User login
Genetic testing for best antidepressant accurate, cost effective
new research suggests.
CYP2D6 and CYP2C19, from the cytochrome P450 family, are involved in the metabolism and elimination of various molecules, including medications. Variants in the genes encoding these enzymes affect the speed at which drugs are metabolized, altering their pharmacokinetic profiles.
The researchers studied 125 patients with MDD and used CYP2D6 and CYP2C19 genotyping to determine the presence of actionable phenotypes in line with Food and Drug Administration labeling.
They found that, in many cases, pharmacogenetic testing could have predicted poor response to the initial treatment selection and could have helped guide subsequent choices to improve outcomes.
In addition, a pharmacoeconomic evaluation that combined direct and indirect costs resulting from MDD with the prevalence of CYP2D6 and CYP2C19 phenotypes showed that testing for functional variants in both genes would be cost effective at a national level.
Had psychiatrists who treated patients in the study known about their metabolizing profiles, it “might have contributed to switches in medication” and could have reduced “delays in response,” said lead researcher Alessio Squassina, PhD, associate professor of pharmacology at the University of Cagliari (Italy).
The findings were presented at the European Psychiatric Association 2022 Congress.
Highly variable response rates
Dr. Squassina noted that the response to antidepressants is a “highly variable trait,” and while it is known that genetics play a role, their contribution is “still not completely understood.”
He explained that the use of pharmacogenetics, which leverages genetic information to guide treatment decision-making, has increased significantly.
While regulatory bodies, including the FDA, have been “very active” in defining strict criteria for interpreting the information from pharmacogenetic tests, there remains some “discrepancy” in their clinical utility.
Dr. Squassina said the FDA provides guidance on use of genetic testing on the labels of 34 psychiatric medications. Of these, 79% relate to CYP2D6, 12% relate to CYP2C19, and 9% relate to other genes.
These labels provide guidance on when genetic testing is recommended or required, as well as potentially clinically actionable gene-drug associations in patients with certain functional alleles.
However, Dr. Squassina noted that the distribution of such alleles is not the same across Europe, so it’s possible that a psychiatrist in Italy may be less likely to treat a patient with a phenotype affecting response to treatment or risk of adverse events than one in Norway or Sweden.
For the study, the investigators examined the frequency of CYP2D6 and CYP2C19 phenotypes in psychiatric patients in Sardinia and their relationship with pharmacologic treatment and cost-effectiveness.
They set out to recruit 200 patients with MDD who had a documented 5-year medical and treatment history, including alterations in treatment, adverse events, hospitalizations, suicide, and symptom scores, as well as sociodemographic variables.
An interim analysis of the first 125 patients recruited to the study showed that the most common CYP2D6 phenotype was normal metabolizers (NM), at 60.5%, followed by intermediate metabolizers (IM), at 28.2%, ultrarapid metabolizers (UR), at 8.9%, and poor metabolizers (PM), at 2.4%.
For CYP2C19, the most common phenotype was NM (49%), followed by IM (29.0%), UR (25.0%), and PM (4.0%). While there were differences in the overall European averages, they were not significant.
To highlight the potential impact that pharmacogenetic testing could have had on patient care and outcome, Dr. Squassina highlighted two cases.
The first concerned a patient with a CYP2D6 IM and CYP2C19 UR phenotype, who did not respond to escitalopram. The FDA drug label indicates this phenotype is actionable and recommends an alternative drug.
The patient was subsequently switched to venlafaxine. The FDA drug label on venlafaxine notes that patients with this phenotype are likely to have a suboptimal response to this drug, and again, this patient did not respond to treatment.
Another patient with a CYP2D6 NM and CYP2C19 IM phenotype was also prescribed escitalopram. The FDA label on this drug notes that patients with this phenotype can try venlafaxine but may not respond. Indeed, this patient did not respond and was switched to venlafaxine and started responding.
