASCO 2018, Abstract 11513.
FDA authorizes ClonoSEQ to detect MRD in ALL, myeloma
, the U.S. Food and Drug Administration announced. Marketing authorization of the ClonoSEQ assay was granted to Adaptive Biotechnologies.
The ClonoSEQ assay is an in vitro diagnostic test that uses multiplex polymerase chain reaction and next-generation sequencing to identify and quantify certain gene sequences in DNA extracted from the bone marrow from patients with ALL or multiple myeloma. This is a single-site assay collected by the patient’s provider and sent to Adaptive Biotechnologies for evaluation.
The ClonoSEQ assay is capable of detecting minimal residual disease at levels below 1 in 1 million cells. Currently, providers test for MRD using flow cytometry assays or polymerase chain reaction–based assays. Those methods are usually capable of measuring MRD down to 1 in 10,000 or 1 in 100,000 cells.
“Determining whether a patient has residual cancer cells remaining after treatment provides information on how well a patient has responded to therapy and how long remission may last. Having a highly sensitive test available to measure minimal residual disease in ALL or multiple myeloma patients can help providers manage their patients’ care,” FDA Commissioner Scott Gottlieb, MD, said in a press release.
Along with this authorization, the FDA is establishing criteria, called special controls, which clarify the agency’s expectations in assuring the accuracy, reliability, and effectiveness of tests intended to be used as an aid to measure MRD to assess the change in burden of disease during and after treatment. These special controls, when met along with general controls, provide a reasonable assurance of safety and effectiveness for these tests, the agency said in the release. This action also creates a new regulatory classification, which means that subsequent devices of the same type with the same intended use may go through the FDA’s 510(k) process, whereby devices can obtain marketing authorization by demonstrating substantial equivalence to a previously approved device.
“The FDA is applying novel regulatory approaches to make sure that these rapidly evolving [next-generation sequencing] tests are accurate and reliable. At the same time, we’re seeing more and more laboratory-developed tests seek marketing authorization from the FDA,” he said, adding that the agency has put forward a plan to modernize the regulatory framework for all in vitro clinical tests.
The FDA evaluated data to demonstrate clinical validity from a retrospective analysis of samples obtained from three previously conducted clinical studies including 273 patients with ALL, an ongoing study of 323 patients with multiple myeloma, and a study of 706 patients with multiple myeloma, according to the FDA release.
For patients with ALL, the ClonoSEQ assay was used to assess MRD at various disease burden thresholds to show that the MRD level correlated with event-free survival – the length of time, after treatment, that the patient remains free of certain complications or events. Patients whose ClonoSEQ assay result was MRD negative had longer event-free survival, while patients with higher MRD assay results had lower event-free survival. Similar patterns of results were seen for progression-free and disease-free survival in patients with multiple myeloma.
, the U.S. Food and Drug Administration announced. Marketing authorization of the ClonoSEQ assay was granted to Adaptive Biotechnologies.
The ClonoSEQ assay is an in vitro diagnostic test that uses multiplex polymerase chain reaction and next-generation sequencing to identify and quantify certain gene sequences in DNA extracted from the bone marrow from patients with ALL or multiple myeloma. This is a single-site assay collected by the patient’s provider and sent to Adaptive Biotechnologies for evaluation.
The ClonoSEQ assay is capable of detecting minimal residual disease at levels below 1 in 1 million cells. Currently, providers test for MRD using flow cytometry assays or polymerase chain reaction–based assays. Those methods are usually capable of measuring MRD down to 1 in 10,000 or 1 in 100,000 cells.
“Determining whether a patient has residual cancer cells remaining after treatment provides information on how well a patient has responded to therapy and how long remission may last. Having a highly sensitive test available to measure minimal residual disease in ALL or multiple myeloma patients can help providers manage their patients’ care,” FDA Commissioner Scott Gottlieb, MD, said in a press release.
Along with this authorization, the FDA is establishing criteria, called special controls, which clarify the agency’s expectations in assuring the accuracy, reliability, and effectiveness of tests intended to be used as an aid to measure MRD to assess the change in burden of disease during and after treatment. These special controls, when met along with general controls, provide a reasonable assurance of safety and effectiveness for these tests, the agency said in the release. This action also creates a new regulatory classification, which means that subsequent devices of the same type with the same intended use may go through the FDA’s 510(k) process, whereby devices can obtain marketing authorization by demonstrating substantial equivalence to a previously approved device.
“The FDA is applying novel regulatory approaches to make sure that these rapidly evolving [next-generation sequencing] tests are accurate and reliable. At the same time, we’re seeing more and more laboratory-developed tests seek marketing authorization from the FDA,” he said, adding that the agency has put forward a plan to modernize the regulatory framework for all in vitro clinical tests.
The FDA evaluated data to demonstrate clinical validity from a retrospective analysis of samples obtained from three previously conducted clinical studies including 273 patients with ALL, an ongoing study of 323 patients with multiple myeloma, and a study of 706 patients with multiple myeloma, according to the FDA release.
For patients with ALL, the ClonoSEQ assay was used to assess MRD at various disease burden thresholds to show that the MRD level correlated with event-free survival – the length of time, after treatment, that the patient remains free of certain complications or events. Patients whose ClonoSEQ assay result was MRD negative had longer event-free survival, while patients with higher MRD assay results had lower event-free survival. Similar patterns of results were seen for progression-free and disease-free survival in patients with multiple myeloma.
, the U.S. Food and Drug Administration announced. Marketing authorization of the ClonoSEQ assay was granted to Adaptive Biotechnologies.
The ClonoSEQ assay is an in vitro diagnostic test that uses multiplex polymerase chain reaction and next-generation sequencing to identify and quantify certain gene sequences in DNA extracted from the bone marrow from patients with ALL or multiple myeloma. This is a single-site assay collected by the patient’s provider and sent to Adaptive Biotechnologies for evaluation.
The ClonoSEQ assay is capable of detecting minimal residual disease at levels below 1 in 1 million cells. Currently, providers test for MRD using flow cytometry assays or polymerase chain reaction–based assays. Those methods are usually capable of measuring MRD down to 1 in 10,000 or 1 in 100,000 cells.
“Determining whether a patient has residual cancer cells remaining after treatment provides information on how well a patient has responded to therapy and how long remission may last. Having a highly sensitive test available to measure minimal residual disease in ALL or multiple myeloma patients can help providers manage their patients’ care,” FDA Commissioner Scott Gottlieb, MD, said in a press release.
Along with this authorization, the FDA is establishing criteria, called special controls, which clarify the agency’s expectations in assuring the accuracy, reliability, and effectiveness of tests intended to be used as an aid to measure MRD to assess the change in burden of disease during and after treatment. These special controls, when met along with general controls, provide a reasonable assurance of safety and effectiveness for these tests, the agency said in the release. This action also creates a new regulatory classification, which means that subsequent devices of the same type with the same intended use may go through the FDA’s 510(k) process, whereby devices can obtain marketing authorization by demonstrating substantial equivalence to a previously approved device.
“The FDA is applying novel regulatory approaches to make sure that these rapidly evolving [next-generation sequencing] tests are accurate and reliable. At the same time, we’re seeing more and more laboratory-developed tests seek marketing authorization from the FDA,” he said, adding that the agency has put forward a plan to modernize the regulatory framework for all in vitro clinical tests.
The FDA evaluated data to demonstrate clinical validity from a retrospective analysis of samples obtained from three previously conducted clinical studies including 273 patients with ALL, an ongoing study of 323 patients with multiple myeloma, and a study of 706 patients with multiple myeloma, according to the FDA release.
For patients with ALL, the ClonoSEQ assay was used to assess MRD at various disease burden thresholds to show that the MRD level correlated with event-free survival – the length of time, after treatment, that the patient remains free of certain complications or events. Patients whose ClonoSEQ assay result was MRD negative had longer event-free survival, while patients with higher MRD assay results had lower event-free survival. Similar patterns of results were seen for progression-free and disease-free survival in patients with multiple myeloma.
Fish oil phoenix
A 4 g/day dose of the triglyceride-reducing drug Vascepa (Amarin), compared to placebo, was associated with a 25% lower risk of a heart attack, a stroke, an intervention for arterial thrombosis, or chest pain requiring a hospitalization in a study of 8,179 people who had high triglycerides and previous cardiovascular disorders or diabetes and another risk factor for heart disease.
In the ASCEND study, presented at the annual congress of the European Society of Cardiology, 1 g/day of omega-3 fatty acids showed no net cardiovascular benefits in people with diabetes and no known cardiovascular disease.
The results of the Amarin study, announced in a press release, are slated for presentation at the American Heart Association scientific sessions in November.
A 4 g/day dose of the triglyceride-reducing drug Vascepa (Amarin), compared to placebo, was associated with a 25% lower risk of a heart attack, a stroke, an intervention for arterial thrombosis, or chest pain requiring a hospitalization in a study of 8,179 people who had high triglycerides and previous cardiovascular disorders or diabetes and another risk factor for heart disease.
In the ASCEND study, presented at the annual congress of the European Society of Cardiology, 1 g/day of omega-3 fatty acids showed no net cardiovascular benefits in people with diabetes and no known cardiovascular disease.
The results of the Amarin study, announced in a press release, are slated for presentation at the American Heart Association scientific sessions in November.
A 4 g/day dose of the triglyceride-reducing drug Vascepa (Amarin), compared to placebo, was associated with a 25% lower risk of a heart attack, a stroke, an intervention for arterial thrombosis, or chest pain requiring a hospitalization in a study of 8,179 people who had high triglycerides and previous cardiovascular disorders or diabetes and another risk factor for heart disease.
In the ASCEND study, presented at the annual congress of the European Society of Cardiology, 1 g/day of omega-3 fatty acids showed no net cardiovascular benefits in people with diabetes and no known cardiovascular disease.
The results of the Amarin study, announced in a press release, are slated for presentation at the American Heart Association scientific sessions in November.
FDA approves Cassipa for opioid dependence
Cassipa sublingual film, made by Teva Pharmaceuticals, is a 16 mg/4 mg dosage of buprenorphine and naloxone for the maintenance treatment of opioid dependence. Buprenorphine and naloxone sublingual film also is approved in both brand name and generic versions and in various strengths, the FDA said in a press release.
Cassipa should be used as part of a complete treatment plan that includes counseling and psychosocial support and should be used only after patient induction and stabilization up to a dose of 16 mg of buprenorphine using another marketed product. These products may only be prescribed by Drug Addiction Treatment Act (DATA)–certified prescribers.
“There’s an urgent need to ensure access to, and wider use and understanding of, medication-assisted treatment for opioid use disorder ... the FDA recently described a streamlined approach to drug development for certain medication-assisted treatments that are based on buprenorphine. This streamlined approach can reduce drug development costs, so products may be offered at a lower price to patients and we can broaden access to treatment,” FDA Commissioner Scott Gottlieb, MD, said in the statement.
He added that “individuals who successfully transition onto medication-assisted treatment are not swapping one addiction for another. Opioid replacement therapy can be an important part of effective treatment. Opioid use disorder should be viewed similarly to any other chronic condition that is treated with medication.”
Medication-assisted treatment (MAT) is a comprehensive approach that combines FDA-approved medications (currently methadone, buprenorphine, or naltrexone) with counseling and other behavioral therapies to treat patients with opioid use disorder. Regular adherence to MAT with buprenorphine reduces opioid withdrawal symptoms and the desire to use opioids. According to the Substance Abuse and Mental Health Services Administration, patients receiving MAT for treatment of their opioid use disorder cut their risk of death from all causes in half.
Improving access to prevention, treatment, and recovery services, including the full range of MAT, is part of the Department of Health and Human Services’ Five-Point Strategy to Combat the Opioid Crisis. Last month, the FDA issued draft guidance outlining new ways for drug developers to consider measuring and demonstrating the effectiveness and benefits of new or existing MAT products, building on another draft guidance issued in April outlining the agency’s current thinking about drug development and trial design issues relevant to the study of depot buprenorphine products (i.e., modified-release products for injection or implantation). In June, the agency also approved the first generic versions of Suboxone (buprenorphine and naloxone) sublingual film in multiple strengths, the statement said.
Cassipa was approved through the abbreviated 505(b)(2) approval pathway and its application relied, in part, on the FDA’s finding of safety and effectiveness for Suboxone sublingual film to support approval. The applicant demonstrated that reliance on the FDA’s finding of safety and effectiveness for Suboxone was scientifically justified and provided Cassipa-specific pharmacokinetic data to establish the drug’s safety and efficacy for its approved uses, according to the FDA.
Adverse events commonly observed with the buprenorphine and naloxone sublingual film are oral hypoesthesia, glossodynia, oral mucosal erythema, headache, nausea, vomiting, hyperhidrosis, constipation, signs and symptoms of withdrawal, insomnia, pain, and peripheral edema.
Cassipa sublingual film, made by Teva Pharmaceuticals, is a 16 mg/4 mg dosage of buprenorphine and naloxone for the maintenance treatment of opioid dependence. Buprenorphine and naloxone sublingual film also is approved in both brand name and generic versions and in various strengths, the FDA said in a press release.
Cassipa should be used as part of a complete treatment plan that includes counseling and psychosocial support and should be used only after patient induction and stabilization up to a dose of 16 mg of buprenorphine using another marketed product. These products may only be prescribed by Drug Addiction Treatment Act (DATA)–certified prescribers.
“There’s an urgent need to ensure access to, and wider use and understanding of, medication-assisted treatment for opioid use disorder ... the FDA recently described a streamlined approach to drug development for certain medication-assisted treatments that are based on buprenorphine. This streamlined approach can reduce drug development costs, so products may be offered at a lower price to patients and we can broaden access to treatment,” FDA Commissioner Scott Gottlieb, MD, said in the statement.
He added that “individuals who successfully transition onto medication-assisted treatment are not swapping one addiction for another. Opioid replacement therapy can be an important part of effective treatment. Opioid use disorder should be viewed similarly to any other chronic condition that is treated with medication.”
Medication-assisted treatment (MAT) is a comprehensive approach that combines FDA-approved medications (currently methadone, buprenorphine, or naltrexone) with counseling and other behavioral therapies to treat patients with opioid use disorder. Regular adherence to MAT with buprenorphine reduces opioid withdrawal symptoms and the desire to use opioids. According to the Substance Abuse and Mental Health Services Administration, patients receiving MAT for treatment of their opioid use disorder cut their risk of death from all causes in half.
Improving access to prevention, treatment, and recovery services, including the full range of MAT, is part of the Department of Health and Human Services’ Five-Point Strategy to Combat the Opioid Crisis. Last month, the FDA issued draft guidance outlining new ways for drug developers to consider measuring and demonstrating the effectiveness and benefits of new or existing MAT products, building on another draft guidance issued in April outlining the agency’s current thinking about drug development and trial design issues relevant to the study of depot buprenorphine products (i.e., modified-release products for injection or implantation). In June, the agency also approved the first generic versions of Suboxone (buprenorphine and naloxone) sublingual film in multiple strengths, the statement said.
Cassipa was approved through the abbreviated 505(b)(2) approval pathway and its application relied, in part, on the FDA’s finding of safety and effectiveness for Suboxone sublingual film to support approval. The applicant demonstrated that reliance on the FDA’s finding of safety and effectiveness for Suboxone was scientifically justified and provided Cassipa-specific pharmacokinetic data to establish the drug’s safety and efficacy for its approved uses, according to the FDA.
Adverse events commonly observed with the buprenorphine and naloxone sublingual film are oral hypoesthesia, glossodynia, oral mucosal erythema, headache, nausea, vomiting, hyperhidrosis, constipation, signs and symptoms of withdrawal, insomnia, pain, and peripheral edema.
Cassipa sublingual film, made by Teva Pharmaceuticals, is a 16 mg/4 mg dosage of buprenorphine and naloxone for the maintenance treatment of opioid dependence. Buprenorphine and naloxone sublingual film also is approved in both brand name and generic versions and in various strengths, the FDA said in a press release.
Cassipa should be used as part of a complete treatment plan that includes counseling and psychosocial support and should be used only after patient induction and stabilization up to a dose of 16 mg of buprenorphine using another marketed product. These products may only be prescribed by Drug Addiction Treatment Act (DATA)–certified prescribers.
“There’s an urgent need to ensure access to, and wider use and understanding of, medication-assisted treatment for opioid use disorder ... the FDA recently described a streamlined approach to drug development for certain medication-assisted treatments that are based on buprenorphine. This streamlined approach can reduce drug development costs, so products may be offered at a lower price to patients and we can broaden access to treatment,” FDA Commissioner Scott Gottlieb, MD, said in the statement.
He added that “individuals who successfully transition onto medication-assisted treatment are not swapping one addiction for another. Opioid replacement therapy can be an important part of effective treatment. Opioid use disorder should be viewed similarly to any other chronic condition that is treated with medication.”
Medication-assisted treatment (MAT) is a comprehensive approach that combines FDA-approved medications (currently methadone, buprenorphine, or naltrexone) with counseling and other behavioral therapies to treat patients with opioid use disorder. Regular adherence to MAT with buprenorphine reduces opioid withdrawal symptoms and the desire to use opioids. According to the Substance Abuse and Mental Health Services Administration, patients receiving MAT for treatment of their opioid use disorder cut their risk of death from all causes in half.
Improving access to prevention, treatment, and recovery services, including the full range of MAT, is part of the Department of Health and Human Services’ Five-Point Strategy to Combat the Opioid Crisis. Last month, the FDA issued draft guidance outlining new ways for drug developers to consider measuring and demonstrating the effectiveness and benefits of new or existing MAT products, building on another draft guidance issued in April outlining the agency’s current thinking about drug development and trial design issues relevant to the study of depot buprenorphine products (i.e., modified-release products for injection or implantation). In June, the agency also approved the first generic versions of Suboxone (buprenorphine and naloxone) sublingual film in multiple strengths, the statement said.
Cassipa was approved through the abbreviated 505(b)(2) approval pathway and its application relied, in part, on the FDA’s finding of safety and effectiveness for Suboxone sublingual film to support approval. The applicant demonstrated that reliance on the FDA’s finding of safety and effectiveness for Suboxone was scientifically justified and provided Cassipa-specific pharmacokinetic data to establish the drug’s safety and efficacy for its approved uses, according to the FDA.
Adverse events commonly observed with the buprenorphine and naloxone sublingual film are oral hypoesthesia, glossodynia, oral mucosal erythema, headache, nausea, vomiting, hyperhidrosis, constipation, signs and symptoms of withdrawal, insomnia, pain, and peripheral edema.
SEAL: Selinexor extends PFS in advanced dedifferentiated liposarcoma
The investigational drug selinexor appears to be improving progression-free survival in patients with advanced dedifferentiated liposarcoma, based on phase 2 results from the randomized, placebo-controlled SEAL study.