“The psychiatrists [in these cases] may made have made different [drug] choices if they had known the genotypes in advance,” Dr. Squassina said.
Cost effective?
To determine the cost-effectiveness of screening for CYP2D6 and CYP2C19 phenotypes in patients with MDD, the researchers used real-world data to develop a Markov model with a hypothetical cohort of 2000 MDD patients, half of whom underwent pharmacogenetic testing, to determine the potential impact on outcomes over an 18-week period.
The model included the cost of medications and hospitalization, psychiatric counseling, loss of productivity, and the estimated probability of response and adverse events, adjusted for the patient’s likelihood of having a particular metabolizing phenotype.
Results showed that, for CYP2C19, compared to no testing, pharmacogenetic testing would be cost-effective at an incremental cost-effective ratio (ICER) of €60,000 ($64,000 USD) per quality-adjusted life-year (QALY).
This, Squassina said, is “below the willingness to pay threshold” for health authorities in developed countries.
For CYP2D6, pharmacogenetic testing would become cost-effective at an ICER of approximately €47,000 ($40,000 USD) per QALY.
The team plans to complete recruitment and perform a “detailed evaluation of all the variables, especially those relating to the medication history and changes in dosage, and adverse drug reactions.” The researchers would also like to study genetic phenotypes for other metabolizing enzymes and repeat the pharmacoeconomic analysis with the complete dataset.
A glimpse into the future
Approached for comment, Alessandro Serretti, MD, PhD, department of biomedical and neuromotor sciences, University of Bologna (Italy), who was not involved in the study, said the findings show there is a “small but evident benefit” from CYP profiling, “which makes sense.”
He added that in the Netherlands and other European countries, efforts are already underway to record the CYP status of patients at a national level. “Sooner or later, all Western countries will implement it as a routine,” he said in an interview.
He explained that, when such testing is widely available, electronic health record data will allow physicians to immediately select the optimal antidepressant for an individual patient. This will end the current trial-and-error process that leads to delayed treatment and will help avoid serious consequences, such as suicide.
While reducing a single patient’s treatment by a few weeks with the most appropriate antidepressant choice does not make a large difference in the cost per episode, at a population level, it has the potential to make a significant difference.
Dr. Serretti does not envisage genotyping all 333 million Europeans for the CYP phenotype at this point but imagines that in the future, individuals will undergo whole-genome sequencing to determine risks for cancer, dementia, and heart disease, at which point they will also undergo CYP functional allele profiling, and all these data will be recorded on individuals’ EHR.
“So, every doctor, a psychiatrist or cardiologist, can see everything, whenever they need it,” he said.
The study was funded by Fondazione di Sardegna and Regione Autonoma della Sardegna. The authors disclosed no relevant financial relationships.
A version of this article first appeared on Medscape.com.
new research suggests.
CYP2D6 and CYP2C19, from the cytochrome P450 family, are involved in the metabolism and elimination of various molecules, including medications. Variants in the genes encoding these enzymes affect the speed at which drugs are metabolized, altering their pharmacokinetic profiles.
The researchers studied 125 patients with MDD and used CYP2D6 and CYP2C19 genotyping to determine the presence of actionable phenotypes in line with Food and Drug Administration labeling.
They found that, in many cases, pharmacogenetic testing could have predicted poor response to the initial treatment selection and could have helped guide subsequent choices to improve outcomes.
In addition, a pharmacoeconomic evaluation that combined direct and indirect costs resulting from MDD with the prevalence of CYP2D6 and CYP2C19 phenotypes showed that testing for functional variants in both genes would be cost effective at a national level.
Had psychiatrists who treated patients in the study known about their metabolizing profiles, it “might have contributed to switches in medication” and could have reduced “delays in response,” said lead researcher Alessio Squassina, PhD, associate professor of pharmacology at the University of Cagliari (Italy).
The findings were presented at the European Psychiatric Association 2022 Congress.