But the statistical significance of the improvements varied depending on whether progression-free survival (PFS) was assessed by the World Health Organization criteria, which looks at two-dimensional measurements of these irregular three-dimensional objects, or RECIST v1.1 criteria, which only looks at a unidimensional measure, reported Mrinal M. Gounder, MD, of Memorial Sloan Kettering Cancer Center, New York, at the annual meeting of the American Society of Clinical Oncology. When tumor response was based on WHO criteria, there was no difference in median PFS for the 24 patients on active therapy (1.4 months) and the 27 patients on placebo (1.8 months). By RECIST v1.1 criteria, however, median PFS was 5.6 months with selinexor.
Dedifferentiated liposarcoma is incurable, and palliative therapies are associated with an overall survival of 11-20 months in these patients. Selinexor is an oral selective inhibitor of exportin-1 which exports proteins from the nucleus into the cytoplasm. The drug appears to prevent p53 from leaving the nucleus, thereby protecting it from overexpressed MDM2, which is a negative regulator of p53, but the drug might have other potential mechanisms of action.
The double-blind study included 56 evaluable patients who had progressive dedifferentiated liposarcoma and had received at least one prior systemic therapy. Patients’ median age was 61 years and they had received a median of two prior therapies. Patients were randomized to get either 60 mg of selinexor (26 patients) or placebo (30 patients) twice weekly until their disease progressed or they were no longer able to tolerate therapy. Patients whose disease progressed on placebo (24 patients) were allowed to cross over to open-label selinexor therapy.
Treatments were unblinded for 51 of the patients, 24 on selinexor and 27 on placebo. Disease progression as confirmed by Independent Central Radiological Review using WHO criteria was the main reason for ending blinded treatment.
Grade 1/2 adverse events for selinexor versus placebo, respectively, were nausea (85% vs. 31%), anorexia (62% vs. 14%), and fatigue (58% vs. 45%). The comparable rates of grade 3/4 adverse events were hyponatremia (15% vs. 0%), anemia (15% vs. 7%), and thrombocytopenia (12% vs. 0%). Selinexor dose was reduced because of adverse events in 12 patients.
In a discussion of the study’s implications, Mark Andrew Dickson, MD, also of Memorial Sloan Kettering Cancer Center, called the adverse events profile “mostly manageable but predictable grade 1/2 adverse events ... and median progression-free survival of 5 and a half months is quite encouraging.
“Changing response assessment method midtrial in a study with progression-free survival as the primary endpoint is obviously problematic, but it also highlights how difficult it is to measure three-dimensional tumors like complex retroperitoneal liposarcomas, which move and change and grow and shrink over time,” he said. “And I would conclude that RECIST is probably the worst method of tumor assessment for sarcoma, except for all the other methods of tumor assessment.”
To illustrate the difficulty of measuring tumor response, Dr. Dickson presented examples of different tumor shapes and scenarios where one method would indicate tumor progression and the other would indicate stable disease.
“There can be differences between the two methods in how progression responds and is determined. And you can do this experiment with a number of different shapes and find scenarios where one method would call it progression at a different time than the other. So this is really critically important when we look at the results of the clinical trial, because it was designed to look at WHO PFS. And you can see that, based on that, there was no significant difference between the selinexor and placebo arm,” he said.
Additionally, he reviewed cases from the study where “either way you measure this, you can see that [the] tumor is getting smaller over time,” as well as cases where the tumor grew in patients on placebo first, but decreased in size after switching to the active therapy.
“The improvement in progression-free survival is promising and ... selinexor probably does have activity in dediff lipo compared to historical data,” said Dr. Dickson, adding that he looks forward to selinexor progressing to a randomized, phase 3 trial and “seeing those data perhaps next year.”
Dr. Gounder disclosed financial relationships with multiple drug companies including Karyopharm Therapeutics, the maker of selinexor. Dr. Dickson disclosed a consult or adviser role with Celgene and research funding from Eli Lilly.
SOURCE: Gounder M et al. ASCO 2018, Abstract 11512.
The investigational drug selinexor appears to be improving progression-free survival in patients with advanced dedifferentiated liposarcoma, based on phase 2 results from the randomized, placebo-controlled SEAL study.
But the statistical significance of the improvements varied depending on whether progression-free survival (PFS) was assessed by the World Health Organization criteria, which looks at two-dimensional measurements of these irregular three-dimensional objects, or RECIST v1.1 criteria, which only looks at a unidimensional measure, reported Mrinal M. Gounder, MD, of Memorial Sloan Kettering Cancer Center, New York, at the annual meeting of the American Society of Clinical Oncology. When tumor response was based on WHO criteria, there was no difference in median PFS for the 24 patients on active therapy (1.4 months) and the 27 patients on placebo (1.8 months). By RECIST v1.1 criteria, however, median PFS was 5.6 months with selinexor.
Dedifferentiated liposarcoma is incurable, and palliative therapies are associated with an overall survival of 11-20 months in these patients. Selinexor is an oral selective inhibitor of exportin-1 which exports proteins from the nucleus into the cytoplasm. The drug appears to prevent p53 from leaving the nucleus, thereby protecting it from overexpressed MDM2, which is a negative regulator of p53, but the drug might have other potential mechanisms of action.
The double-blind study included 56 evaluable patients who had progressive dedifferentiated liposarcoma and had received at least one prior systemic therapy. Patients’ median age was 61 years and they had received a median of two prior therapies. Patients were randomized to get either 60 mg of selinexor (26 patients) or placebo (30 patients) twice weekly until their disease progressed or they were no longer able to tolerate therapy. Patients whose disease progressed on placebo (24 patients) were allowed to cross over to open-label selinexor therapy.
Treatments were unblinded for 51 of the patients, 24 on selinexor and 27 on placebo. Disease progression as confirmed by Independent Central Radiological Review using WHO criteria was the main reason for ending blinded treatment.
Grade 1/2 adverse events for selinexor versus placebo, respectively, were nausea (85% vs. 31%), anorexia (62% vs. 14%), and fatigue (58% vs. 45%). The comparable rates of grade 3/4 adverse events were hyponatremia (15% vs. 0%), anemia (15% vs. 7%), and thrombocytopenia (12% vs. 0%). Selinexor dose was reduced because of adverse events in 12 patients.
In a discussion of the study’s implications, Mark Andrew Dickson, MD, also of Memorial Sloan Kettering Cancer Center, called the adverse events profile “mostly manageable but predictable grade 1/2 adverse events ... and median progression-free survival of 5 and a half months is quite encouraging.
“Changing response assessment method midtrial in a study with progression-free survival as the primary endpoint is obviously problematic, but it also highlights how difficult it is to measure three-dimensional tumors like complex retroperitoneal liposarcomas, which move and change and grow and shrink over time,” he said. “And I would conclude that RECIST is probably the worst method of tumor assessment for sarcoma, except for all the other methods of tumor assessment.”
To illustrate the difficulty of measuring tumor response, Dr. Dickson presented examples of different tumor shapes and scenarios where one method would indicate tumor progression and the other would indicate stable disease.
“There can be differences between the two methods in how progression responds and is determined. And you can do this experiment with a number of different shapes and find scenarios where one method would call it progression at a different time than the other. So this is really critically important when we look at the results of the clinical trial, because it was designed to look at WHO PFS. And you can see that, based on that, there was no significant difference between the selinexor and placebo arm,” he said.
Additionally, he reviewed cases from the study where “either way you measure this, you can see that [the] tumor is getting smaller over time,” as well as cases where the tumor grew in patients on placebo first, but decreased in size after switching to the active therapy.
“The improvement in progression-free survival is promising and ... selinexor probably does have activity in dediff lipo compared to historical data,” said Dr. Dickson, adding that he looks forward to selinexor progressing to a randomized, phase 3 trial and “seeing those data perhaps next year.”
Dr. Gounder disclosed financial relationships with multiple drug companies including Karyopharm Therapeutics, the maker of selinexor. Dr. Dickson disclosed a consult or adviser role with Celgene and research funding from Eli Lilly.
SOURCE: Gounder M et al. ASCO 2018, Abstract 11512.
The investigational drug selinexor appears to be improving progression-free survival in patients with advanced dedifferentiated liposarcoma, based on phase 2 results from the randomized, placebo-controlled SEAL study.
But the statistical significance of the improvements varied depending on whether progression-free survival (PFS) was assessed by the World Health Organization criteria, which looks at two-dimensional measurements of these irregular three-dimensional objects, or RECIST v1.1 criteria, which only looks at a unidimensional measure, reported Mrinal M. Gounder, MD, of Memorial Sloan Kettering Cancer Center, New York, at the annual meeting of the American Society of Clinical Oncology. When tumor response was based on WHO criteria, there was no difference in median PFS for the 24 patients on active therapy (1.4 months) and the 27 patients on placebo (1.8 months). By RECIST v1.1 criteria, however, median PFS was 5.6 months with selinexor.
Dedifferentiated liposarcoma is incurable, and palliative therapies are associated with an overall survival of 11-20 months in these patients. Selinexor is an oral selective inhibitor of exportin-1 which exports proteins from the nucleus into the cytoplasm. The drug appears to prevent p53 from leaving the nucleus, thereby protecting it from overexpressed MDM2, which is a negative regulator of p53, but the drug might have other potential mechanisms of action.
The double-blind study included 56 evaluable patients who had progressive dedifferentiated liposarcoma and had received at least one prior systemic therapy. Patients’ median age was 61 years and they had received a median of two prior therapies. Patients were randomized to get either 60 mg of selinexor (26 patients) or placebo (30 patients) twice weekly until their disease progressed or they were no longer able to tolerate therapy. Patients whose disease progressed on placebo (24 patients) were allowed to cross over to open-label selinexor therapy.
Treatments were unblinded for 51 of the patients, 24 on selinexor and 27 on placebo. Disease progression as confirmed by Independent Central Radiological Review using WHO criteria was the main reason for ending blinded treatment.