Highly variable response rates
Dr. Squassina noted that the response to antidepressants is a “highly variable trait,” and while it is known that genetics play a role, their contribution is “still not completely understood.”
He explained that the use of pharmacogenetics, which leverages genetic information to guide treatment decision-making, has increased significantly.
While regulatory bodies, including the FDA, have been “very active” in defining strict criteria for interpreting the information from pharmacogenetic tests, there remains some “discrepancy” in their clinical utility.
Dr. Squassina said the FDA provides guidance on use of genetic testing on the labels of 34 psychiatric medications. Of these, 79% relate to CYP2D6, 12% relate to CYP2C19, and 9% relate to other genes.
These labels provide guidance on when genetic testing is recommended or required, as well as potentially clinically actionable gene-drug associations in patients with certain functional alleles.
However, Dr. Squassina noted that the distribution of such alleles is not the same across Europe, so it’s possible that a psychiatrist in Italy may be less likely to treat a patient with a phenotype affecting response to treatment or risk of adverse events than one in Norway or Sweden.
For the study, the investigators examined the frequency of CYP2D6 and CYP2C19 phenotypes in psychiatric patients in Sardinia and their relationship with pharmacologic treatment and cost-effectiveness.
They set out to recruit 200 patients with MDD who had a documented 5-year medical and treatment history, including alterations in treatment, adverse events, hospitalizations, suicide, and symptom scores, as well as sociodemographic variables.
An interim analysis of the first 125 patients recruited to the study showed that the most common CYP2D6 phenotype was normal metabolizers (NM), at 60.5%, followed by intermediate metabolizers (IM), at 28.2%, ultrarapid metabolizers (UR), at 8.9%, and poor metabolizers (PM), at 2.4%.
For CYP2C19, the most common phenotype was NM (49%), followed by IM (29.0%), UR (25.0%), and PM (4.0%). While there were differences in the overall European averages, they were not significant.
To highlight the potential impact that pharmacogenetic testing could have had on patient care and outcome, Dr. Squassina highlighted two cases.
The first concerned a patient with a CYP2D6 IM and CYP2C19 UR phenotype, who did not respond to escitalopram. The FDA drug label indicates this phenotype is actionable and recommends an alternative drug.
The patient was subsequently switched to venlafaxine. The FDA drug label on venlafaxine notes that patients with this phenotype are likely to have a suboptimal response to this drug, and again, this patient did not respond to treatment.
Another patient with a CYP2D6 NM and CYP2C19 IM phenotype was also prescribed escitalopram. The FDA label on this drug notes that patients with this phenotype can try venlafaxine but may not respond. Indeed, this patient did not respond and was switched to venlafaxine and started responding.
“The psychiatrists [in these cases] may made have made different [drug] choices if they had known the genotypes in advance,” Dr. Squassina said.
Cost effective?
To determine the cost-effectiveness of screening for CYP2D6 and CYP2C19 phenotypes in patients with MDD, the researchers used real-world data to develop a Markov model with a hypothetical cohort of 2000 MDD patients, half of whom underwent pharmacogenetic testing, to determine the potential impact on outcomes over an 18-week period.
The model included the cost of medications and hospitalization, psychiatric counseling, loss of productivity, and the estimated probability of response and adverse events, adjusted for the patient’s likelihood of having a particular metabolizing phenotype.
Results showed that, for CYP2C19, compared to no testing, pharmacogenetic testing would be cost-effective at an incremental cost-effective ratio (ICER) of €60,000 ($64,000 USD) per quality-adjusted life-year (QALY).
This, Squassina said, is “below the willingness to pay threshold” for health authorities in developed countries.
For CYP2D6, pharmacogenetic testing would become cost-effective at an ICER of approximately €47,000 ($40,000 USD) per QALY.
The team plans to complete recruitment and perform a “detailed evaluation of all the variables, especially those relating to the medication history and changes in dosage, and adverse drug reactions.” The researchers would also like to study genetic phenotypes for other metabolizing enzymes and repeat the pharmacoeconomic analysis with the complete dataset.