Grade 1/2 adverse events for selinexor versus placebo, respectively, were nausea (85% vs. 31%), anorexia (62% vs. 14%), and fatigue (58% vs. 45%). The comparable rates of grade 3/4 adverse events were hyponatremia (15% vs. 0%), anemia (15% vs. 7%), and thrombocytopenia (12% vs. 0%). Selinexor dose was reduced because of adverse events in 12 patients.
In a discussion of the study’s implications, Mark Andrew Dickson, MD, also of Memorial Sloan Kettering Cancer Center, called the adverse events profile “mostly manageable but predictable grade 1/2 adverse events ... and median progression-free survival of 5 and a half months is quite encouraging.
“Changing response assessment method midtrial in a study with progression-free survival as the primary endpoint is obviously problematic, but it also highlights how difficult it is to measure three-dimensional tumors like complex retroperitoneal liposarcomas, which move and change and grow and shrink over time,” he said. “And I would conclude that RECIST is probably the worst method of tumor assessment for sarcoma, except for all the other methods of tumor assessment.”
To illustrate the difficulty of measuring tumor response, Dr. Dickson presented examples of different tumor shapes and scenarios where one method would indicate tumor progression and the other would indicate stable disease.
“There can be differences between the two methods in how progression responds and is determined. And you can do this experiment with a number of different shapes and find scenarios where one method would call it progression at a different time than the other. So this is really critically important when we look at the results of the clinical trial, because it was designed to look at WHO PFS. And you can see that, based on that, there was no significant difference between the selinexor and placebo arm,” he said.
Additionally, he reviewed cases from the study where “either way you measure this, you can see that [the] tumor is getting smaller over time,” as well as cases where the tumor grew in patients on placebo first, but decreased in size after switching to the active therapy.
“The improvement in progression-free survival is promising and ... selinexor probably does have activity in dediff lipo compared to historical data,” said Dr. Dickson, adding that he looks forward to selinexor progressing to a randomized, phase 3 trial and “seeing those data perhaps next year.”
Dr. Gounder disclosed financial relationships with multiple drug companies including Karyopharm Therapeutics, the maker of selinexor. Dr. Dickson disclosed a consult or adviser role with Celgene and research funding from Eli Lilly.
SOURCE: Gounder M et al. ASCO 2018, Abstract 11512.
FROM ASCO 2018
Key clinical point: The investigational drug selinexor appears to be improving progression-free survival (PFS) in patients with advanced dedifferentiated liposarcoma.
Major finding: When tumor response was based on World Health Organization criteria, there was no difference in median PFS for the 24 patients on active therapy (1.4 months) and the 27 patients on placebo (1.8 months). By RECIST v1.1 criteria, however, median PFS was 5.6 months with selinexor.
Study details: Phase 2 results from 56 patients with dedifferentiated liposarcoma in the randomized, placebo-controlled SEAL study.
Disclosures: Dr. Gounder reported financial relationships with multiple drug companies including Karyopharm Therapeutics, the maker of selinexor. Dr. Dickson reported a consultant or adviser role with Celgene and research funding from Eli Lilly.
Source: Gounder M et al. ASCO 2018, Abstract 11512.
Chromoplexy linked to aggressive Ewing sarcomas
Chromoplexy, a sudden burst of complex, loop-like gene rearrangements that gives rise to a fusion gene, appears to be associated with aggressive Ewing sarcomas, based on a study of 124 tumors reported in Science.
Ewing sarcomas with complex karyotypes are associated with a poorer prognosis compared with those with simpler karyotypes. The new findings show that these complex karyotypes are the product of chromoplexy, and that chromoplexy-generated fusions arise early, giving rise to both primary and relapse Ewing sarcoma tumors, which can continue to evolve in parallel.
Analysis of the sequence context surrounding chromoplexy breaks may provide clues and potentially point to a therapeutic vulnerability that could be used to treat Ewing sarcomas. Further, given the preference of chromoplexy events for transcriptionally active regions, Ewing sarcomas arising from chromoplexy may be responsive to immune checkpoint inhibition.
In a study of the whole genomes of 124 Ewing sarcomas, chromoplexy rather than simple reciprocal translocations defined the gene fusions seen in 52 tumors (42%). Ewing sarcoma involves fusions between EWSR1, a gene encoding an RNA binding protein, and E26 transformation-specific (ETS) transcription factors.
“Our analyses reveal rearrangement bursts (chromoplectic loops) as a source of gene fusion in human bone and soft tissue tumors. Ewing sarcomas with complex karyotypes are associated with a poorer prognosis than those with simpler karyotypes, and here we show chromoplexy as the mechanism in 42% of tumors. It is possible that the chromoplectic tumor’s additional gene disruptions and fusions contribute to the difference in patient survival,” wrote Nathaniel D. Anderson of the Hospital for Sick Children, Toronto, and the University of Toronto, and his colleagues.
Standard reciprocal translocations involve DNA breaks in two fusion partners. Chromoplexy involves three or more breakpoints in the genome. A loop pattern emerges as these three or more broken chromosome ends are forced to find a new partner. The result is the formation of functional EWSR1-FLI1 or EWSR1-ERG fusions that, upon expression, provide a selective growth or survival advantage
The researchers found that the loop rearrangements always contained the disease-defining fusion at the center, but they disrupted multiple additional genes. The loops occurred preferentially in early replicating and transcriptionally active genomic regions.
They found similar loops forming canonical fusions in three other sarcoma types.
“Our whole-genome sequence data support a model in which there is an early clone of (Ewing sarcoma), containing EWSR1-ETS and chromoplexy, arising at least 1 year before diagnosis, which gives rise to both the primary and metastatic or relapse tumors. Whether the bursts ... are chance events or driven by specific mutational processes, akin to the RAG machinery operative in leukemia, remains to be established. As an increasing and diverse number of tumor genome sequences become available, we may be able to define further rearrangement processes that underlie fusion genes and thus unravel the causes of fusion-driven human cancers,” the researchers wrote.
The clinical features and demographics of the study patients were typical of Ewing sarcoma patients. Average patient age at diagnosis was 14.8 years (2.8 to 36.6 years); the male to female ratio was 1.38:1; and 14 patients had relapsed, with 13 having died from their disease.
About half of fusions between the EWS RNA binding protein 1 (EWSR1) gene on chromosome 22 and an E26 transformation-specific (ETS) family transcription factor gene, either FLI1 at 11q24 or ERG at 21q11 arose via chromoplexy.
SOURCE: Anderson et al. Science 2018 Aug 31. doi: 10.1126/science.aam8419.
The contribution of genetic analysis to the current standard of care for Ewing sarcoma is limited to confirmation of the diagnostic EWSR1-FLI1 or EWSR1-ERG fusions. The discovery of genomic patterns associated with subsets of Ewing sarcomas raises the question of whether additional molecular diagnostic modalities are warranted. If chromoplexy events are important clinical biomarkers for disease aggressiveness in this tumor, as the authors suggest, their findings may support a new indication for clinical whole genome sequencing.
Analysis of additional patient samples will be needed, however, to confirm that the presence of chromoplexy is an independent prognostic predictor in Ewing sarcoma. This is because the researchers find that chromoplexy-driven Ewing sarcoma more likely contains tumor protein 53 (TP53) mutations. Because TP53 and stromal antigen 2 (STAG2) mutations and genomic complexity have each been associated with more aggressive Ewing sarcoma, dissecting the contribution of these factors to poor clinical outcomes in chromoplexy-derived Ewing sarcoma will be an important area of future work.
More generally, the study has important clinical implications for the genomic diagnosis of these and other cancers, as well as the expanding biological role of complex rearrangements in cancer evolution.
Could chromoplexy events in Ewing sarcoma be linked, for example, to the activity of an aberrantly expressed endogenous transposase such as PiggyBac transposase 5 (PGBD5), which was recently implicated in the genesis of the pathogenic gene rearrangements in childhood malignant rhabdoid tumors? An alternative possibility is a constitutional or acquired DNA repair defect (Science 2018 Aug 31. doi: 10.1126/science.aau8231).
Marcin Imielinski is with the Meyer Cancer Center, Cornell University, and the New York Genome Center, New York. Marc Ladanyi is with Memorial Sloan Kettering Cancer Center, New York. They made their remarks in an editorial in Science that accompanied the study.
The contribution of genetic analysis to the current standard of care for Ewing sarcoma is limited to confirmation of the diagnostic EWSR1-FLI1 or EWSR1-ERG fusions. The discovery of genomic patterns associated with subsets of Ewing sarcomas raises the question of whether additional molecular diagnostic modalities are warranted. If chromoplexy events are important clinical biomarkers for disease aggressiveness in this tumor, as the authors suggest, their findings may support a new indication for clinical whole genome sequencing.
Analysis of additional patient samples will be needed, however, to confirm that the presence of chromoplexy is an independent prognostic predictor in Ewing sarcoma. This is because the researchers find that chromoplexy-driven Ewing sarcoma more likely contains tumor protein 53 (TP53) mutations. Because TP53 and stromal antigen 2 (STAG2) mutations and genomic complexity have each been associated with more aggressive Ewing sarcoma, dissecting the contribution of these factors to poor clinical outcomes in chromoplexy-derived Ewing sarcoma will be an important area of future work.
More generally, the study has important clinical implications for the genomic diagnosis of these and other cancers, as well as the expanding biological role of complex rearrangements in cancer evolution.
Could chromoplexy events in Ewing sarcoma be linked, for example, to the activity of an aberrantly expressed endogenous transposase such as PiggyBac transposase 5 (PGBD5), which was recently implicated in the genesis of the pathogenic gene rearrangements in childhood malignant rhabdoid tumors? An alternative possibility is a constitutional or acquired DNA repair defect (Science 2018 Aug 31. doi: 10.1126/science.aau8231).
Marcin Imielinski is with the Meyer Cancer Center, Cornell University, and the New York Genome Center, New York. Marc Ladanyi is with Memorial Sloan Kettering Cancer Center, New York. They made their remarks in an editorial in Science that accompanied the study.
The contribution of genetic analysis to the current standard of care for Ewing sarcoma is limited to confirmation of the diagnostic EWSR1-FLI1 or EWSR1-ERG fusions. The discovery of genomic patterns associated with subsets of Ewing sarcomas raises the question of whether additional molecular diagnostic modalities are warranted. If chromoplexy events are important clinical biomarkers for disease aggressiveness in this tumor, as the authors suggest, their findings may support a new indication for clinical whole genome sequencing.
Analysis of additional patient samples will be needed, however, to confirm that the presence of chromoplexy is an independent prognostic predictor in Ewing sarcoma. This is because the researchers find that chromoplexy-driven Ewing sarcoma more likely contains tumor protein 53 (TP53) mutations. Because TP53 and stromal antigen 2 (STAG2) mutations and genomic complexity have each been associated with more aggressive Ewing sarcoma, dissecting the contribution of these factors to poor clinical outcomes in chromoplexy-derived Ewing sarcoma will be an important area of future work.
More generally, the study has important clinical implications for the genomic diagnosis of these and other cancers, as well as the expanding biological role of complex rearrangements in cancer evolution.
Could chromoplexy events in Ewing sarcoma be linked, for example, to the activity of an aberrantly expressed endogenous transposase such as PiggyBac transposase 5 (PGBD5), which was recently implicated in the genesis of the pathogenic gene rearrangements in childhood malignant rhabdoid tumors? An alternative possibility is a constitutional or acquired DNA repair defect (Science 2018 Aug 31. doi: 10.1126/science.aau8231).
Marcin Imielinski is with the Meyer Cancer Center, Cornell University, and the New York Genome Center, New York. Marc Ladanyi is with Memorial Sloan Kettering Cancer Center, New York. They made their remarks in an editorial in Science that accompanied the study.
Chromoplexy, a sudden burst of complex, loop-like gene rearrangements that gives rise to a fusion gene, appears to be associated with aggressive Ewing sarcomas, based on a study of 124 tumors reported in Science.
Ewing sarcomas with complex karyotypes are associated with a poorer prognosis compared with those with simpler karyotypes. The new findings show that these complex karyotypes are the product of chromoplexy, and that chromoplexy-generated fusions arise early, giving rise to both primary and relapse Ewing sarcoma tumors, which can continue to evolve in parallel.
Analysis of the sequence context surrounding chromoplexy breaks may provide clues and potentially point to a therapeutic vulnerability that could be used to treat Ewing sarcomas. Further, given the preference of chromoplexy events for transcriptionally active regions, Ewing sarcomas arising from chromoplexy may be responsive to immune checkpoint inhibition.
In a study of the whole genomes of 124 Ewing sarcomas, chromoplexy rather than simple reciprocal translocations defined the gene fusions seen in 52 tumors (42%). Ewing sarcoma involves fusions between EWSR1, a gene encoding an RNA binding protein, and E26 transformation-specific (ETS) transcription factors.
“Our analyses reveal rearrangement bursts (chromoplectic loops) as a source of gene fusion in human bone and soft tissue tumors. Ewing sarcomas with complex karyotypes are associated with a poorer prognosis than those with simpler karyotypes, and here we show chromoplexy as the mechanism in 42% of tumors. It is possible that the chromoplectic tumor’s additional gene disruptions and fusions contribute to the difference in patient survival,” wrote Nathaniel D. Anderson of the Hospital for Sick Children, Toronto, and the University of Toronto, and his colleagues.
Standard reciprocal translocations involve DNA breaks in two fusion partners. Chromoplexy involves three or more breakpoints in the genome. A loop pattern emerges as these three or more broken chromosome ends are forced to find a new partner. The result is the formation of functional EWSR1-FLI1 or EWSR1-ERG fusions that, upon expression, provide a selective growth or survival advantage
The researchers found that the loop rearrangements always contained the disease-defining fusion at the center, but they disrupted multiple additional genes. The loops occurred preferentially in early replicating and transcriptionally active genomic regions.
They found similar loops forming canonical fusions in three other sarcoma types.
“Our whole-genome sequence data support a model in which there is an early clone of (Ewing sarcoma), containing EWSR1-ETS and chromoplexy, arising at least 1 year before diagnosis, which gives rise to both the primary and metastatic or relapse tumors. Whether the bursts ... are chance events or driven by specific mutational processes, akin to the RAG machinery operative in leukemia, remains to be established. As an increasing and diverse number of tumor genome sequences become available, we may be able to define further rearrangement processes that underlie fusion genes and thus unravel the causes of fusion-driven human cancers,” the researchers wrote.
The clinical features and demographics of the study patients were typical of Ewing sarcoma patients. Average patient age at diagnosis was 14.8 years (2.8 to 36.6 years); the male to female ratio was 1.38:1; and 14 patients had relapsed, with 13 having died from their disease.
About half of fusions between the EWS RNA binding protein 1 (EWSR1) gene on chromosome 22 and an E26 transformation-specific (ETS) family transcription factor gene, either FLI1 at 11q24 or ERG at 21q11 arose via chromoplexy.
SOURCE: Anderson et al. Science 2018 Aug 31. doi: 10.1126/science.aam8419.
Chromoplexy, a sudden burst of complex, loop-like gene rearrangements that gives rise to a fusion gene, appears to be associated with aggressive Ewing sarcomas, based on a study of 124 tumors reported in Science.
Ewing sarcomas with complex karyotypes are associated with a poorer prognosis compared with those with simpler karyotypes. The new findings show that these complex karyotypes are the product of chromoplexy, and that chromoplexy-generated fusions arise early, giving rise to both primary and relapse Ewing sarcoma tumors, which can continue to evolve in parallel.
Analysis of the sequence context surrounding chromoplexy breaks may provide clues and potentially point to a therapeutic vulnerability that could be used to treat Ewing sarcomas. Further, given the preference of chromoplexy events for transcriptionally active regions, Ewing sarcomas arising from chromoplexy may be responsive to immune checkpoint inhibition.
In a study of the whole genomes of 124 Ewing sarcomas, chromoplexy rather than simple reciprocal translocations defined the gene fusions seen in 52 tumors (42%). Ewing sarcoma involves fusions between EWSR1, a gene encoding an RNA binding protein, and E26 transformation-specific (ETS) transcription factors.
“Our analyses reveal rearrangement bursts (chromoplectic loops) as a source of gene fusion in human bone and soft tissue tumors. Ewing sarcomas with complex karyotypes are associated with a poorer prognosis than those with simpler karyotypes, and here we show chromoplexy as the mechanism in 42% of tumors. It is possible that the chromoplectic tumor’s additional gene disruptions and fusions contribute to the difference in patient survival,” wrote Nathaniel D. Anderson of the Hospital for Sick Children, Toronto, and the University of Toronto, and his colleagues.
Standard reciprocal translocations involve DNA breaks in two fusion partners. Chromoplexy involves three or more breakpoints in the genome. A loop pattern emerges as these three or more broken chromosome ends are forced to find a new partner. The result is the formation of functional EWSR1-FLI1 or EWSR1-ERG fusions that, upon expression, provide a selective growth or survival advantage
The researchers found that the loop rearrangements always contained the disease-defining fusion at the center, but they disrupted multiple additional genes. The loops occurred preferentially in early replicating and transcriptionally active genomic regions.
They found similar loops forming canonical fusions in three other sarcoma types.
“Our whole-genome sequence data support a model in which there is an early clone of (Ewing sarcoma), containing EWSR1-ETS and chromoplexy, arising at least 1 year before diagnosis, which gives rise to both the primary and metastatic or relapse tumors. Whether the bursts ... are chance events or driven by specific mutational processes, akin to the RAG machinery operative in leukemia, remains to be established. As an increasing and diverse number of tumor genome sequences become available, we may be able to define further rearrangement processes that underlie fusion genes and thus unravel the causes of fusion-driven human cancers,” the researchers wrote.
The clinical features and demographics of the study patients were typical of Ewing sarcoma patients. Average patient age at diagnosis was 14.8 years (2.8 to 36.6 years); the male to female ratio was 1.38:1; and 14 patients had relapsed, with 13 having died from their disease.
About half of fusions between the EWS RNA binding protein 1 (EWSR1) gene on chromosome 22 and an E26 transformation-specific (ETS) family transcription factor gene, either FLI1 at 11q24 or ERG at 21q11 arose via chromoplexy.
SOURCE: Anderson et al. Science 2018 Aug 31. doi: 10.1126/science.aam8419.
FROM SCIENCE
Key clinical point: Chromoplexy, a sudden burst of complex, loop-like gene rearrangements that gives rise to a fusion gene, appears to be associated with aggressive Ewing sarcomas.
Major finding: Chromoplexy rather than simple reciprocal translocations defined the gene fusions seen in 42% of Ewing sarcoma tumors.
Study details: A study of the whole genomes of 124 Ewing sarcomas.
Disclosures: This research project was conducted with support from C17 and partially funded by Ewings Cancer Foundation of Canada and Childhood Cancer Canada Foundation. The authors declared no competing interests.
Source: Anderson et al. Science 2018 Aug 31. doi: 10.1126/science.aam8419.