A glimpse into the future
Approached for comment, Alessandro Serretti, MD, PhD, department of biomedical and neuromotor sciences, University of Bologna (Italy), who was not involved in the study, said the findings show there is a “small but evident benefit” from CYP profiling, “which makes sense.”
He added that in the Netherlands and other European countries, efforts are already underway to record the CYP status of patients at a national level. “Sooner or later, all Western countries will implement it as a routine,” he said in an interview.
He explained that, when such testing is widely available, electronic health record data will allow physicians to immediately select the optimal antidepressant for an individual patient. This will end the current trial-and-error process that leads to delayed treatment and will help avoid serious consequences, such as suicide.
While reducing a single patient’s treatment by a few weeks with the most appropriate antidepressant choice does not make a large difference in the cost per episode, at a population level, it has the potential to make a significant difference.
Dr. Serretti does not envisage genotyping all 333 million Europeans for the CYP phenotype at this point but imagines that in the future, individuals will undergo whole-genome sequencing to determine risks for cancer, dementia, and heart disease, at which point they will also undergo CYP functional allele profiling, and all these data will be recorded on individuals’ EHR.
“So, every doctor, a psychiatrist or cardiologist, can see everything, whenever they need it,” he said.
The study was funded by Fondazione di Sardegna and Regione Autonoma della Sardegna. The authors disclosed no relevant financial relationships.
A version of this article first appeared on Medscape.com.
new research suggests.
CYP2D6 and CYP2C19, from the cytochrome P450 family, are involved in the metabolism and elimination of various molecules, including medications. Variants in the genes encoding these enzymes affect the speed at which drugs are metabolized, altering their pharmacokinetic profiles.
The researchers studied 125 patients with MDD and used CYP2D6 and CYP2C19 genotyping to determine the presence of actionable phenotypes in line with Food and Drug Administration labeling.
They found that, in many cases, pharmacogenetic testing could have predicted poor response to the initial treatment selection and could have helped guide subsequent choices to improve outcomes.
In addition, a pharmacoeconomic evaluation that combined direct and indirect costs resulting from MDD with the prevalence of CYP2D6 and CYP2C19 phenotypes showed that testing for functional variants in both genes would be cost effective at a national level.
Had psychiatrists who treated patients in the study known about their metabolizing profiles, it “might have contributed to switches in medication” and could have reduced “delays in response,” said lead researcher Alessio Squassina, PhD, associate professor of pharmacology at the University of Cagliari (Italy).
The findings were presented at the European Psychiatric Association 2022 Congress.
Highly variable response rates
Dr. Squassina noted that the response to antidepressants is a “highly variable trait,” and while it is known that genetics play a role, their contribution is “still not completely understood.”
He explained that the use of pharmacogenetics, which leverages genetic information to guide treatment decision-making, has increased significantly.
While regulatory bodies, including the FDA, have been “very active” in defining strict criteria for interpreting the information from pharmacogenetic tests, there remains some “discrepancy” in their clinical utility.
Dr. Squassina said the FDA provides guidance on use of genetic testing on the labels of 34 psychiatric medications. Of these, 79% relate to CYP2D6, 12% relate to CYP2C19, and 9% relate to other genes.
These labels provide guidance on when genetic testing is recommended or required, as well as potentially clinically actionable gene-drug associations in patients with certain functional alleles.
However, Dr. Squassina noted that the distribution of such alleles is not the same across Europe, so it’s possible that a psychiatrist in Italy may be less likely to treat a patient with a phenotype affecting response to treatment or risk of adverse events than one in Norway or Sweden.
For the study, the investigators examined the frequency of CYP2D6 and CYP2C19 phenotypes in psychiatric patients in Sardinia and their relationship with pharmacologic treatment and cost-effectiveness.
They set out to recruit 200 patients with MDD who had a documented 5-year medical and treatment history, including alterations in treatment, adverse events, hospitalizations, suicide, and symptom scores, as well as sociodemographic variables.
An interim analysis of the first 125 patients recruited to the study showed that the most common CYP2D6 phenotype was normal metabolizers (NM), at 60.5%, followed by intermediate metabolizers (IM), at 28.2%, ultrarapid metabolizers (UR), at 8.9%, and poor metabolizers (PM), at 2.4%.
For CYP2C19, the most common phenotype was NM (49%), followed by IM (29.0%), UR (25.0%), and PM (4.0%). While there were differences in the overall European averages, they were not significant.
To highlight the potential impact that pharmacogenetic testing could have had on patient care and outcome, Dr. Squassina highlighted two cases.
The first concerned a patient with a CYP2D6 IM and CYP2C19 UR phenotype, who did not respond to escitalopram. The FDA drug label indicates this phenotype is actionable and recommends an alternative drug.
The patient was subsequently switched to venlafaxine. The FDA drug label on venlafaxine notes that patients with this phenotype are likely to have a suboptimal response to this drug, and again, this patient did not respond to treatment.
Another patient with a CYP2D6 NM and CYP2C19 IM phenotype was also prescribed escitalopram. The FDA label on this drug notes that patients with this phenotype can try venlafaxine but may not respond. Indeed, this patient did not respond and was switched to venlafaxine and started responding.
“The psychiatrists [in these cases] may made have made different [drug] choices if they had known the genotypes in advance,” Dr. Squassina said.
Cost effective?
To determine the cost-effectiveness of screening for CYP2D6 and CYP2C19 phenotypes in patients with MDD, the researchers used real-world data to develop a Markov model with a hypothetical cohort of 2000 MDD patients, half of whom underwent pharmacogenetic testing, to determine the potential impact on outcomes over an 18-week period.
The model included the cost of medications and hospitalization, psychiatric counseling, loss of productivity, and the estimated probability of response and adverse events, adjusted for the patient’s likelihood of having a particular metabolizing phenotype.
Results showed that, for CYP2C19, compared to no testing, pharmacogenetic testing would be cost-effective at an incremental cost-effective ratio (ICER) of €60,000 ($64,000 USD) per quality-adjusted life-year (QALY).
This, Squassina said, is “below the willingness to pay threshold” for health authorities in developed countries.
For CYP2D6, pharmacogenetic testing would become cost-effective at an ICER of approximately €47,000 ($40,000 USD) per QALY.
The team plans to complete recruitment and perform a “detailed evaluation of all the variables, especially those relating to the medication history and changes in dosage, and adverse drug reactions.” The researchers would also like to study genetic phenotypes for other metabolizing enzymes and repeat the pharmacoeconomic analysis with the complete dataset.
A glimpse into the future
Approached for comment, Alessandro Serretti, MD, PhD, department of biomedical and neuromotor sciences, University of Bologna (Italy), who was not involved in the study, said the findings show there is a “small but evident benefit” from CYP profiling, “which makes sense.”
He added that in the Netherlands and other European countries, efforts are already underway to record the CYP status of patients at a national level. “Sooner or later, all Western countries will implement it as a routine,” he said in an interview.
He explained that, when such testing is widely available, electronic health record data will allow physicians to immediately select the optimal antidepressant for an individual patient. This will end the current trial-and-error process that leads to delayed treatment and will help avoid serious consequences, such as suicide.
While reducing a single patient’s treatment by a few weeks with the most appropriate antidepressant choice does not make a large difference in the cost per episode, at a population level, it has the potential to make a significant difference.
Dr. Serretti does not envisage genotyping all 333 million Europeans for the CYP phenotype at this point but imagines that in the future, individuals will undergo whole-genome sequencing to determine risks for cancer, dementia, and heart disease, at which point they will also undergo CYP functional allele profiling, and all these data will be recorded on individuals’ EHR.