Valsartan recalls: FDA, manufacturers issue advisories
This story updated Aug. 23 to include additional recall and release of new test. The FDA added an updated statement on their ongoing investigation on Aug. 30 and again on Oct. 24.
for recognizing the recalled products and prescribing replacement products.
The affected products containing the active ingredient valsartan were voluntarily recalled because of the detection of N-nitrosodimethylamine (NDMA), an impurity that is classified as a probable carcinogen. The presence of NDMA was unexpected and is thought to be related to changes in the manufacturing process, the FDA announced in a press release.
The voluntary recall affects all lots of nonexpired products that contain the ingredient valsartan supplied to companies by Zhejiang Huahai Pharmaceuticals, Linhai, China. This company has stopped distributing valsartan. The FDA is working with the affected manufacturers – Major Pharmaceuticals, Solco Healthcare, and Teva Pharmaceuticals – to reduce or eliminate impure valsartan from future products. The voluntary recall also applies to Solco and Teva valsartan/hydrochlorothiazide (HCTZ) combination products.
On Aug. 23, the FDA announced that the recall was extended to all valsartan-containing products from Torrent Pharmaceuticals Limited.
The agency said its review is ongoing and includes investigating the levels of NDMA in the recalled products, assessing the possible effect on patients who have been taking them, and what measures can be taken to reduce or eliminate the impurity from future batches.
“Our drug shortages team is also working hard to ensure patients’ therapeutic needs are met in the United States with an adequate supply of unaffected medications,” FDA Commissioner Scott Gottlieb, MD, said.
Additionally, the FDA on Aug. 23 released a gas chromatography-mass spectrometry (GC/MS) headspace method that drug manufacturers and regulators can use to detect and quantify NDMA in valsartan and finished drug products.
In the interim, patients taking the recalled valsartan-containing medicines should continue taking their medicine until they have a replacement product, the statement said. To determine whether a specific product has been recalled, patients should be instructed to look at the drug name and company name on the label of their prescription bottle. If the information is not on the bottle, patients should contact the pharmacy that dispensed the medicine.
If a patient is taking one of the recalled medicines, they should follow the recall instructions provided by the specific company, according to the FDA.
Contact information for each manufacturer can be found at the following links:
Major Pharmaceuticals: www.fda.gov/Safety/Recalls/ucm613625.htm.
Solco Healthcare: www.fda.gov/Safety/Recalls/ucm613504.htm.
Teva Pharmaceuticals: www.fda.gov/Safety/Recalls/ucm613729.htm.
Torrent Pharmaceuticals Limited: https://www.fda.gov/Safety/Recalls/ucm617821.htm
This story updated Aug. 23 to include additional recall and release of new test. The FDA added an updated statement on their ongoing investigation on Aug. 30 and again on Oct. 24.
for recognizing the recalled products and prescribing replacement products.
The affected products containing the active ingredient valsartan were voluntarily recalled because of the detection of N-nitrosodimethylamine (NDMA), an impurity that is classified as a probable carcinogen. The presence of NDMA was unexpected and is thought to be related to changes in the manufacturing process, the FDA announced in a press release.
The voluntary recall affects all lots of nonexpired products that contain the ingredient valsartan supplied to companies by Zhejiang Huahai Pharmaceuticals, Linhai, China. This company has stopped distributing valsartan. The FDA is working with the affected manufacturers – Major Pharmaceuticals, Solco Healthcare, and Teva Pharmaceuticals – to reduce or eliminate impure valsartan from future products. The voluntary recall also applies to Solco and Teva valsartan/hydrochlorothiazide (HCTZ) combination products.
On Aug. 23, the FDA announced that the recall was extended to all valsartan-containing products from Torrent Pharmaceuticals Limited.
The agency said its review is ongoing and includes investigating the levels of NDMA in the recalled products, assessing the possible effect on patients who have been taking them, and what measures can be taken to reduce or eliminate the impurity from future batches.
“Our drug shortages team is also working hard to ensure patients’ therapeutic needs are met in the United States with an adequate supply of unaffected medications,” FDA Commissioner Scott Gottlieb, MD, said.
Additionally, the FDA on Aug. 23 released a gas chromatography-mass spectrometry (GC/MS) headspace method that drug manufacturers and regulators can use to detect and quantify NDMA in valsartan and finished drug products.
In the interim, patients taking the recalled valsartan-containing medicines should continue taking their medicine until they have a replacement product, the statement said. To determine whether a specific product has been recalled, patients should be instructed to look at the drug name and company name on the label of their prescription bottle. If the information is not on the bottle, patients should contact the pharmacy that dispensed the medicine.
If a patient is taking one of the recalled medicines, they should follow the recall instructions provided by the specific company, according to the FDA.
Contact information for each manufacturer can be found at the following links:
Major Pharmaceuticals: www.fda.gov/Safety/Recalls/ucm613625.htm.
Solco Healthcare: www.fda.gov/Safety/Recalls/ucm613504.htm.
Teva Pharmaceuticals: www.fda.gov/Safety/Recalls/ucm613729.htm.
Torrent Pharmaceuticals Limited: https://www.fda.gov/Safety/Recalls/ucm617821.htm
This story updated Aug. 23 to include additional recall and release of new test. The FDA added an updated statement on their ongoing investigation on Aug. 30 and again on Oct. 24.
for recognizing the recalled products and prescribing replacement products.
The affected products containing the active ingredient valsartan were voluntarily recalled because of the detection of N-nitrosodimethylamine (NDMA), an impurity that is classified as a probable carcinogen. The presence of NDMA was unexpected and is thought to be related to changes in the manufacturing process, the FDA announced in a press release.
The voluntary recall affects all lots of nonexpired products that contain the ingredient valsartan supplied to companies by Zhejiang Huahai Pharmaceuticals, Linhai, China. This company has stopped distributing valsartan. The FDA is working with the affected manufacturers – Major Pharmaceuticals, Solco Healthcare, and Teva Pharmaceuticals – to reduce or eliminate impure valsartan from future products. The voluntary recall also applies to Solco and Teva valsartan/hydrochlorothiazide (HCTZ) combination products.
On Aug. 23, the FDA announced that the recall was extended to all valsartan-containing products from Torrent Pharmaceuticals Limited.
The agency said its review is ongoing and includes investigating the levels of NDMA in the recalled products, assessing the possible effect on patients who have been taking them, and what measures can be taken to reduce or eliminate the impurity from future batches.
“Our drug shortages team is also working hard to ensure patients’ therapeutic needs are met in the United States with an adequate supply of unaffected medications,” FDA Commissioner Scott Gottlieb, MD, said.
Additionally, the FDA on Aug. 23 released a gas chromatography-mass spectrometry (GC/MS) headspace method that drug manufacturers and regulators can use to detect and quantify NDMA in valsartan and finished drug products.
In the interim, patients taking the recalled valsartan-containing medicines should continue taking their medicine until they have a replacement product, the statement said. To determine whether a specific product has been recalled, patients should be instructed to look at the drug name and company name on the label of their prescription bottle. If the information is not on the bottle, patients should contact the pharmacy that dispensed the medicine.
If a patient is taking one of the recalled medicines, they should follow the recall instructions provided by the specific company, according to the FDA.
Contact information for each manufacturer can be found at the following links:
Major Pharmaceuticals: www.fda.gov/Safety/Recalls/ucm613625.htm.
Solco Healthcare: www.fda.gov/Safety/Recalls/ucm613504.htm.
Teva Pharmaceuticals: www.fda.gov/Safety/Recalls/ucm613729.htm.
Torrent Pharmaceuticals Limited: https://www.fda.gov/Safety/Recalls/ucm617821.htm
FDA approves vaginal ring contraceptive Annovera
The first vaginal ring contraceptive that can be used for 1 year has been approved by the Food and Drug Administration.
The FDA granted approval of Annovera (segesterone acetate and ethinyl estradiol vaginal system), a reusable donut-shaped ring, to the Population Council. The nonbiodegradable, flexible vaginal system is placed in the vagina for 3 weeks followed by 1 week out of the vagina, at which time women may experience a menstrual period. This schedule is repeated every 4 weeks for 13 28-day menstrual cycles.
The contraceptive ring is washed and stored in a compact case for the 7 days when it is not in use. Annovera does not require refrigeration prior to dispensing and can withstand storage temperatures up to 30° C (86° F).
“Today’s approval builds on available birth control options,” said Victor Crentsil, MD, acting deputy director of the Office of Drug Evaluation III in FDA’s Center for Drug Evaluation and Research.
The efficacy and safety of Annovera were studied in three, open-label clinical trials with healthy women ranging from 18 to 40 years of age. Based on the results, about 2%-4% of women may get pregnant during the first year they use Annovera.
Annovera carries a boxed warning regarding cigarette smoking and serious cardiovascular events. Women over age 35 who smoke should not use Annovera. Cigarette smoking increases the risk of serious cardiovascular events from combination hormonal contraceptive use.
Annovera is contraindicated for women with a high risk of arterial or venous thrombotic diseases; a history of breast cancer or another estrogen- or progestin-sensitive cancer; liver tumors, acute hepatitis, or severe (decompensated) cirrhosis; undiagnosed abnormal uterine bleeding; hypersensitivity to any of the components of Annovera; and use of hepatitis C drug combinations containing ombitasvir/paritaprevir/ritonavir, with or without dasabuvir, according to an FDA press release.
The most common side effects of Annovera are similar to those of other combined hormonal contraceptive products and include headache, nausea and vomiting, yeast infections, abdominal pain, dysmenorrhea, breast tenderness, irregular bleeding, diarrhea, and genital itching.