“So, every doctor, a psychiatrist or cardiologist, can see everything, whenever they need it,” he said.
The study was funded by Fondazione di Sardegna and Regione Autonoma della Sardegna. The authors disclosed no relevant financial relationships.
A version of this article first appeared on Medscape.com.
FROM EPA 2022
In utero COVID exposure tied to developmental differences in infants
suggests a small-scale analysis that points to the need for further study and monitoring during pregnancy.
The study included 24 pregnant women, half of whom had COVID-19 during pregnancy, and their offspring. It showed impairments at 6 weeks of age on the social interactive dimension of a neonatal assessment.
“Not all babies born to mothers infected with COVID show neurodevelopmental differences, but our data show that their risk is increased in comparison to those not exposed to COVID in the womb. We need a bigger study to confirm the exact extent of the difference,” said lead researcher Rosa Ayesa Arriola, PhD, Valdecilla Research Institute (IDIVAL), Hospital Universitario Marqués de Valdecilla, Santander, Spain, in a release.
The findings were presented at the virtual European Psychiatric Association 2022 Congress.
Differing responses to cuddling
Coauthor Águeda Castro Quintas, PhD student, Network Centre for Biomedical Research in Mental Health, University of Barcelona, explained that the tests showed the children born to mothers who had COVID-19 during pregnancy reacted “slightly differently to being held, or cuddled.”
“We need to note that these are preliminary results, but this is part of a project following a larger sample of 100 mothers and their babies,” she added. The authors plan to compare their results with those from a similar study.
The group will also monitor infant language and motor development aged between 18 and 42 months.
“This is an ongoing project, and we are at an early stage,” Ms. Castro Quintas said. “We don’t know if these effects will result in any longer-term issues,” but longer-term observation “may help us understand this.”
“Of course, in babies who are so young, there are several things we just can’t measure, such as language skills or cognition,” added coinvestigator Nerea San Martín González, department of evolutionary biology, ecology and environmental sciences, University of Barcelona.
While emphasizing the need for larger sample sizes, she said that “in the meantime, we need to stress the importance of medical monitoring to facilitate a healthy pregnancy.”
The researchers note that the consequences of the COVID-19 pandemic for the newborns of affected mothers remain “unknown.”
However, previous studies of other infections during pregnancy suggest that offspring could be “especially vulnerable,”as the pathophysiological mechanisms of the infection, such as cytokine storms and microcoagulation, “could clearly compromise fetal neurodevelopment.”
To investigate further, they examined the neurodevelopment of infants born both immediately before and during the COVID-19 pandemic, from 2017 to 2021.
Twenty-one women who had COVID-19 during pregnancy were matched with 21 healthy controls. They were studied both during pregnancy and in the postpartum period, completing hormonal and other biochemical tests, salivary tests, movement assessments, and psychological questionnaires, adjusted for various factors.
The team also administered the Brazelton Neonatal Behavioural Assessment Scale (NBAS) to the offspring at 6 weeks of age to evaluate neurologic, social, and behavioral aspects of function.
“We have been especially sensitive in how we have conducted these tests,” said Ms. Castro Quintas. “Each mother and baby were closely examined by clinicians with expert training in the field and in the tests.”
Among those offspring exposed to COVID-19 during pregnancy, there was a significant decrease in scores on the social interactive dimension of the NBAS, particularly if infection occurred before week 20 of gestation.
Other NBAS subscales were not associated with maternal COVID-19 during pregnancy.
More research needed
Commenting on the findings, Livio Provenzi, PhD, a psychologist and researcher in developmental psychobiology at the University of Pavia (Italy), noted there is a “great need” to study the direct and indirect effect of the COVID-19 pandemic on parents and their children. “Pregnancy is a period of life which shapes much of our subsequent development, and exposure to adversity in pregnancy can leave long-lasting biological footprints.”