The FDA is requiring postmarketing studies to further evaluate the risks of venous thromboembolism and the effects of CYP3A-modulating drugs and tampon use on the pharmacokinetics of Annovera.
It is very exciting to see ongoing research and development for new contraceptives and approval of these new methods! We know that each person’s contraceptive needs are unique and having more options from which to choose will help us as providers connect our patients to methods that meet their goals and individual needs. These two methods fill important gaps in our current contraceptive portfolio: a patient-controlled, long-acting method and a facilitated non-hormonal, non-prescription method (the Natural Cycles app). I am looking forward to hearing feedback from patients about their thoughts and experiences with these new methods.
Melissa Kottke, MD, MPH, MBA, is an associate professor of obstetrics and gynecology and director of the Jane Fonda Center for Adolescent Reproductive Health, Emory University, Atlanta.
It is very exciting to see ongoing research and development for new contraceptives and approval of these new methods! We know that each person’s contraceptive needs are unique and having more options from which to choose will help us as providers connect our patients to methods that meet their goals and individual needs. These two methods fill important gaps in our current contraceptive portfolio: a patient-controlled, long-acting method and a facilitated non-hormonal, non-prescription method (the Natural Cycles app). I am looking forward to hearing feedback from patients about their thoughts and experiences with these new methods.
Melissa Kottke, MD, MPH, MBA, is an associate professor of obstetrics and gynecology and director of the Jane Fonda Center for Adolescent Reproductive Health, Emory University, Atlanta.
It is very exciting to see ongoing research and development for new contraceptives and approval of these new methods! We know that each person’s contraceptive needs are unique and having more options from which to choose will help us as providers connect our patients to methods that meet their goals and individual needs. These two methods fill important gaps in our current contraceptive portfolio: a patient-controlled, long-acting method and a facilitated non-hormonal, non-prescription method (the Natural Cycles app). I am looking forward to hearing feedback from patients about their thoughts and experiences with these new methods.
Melissa Kottke, MD, MPH, MBA, is an associate professor of obstetrics and gynecology and director of the Jane Fonda Center for Adolescent Reproductive Health, Emory University, Atlanta.
The first vaginal ring contraceptive that can be used for 1 year has been approved by the Food and Drug Administration.
The FDA granted approval of Annovera (segesterone acetate and ethinyl estradiol vaginal system), a reusable donut-shaped ring, to the Population Council. The nonbiodegradable, flexible vaginal system is placed in the vagina for 3 weeks followed by 1 week out of the vagina, at which time women may experience a menstrual period. This schedule is repeated every 4 weeks for 13 28-day menstrual cycles.
The contraceptive ring is washed and stored in a compact case for the 7 days when it is not in use. Annovera does not require refrigeration prior to dispensing and can withstand storage temperatures up to 30° C (86° F).
“Today’s approval builds on available birth control options,” said Victor Crentsil, MD, acting deputy director of the Office of Drug Evaluation III in FDA’s Center for Drug Evaluation and Research.
The efficacy and safety of Annovera were studied in three, open-label clinical trials with healthy women ranging from 18 to 40 years of age. Based on the results, about 2%-4% of women may get pregnant during the first year they use Annovera.
Annovera carries a boxed warning regarding cigarette smoking and serious cardiovascular events. Women over age 35 who smoke should not use Annovera. Cigarette smoking increases the risk of serious cardiovascular events from combination hormonal contraceptive use.
Annovera is contraindicated for women with a high risk of arterial or venous thrombotic diseases; a history of breast cancer or another estrogen- or progestin-sensitive cancer; liver tumors, acute hepatitis, or severe (decompensated) cirrhosis; undiagnosed abnormal uterine bleeding; hypersensitivity to any of the components of Annovera; and use of hepatitis C drug combinations containing ombitasvir/paritaprevir/ritonavir, with or without dasabuvir, according to an FDA press release.
The most common side effects of Annovera are similar to those of other combined hormonal contraceptive products and include headache, nausea and vomiting, yeast infections, abdominal pain, dysmenorrhea, breast tenderness, irregular bleeding, diarrhea, and genital itching.
The FDA is requiring postmarketing studies to further evaluate the risks of venous thromboembolism and the effects of CYP3A-modulating drugs and tampon use on the pharmacokinetics of Annovera.
The first vaginal ring contraceptive that can be used for 1 year has been approved by the Food and Drug Administration.
The FDA granted approval of Annovera (segesterone acetate and ethinyl estradiol vaginal system), a reusable donut-shaped ring, to the Population Council. The nonbiodegradable, flexible vaginal system is placed in the vagina for 3 weeks followed by 1 week out of the vagina, at which time women may experience a menstrual period. This schedule is repeated every 4 weeks for 13 28-day menstrual cycles.
The contraceptive ring is washed and stored in a compact case for the 7 days when it is not in use. Annovera does not require refrigeration prior to dispensing and can withstand storage temperatures up to 30° C (86° F).
“Today’s approval builds on available birth control options,” said Victor Crentsil, MD, acting deputy director of the Office of Drug Evaluation III in FDA’s Center for Drug Evaluation and Research.
The efficacy and safety of Annovera were studied in three, open-label clinical trials with healthy women ranging from 18 to 40 years of age. Based on the results, about 2%-4% of women may get pregnant during the first year they use Annovera.
Annovera carries a boxed warning regarding cigarette smoking and serious cardiovascular events. Women over age 35 who smoke should not use Annovera. Cigarette smoking increases the risk of serious cardiovascular events from combination hormonal contraceptive use.
Annovera is contraindicated for women with a high risk of arterial or venous thrombotic diseases; a history of breast cancer or another estrogen- or progestin-sensitive cancer; liver tumors, acute hepatitis, or severe (decompensated) cirrhosis; undiagnosed abnormal uterine bleeding; hypersensitivity to any of the components of Annovera; and use of hepatitis C drug combinations containing ombitasvir/paritaprevir/ritonavir, with or without dasabuvir, according to an FDA press release.
The most common side effects of Annovera are similar to those of other combined hormonal contraceptive products and include headache, nausea and vomiting, yeast infections, abdominal pain, dysmenorrhea, breast tenderness, irregular bleeding, diarrhea, and genital itching.
The FDA is requiring postmarketing studies to further evaluate the risks of venous thromboembolism and the effects of CYP3A-modulating drugs and tampon use on the pharmacokinetics of Annovera.
FDA approves Nivestym, second biosimilar to Neupogen
Nivestym (filgrastim-aafi), a biosimilar to Neupogen (filgrastim) was approved July 20 by the Food and Drug Administration, according to a statement provided by the agency. Nivestym is the second biosimilar to Neupogen to be approved in the United States.
- Patients with cancer receiving myelosuppressive chemotherapy.
- Patients with acute myeloid leukemia receiving induction or consolidation chemotherapy.
- Patients with cancer undergoing bone marrow transplantation.
- Patients undergoing autologous peripheral blood progenitor cell collection and therapy.
- Patients with severe chronic neutropenia.
According to a press release from Pfizer, the manufacturer of the biosimilar, Nivestym is expected to be available in the United States at a significant discount to the current wholesale acquisition cost of Neupogen, which is not inclusive of discounts to payers, providers, distributors, and other purchasing organizations.
The FDA statement notes that a biosimilar is approved based on a showing that it is highly similar to an already approved biologic product, known as a reference product. The biosimilar also must be shown to have no clinically meaningful differences in terms of safety and effectiveness from the reference product. Only minor differences in clinically inactive components are allowable in biosimilar products.
Prescribing information is available here.
Nivestym (filgrastim-aafi), a biosimilar to Neupogen (filgrastim) was approved July 20 by the Food and Drug Administration, according to a statement provided by the agency. Nivestym is the second biosimilar to Neupogen to be approved in the United States.
- Patients with cancer receiving myelosuppressive chemotherapy.
- Patients with acute myeloid leukemia receiving induction or consolidation chemotherapy.
- Patients with cancer undergoing bone marrow transplantation.
- Patients undergoing autologous peripheral blood progenitor cell collection and therapy.
- Patients with severe chronic neutropenia.
According to a press release from Pfizer, the manufacturer of the biosimilar, Nivestym is expected to be available in the United States at a significant discount to the current wholesale acquisition cost of Neupogen, which is not inclusive of discounts to payers, providers, distributors, and other purchasing organizations.
The FDA statement notes that a biosimilar is approved based on a showing that it is highly similar to an already approved biologic product, known as a reference product. The biosimilar also must be shown to have no clinically meaningful differences in terms of safety and effectiveness from the reference product. Only minor differences in clinically inactive components are allowable in biosimilar products.
Prescribing information is available here.
Nivestym (filgrastim-aafi), a biosimilar to Neupogen (filgrastim) was approved July 20 by the Food and Drug Administration, according to a statement provided by the agency. Nivestym is the second biosimilar to Neupogen to be approved in the United States.
- Patients with cancer receiving myelosuppressive chemotherapy.
- Patients with acute myeloid leukemia receiving induction or consolidation chemotherapy.
- Patients with cancer undergoing bone marrow transplantation.
- Patients undergoing autologous peripheral blood progenitor cell collection and therapy.
- Patients with severe chronic neutropenia.
According to a press release from Pfizer, the manufacturer of the biosimilar, Nivestym is expected to be available in the United States at a significant discount to the current wholesale acquisition cost of Neupogen, which is not inclusive of discounts to payers, providers, distributors, and other purchasing organizations.
The FDA statement notes that a biosimilar is approved based on a showing that it is highly similar to an already approved biologic product, known as a reference product. The biosimilar also must be shown to have no clinically meaningful differences in terms of safety and effectiveness from the reference product. Only minor differences in clinically inactive components are allowable in biosimilar products.