Dr. Provenzi, who was not involved in the study, added in the release that the findings reinforce “evidence of epigenetic alterations in infants born from mothers exposed to pandemic-related stress during pregnancy.
“It shows we need more large-scale, international research to allow us to understand the developmental effects of this health emergency and to deliver better quality of care to parents and infants.”
The study was funded by the Spanish Ministry of Economy and Competitiveness, Instituto de Salud Carlos III through the University of Barcelona multicenter project and the Government of Cantabria. No relevant financial relationships were declared.
A version of this article first appeared on Medscape.com.
suggests a small-scale analysis that points to the need for further study and monitoring during pregnancy.
The study included 24 pregnant women, half of whom had COVID-19 during pregnancy, and their offspring. It showed impairments at 6 weeks of age on the social interactive dimension of a neonatal assessment.
“Not all babies born to mothers infected with COVID show neurodevelopmental differences, but our data show that their risk is increased in comparison to those not exposed to COVID in the womb. We need a bigger study to confirm the exact extent of the difference,” said lead researcher Rosa Ayesa Arriola, PhD, Valdecilla Research Institute (IDIVAL), Hospital Universitario Marqués de Valdecilla, Santander, Spain, in a release.
The findings were presented at the virtual European Psychiatric Association 2022 Congress.
Differing responses to cuddling
Coauthor Águeda Castro Quintas, PhD student, Network Centre for Biomedical Research in Mental Health, University of Barcelona, explained that the tests showed the children born to mothers who had COVID-19 during pregnancy reacted “slightly differently to being held, or cuddled.”
“We need to note that these are preliminary results, but this is part of a project following a larger sample of 100 mothers and their babies,” she added. The authors plan to compare their results with those from a similar study.
The group will also monitor infant language and motor development aged between 18 and 42 months.
“This is an ongoing project, and we are at an early stage,” Ms. Castro Quintas said. “We don’t know if these effects will result in any longer-term issues,” but longer-term observation “may help us understand this.”
“Of course, in babies who are so young, there are several things we just can’t measure, such as language skills or cognition,” added coinvestigator Nerea San Martín González, department of evolutionary biology, ecology and environmental sciences, University of Barcelona.
While emphasizing the need for larger sample sizes, she said that “in the meantime, we need to stress the importance of medical monitoring to facilitate a healthy pregnancy.”
The researchers note that the consequences of the COVID-19 pandemic for the newborns of affected mothers remain “unknown.”
However, previous studies of other infections during pregnancy suggest that offspring could be “especially vulnerable,”as the pathophysiological mechanisms of the infection, such as cytokine storms and microcoagulation, “could clearly compromise fetal neurodevelopment.”
To investigate further, they examined the neurodevelopment of infants born both immediately before and during the COVID-19 pandemic, from 2017 to 2021.
Twenty-one women who had COVID-19 during pregnancy were matched with 21 healthy controls. They were studied both during pregnancy and in the postpartum period, completing hormonal and other biochemical tests, salivary tests, movement assessments, and psychological questionnaires, adjusted for various factors.
The team also administered the Brazelton Neonatal Behavioural Assessment Scale (NBAS) to the offspring at 6 weeks of age to evaluate neurologic, social, and behavioral aspects of function.
“We have been especially sensitive in how we have conducted these tests,” said Ms. Castro Quintas. “Each mother and baby were closely examined by clinicians with expert training in the field and in the tests.”
Among those offspring exposed to COVID-19 during pregnancy, there was a significant decrease in scores on the social interactive dimension of the NBAS, particularly if infection occurred before week 20 of gestation.
Other NBAS subscales were not associated with maternal COVID-19 during pregnancy.
More research needed
Commenting on the findings, Livio Provenzi, PhD, a psychologist and researcher in developmental psychobiology at the University of Pavia (Italy), noted there is a “great need” to study the direct and indirect effect of the COVID-19 pandemic on parents and their children. “Pregnancy is a period of life which shapes much of our subsequent development, and exposure to adversity in pregnancy can leave long-lasting biological footprints.”