Prescribing information is available here.
Essure sales to halt in U.S. by end of 2018
The Essure permanent birth control device will no longer be sold or distributed after Dec. 31, 2018, in the United States.
Bayer, the manufacturer of Essure, notified the Food and Drug Administration of its decision to halt U.S. sales of the device, Commissioner Scott Gottlieb, MD, announced July 20 in a press release. Dr. Gottlieb added that the agency would continue its commitment to postmarketing review of Essure. “We expect Bayer to meet its postmarket obligations concerning this device.”
Since its approval, Essure is estimated to have been used by more than 750,000 patients worldwide, the FDA release stated. The device has been associated with serious risks, including persistent pain, perforation of the uterus and fallopian tubes, and migration of the coils into the pelvis or abdomen.
“In April, when the FDA became aware that many patients were not being adequately counseled, we required a restriction, which limits the sale and distribution of the device to only health care providers and facilities that provide information to patients about the risks and benefits of this device and gives patients the opportunity to sign an acknowledgment that they fully understood these potential risks before having the device implanted. Since the FDA ordered Bayer to conduct the postmarket study and then to add a boxed warning and a Patient Decision Checklist to the labeling, there has been an approximate 70% decline in sales of Essure in the United States,” Dr. Gottlieb said in the FDA press release. The company stated its decision to halt sales and distribution of the device was because of commercial reasons.
“Numerous adverse events ... were reported to the FDA, including a significant collection of recent reports that have mentioned issues involving surgery to remove the device. We’re continuing our evaluation of these reports to better understand reasons for the device removal. The agency is committed to continuing to provide updates on our evaluation of this data as the information is collected and we develop new findings about the device.”
In September 2015, the FDA convened an expert panel to examine and follow up on complaints from Essure users that included abdominal pain, abnormal uterine bleeding, and device migration. In February 2016, the FDA ordered Bayer to conduct a postmarket (522) study to better evaluate the safety profile of the device when used in the real world. The following October, the agency issued the final guidance, “Labeling for Permanent Hysteroscopically Placed Tubal Implants Intended for Sterilization.” Soon thereafter, the FDA approved updated labeling for Essure that added a boxed warning and a Patient Decision Checklist.
In March 2018, the FDA reported a rise in new medical device reports submitted to the agency’s public database in 2017, with more than 90% of the reports involving potential device removal. The April restriction of sales and distribution was in response to concerns that not every patient was receiving adequate risk information.
“I want to stress that, even when Essure is no longer sold, the FDA will remain vigilant in protecting patients who’ve already had this device implanted. We’ll continue to monitor adverse events reported to our database, as well as other data sources. And we’ll communicate publicly on any new findings or concerns. The restriction on sale and distribution will remain in place. Regarding the postmarket 522 study, Bayer will continue to enroll new participants. Each study participant will be followed for a total of 3 years, and the company will continue to submit reports to the FDA on the study’s progress and results. Since Bayer will not be able to meet its expected enrollment numbers for this study that relied on enrolling patients who were newly implanted with Essure, we’ll be working with the company to best determine how to move forward to answer the critical questions we posed concerning certain patient complications that may be experienced by patients who have Essure,” Dr. Gottlieb stated.
He added that women who are using Essure successfully to prevent pregnancy should continue to do so, as “device removal has its own risks.”
The Essure permanent birth control device will no longer be sold or distributed after Dec. 31, 2018, in the United States.
Bayer, the manufacturer of Essure, notified the Food and Drug Administration of its decision to halt U.S. sales of the device, Commissioner Scott Gottlieb, MD, announced July 20 in a press release. Dr. Gottlieb added that the agency would continue its commitment to postmarketing review of Essure. “We expect Bayer to meet its postmarket obligations concerning this device.”
Since its approval, Essure is estimated to have been used by more than 750,000 patients worldwide, the FDA release stated. The device has been associated with serious risks, including persistent pain, perforation of the uterus and fallopian tubes, and migration of the coils into the pelvis or abdomen.
“In April, when the FDA became aware that many patients were not being adequately counseled, we required a restriction, which limits the sale and distribution of the device to only health care providers and facilities that provide information to patients about the risks and benefits of this device and gives patients the opportunity to sign an acknowledgment that they fully understood these potential risks before having the device implanted. Since the FDA ordered Bayer to conduct the postmarket study and then to add a boxed warning and a Patient Decision Checklist to the labeling, there has been an approximate 70% decline in sales of Essure in the United States,” Dr. Gottlieb said in the FDA press release. The company stated its decision to halt sales and distribution of the device was because of commercial reasons.
“Numerous adverse events ... were reported to the FDA, including a significant collection of recent reports that have mentioned issues involving surgery to remove the device. We’re continuing our evaluation of these reports to better understand reasons for the device removal. The agency is committed to continuing to provide updates on our evaluation of this data as the information is collected and we develop new findings about the device.”
In September 2015, the FDA convened an expert panel to examine and follow up on complaints from Essure users that included abdominal pain, abnormal uterine bleeding, and device migration. In February 2016, the FDA ordered Bayer to conduct a postmarket (522) study to better evaluate the safety profile of the device when used in the real world. The following October, the agency issued the final guidance, “Labeling for Permanent Hysteroscopically Placed Tubal Implants Intended for Sterilization.” Soon thereafter, the FDA approved updated labeling for Essure that added a boxed warning and a Patient Decision Checklist.
In March 2018, the FDA reported a rise in new medical device reports submitted to the agency’s public database in 2017, with more than 90% of the reports involving potential device removal. The April restriction of sales and distribution was in response to concerns that not every patient was receiving adequate risk information.
“I want to stress that, even when Essure is no longer sold, the FDA will remain vigilant in protecting patients who’ve already had this device implanted. We’ll continue to monitor adverse events reported to our database, as well as other data sources. And we’ll communicate publicly on any new findings or concerns. The restriction on sale and distribution will remain in place. Regarding the postmarket 522 study, Bayer will continue to enroll new participants. Each study participant will be followed for a total of 3 years, and the company will continue to submit reports to the FDA on the study’s progress and results. Since Bayer will not be able to meet its expected enrollment numbers for this study that relied on enrolling patients who were newly implanted with Essure, we’ll be working with the company to best determine how to move forward to answer the critical questions we posed concerning certain patient complications that may be experienced by patients who have Essure,” Dr. Gottlieb stated.
He added that women who are using Essure successfully to prevent pregnancy should continue to do so, as “device removal has its own risks.”
The Essure permanent birth control device will no longer be sold or distributed after Dec. 31, 2018, in the United States.
Bayer, the manufacturer of Essure, notified the Food and Drug Administration of its decision to halt U.S. sales of the device, Commissioner Scott Gottlieb, MD, announced July 20 in a press release. Dr. Gottlieb added that the agency would continue its commitment to postmarketing review of Essure. “We expect Bayer to meet its postmarket obligations concerning this device.”
Since its approval, Essure is estimated to have been used by more than 750,000 patients worldwide, the FDA release stated. The device has been associated with serious risks, including persistent pain, perforation of the uterus and fallopian tubes, and migration of the coils into the pelvis or abdomen.
“In April, when the FDA became aware that many patients were not being adequately counseled, we required a restriction, which limits the sale and distribution of the device to only health care providers and facilities that provide information to patients about the risks and benefits of this device and gives patients the opportunity to sign an acknowledgment that they fully understood these potential risks before having the device implanted. Since the FDA ordered Bayer to conduct the postmarket study and then to add a boxed warning and a Patient Decision Checklist to the labeling, there has been an approximate 70% decline in sales of Essure in the United States,” Dr. Gottlieb said in the FDA press release. The company stated its decision to halt sales and distribution of the device was because of commercial reasons.
“Numerous adverse events ... were reported to the FDA, including a significant collection of recent reports that have mentioned issues involving surgery to remove the device. We’re continuing our evaluation of these reports to better understand reasons for the device removal. The agency is committed to continuing to provide updates on our evaluation of this data as the information is collected and we develop new findings about the device.”
In September 2015, the FDA convened an expert panel to examine and follow up on complaints from Essure users that included abdominal pain, abnormal uterine bleeding, and device migration. In February 2016, the FDA ordered Bayer to conduct a postmarket (522) study to better evaluate the safety profile of the device when used in the real world. The following October, the agency issued the final guidance, “Labeling for Permanent Hysteroscopically Placed Tubal Implants Intended for Sterilization.” Soon thereafter, the FDA approved updated labeling for Essure that added a boxed warning and a Patient Decision Checklist.
In March 2018, the FDA reported a rise in new medical device reports submitted to the agency’s public database in 2017, with more than 90% of the reports involving potential device removal. The April restriction of sales and distribution was in response to concerns that not every patient was receiving adequate risk information.
“I want to stress that, even when Essure is no longer sold, the FDA will remain vigilant in protecting patients who’ve already had this device implanted. We’ll continue to monitor adverse events reported to our database, as well as other data sources. And we’ll communicate publicly on any new findings or concerns. The restriction on sale and distribution will remain in place. Regarding the postmarket 522 study, Bayer will continue to enroll new participants. Each study participant will be followed for a total of 3 years, and the company will continue to submit reports to the FDA on the study’s progress and results. Since Bayer will not be able to meet its expected enrollment numbers for this study that relied on enrolling patients who were newly implanted with Essure, we’ll be working with the company to best determine how to move forward to answer the critical questions we posed concerning certain patient complications that may be experienced by patients who have Essure,” Dr. Gottlieb stated.
He added that women who are using Essure successfully to prevent pregnancy should continue to do so, as “device removal has its own risks.”