Dr. Provenzi, who was not involved in the study, added in the release that the findings reinforce “evidence of epigenetic alterations in infants born from mothers exposed to pandemic-related stress during pregnancy.
“It shows we need more large-scale, international research to allow us to understand the developmental effects of this health emergency and to deliver better quality of care to parents and infants.”
The study was funded by the Spanish Ministry of Economy and Competitiveness, Instituto de Salud Carlos III through the University of Barcelona multicenter project and the Government of Cantabria. No relevant financial relationships were declared.
A version of this article first appeared on Medscape.com.
suggests a small-scale analysis that points to the need for further study and monitoring during pregnancy.
The study included 24 pregnant women, half of whom had COVID-19 during pregnancy, and their offspring. It showed impairments at 6 weeks of age on the social interactive dimension of a neonatal assessment.
“Not all babies born to mothers infected with COVID show neurodevelopmental differences, but our data show that their risk is increased in comparison to those not exposed to COVID in the womb. We need a bigger study to confirm the exact extent of the difference,” said lead researcher Rosa Ayesa Arriola, PhD, Valdecilla Research Institute (IDIVAL), Hospital Universitario Marqués de Valdecilla, Santander, Spain, in a release.
The findings were presented at the virtual European Psychiatric Association 2022 Congress.
Differing responses to cuddling
Coauthor Águeda Castro Quintas, PhD student, Network Centre for Biomedical Research in Mental Health, University of Barcelona, explained that the tests showed the children born to mothers who had COVID-19 during pregnancy reacted “slightly differently to being held, or cuddled.”
“We need to note that these are preliminary results, but this is part of a project following a larger sample of 100 mothers and their babies,” she added. The authors plan to compare their results with those from a similar study.
The group will also monitor infant language and motor development aged between 18 and 42 months.
“This is an ongoing project, and we are at an early stage,” Ms. Castro Quintas said. “We don’t know if these effects will result in any longer-term issues,” but longer-term observation “may help us understand this.”
“Of course, in babies who are so young, there are several things we just can’t measure, such as language skills or cognition,” added coinvestigator Nerea San Martín González, department of evolutionary biology, ecology and environmental sciences, University of Barcelona.
While emphasizing the need for larger sample sizes, she said that “in the meantime, we need to stress the importance of medical monitoring to facilitate a healthy pregnancy.”
The researchers note that the consequences of the COVID-19 pandemic for the newborns of affected mothers remain “unknown.”
However, previous studies of other infections during pregnancy suggest that offspring could be “especially vulnerable,”as the pathophysiological mechanisms of the infection, such as cytokine storms and microcoagulation, “could clearly compromise fetal neurodevelopment.”
To investigate further, they examined the neurodevelopment of infants born both immediately before and during the COVID-19 pandemic, from 2017 to 2021.
Twenty-one women who had COVID-19 during pregnancy were matched with 21 healthy controls. They were studied both during pregnancy and in the postpartum period, completing hormonal and other biochemical tests, salivary tests, movement assessments, and psychological questionnaires, adjusted for various factors.
The team also administered the Brazelton Neonatal Behavioural Assessment Scale (NBAS) to the offspring at 6 weeks of age to evaluate neurologic, social, and behavioral aspects of function.
“We have been especially sensitive in how we have conducted these tests,” said Ms. Castro Quintas. “Each mother and baby were closely examined by clinicians with expert training in the field and in the tests.”
Among those offspring exposed to COVID-19 during pregnancy, there was a significant decrease in scores on the social interactive dimension of the NBAS, particularly if infection occurred before week 20 of gestation.
Other NBAS subscales were not associated with maternal COVID-19 during pregnancy.
More research needed
Commenting on the findings, Livio Provenzi, PhD, a psychologist and researcher in developmental psychobiology at the University of Pavia (Italy), noted there is a “great need” to study the direct and indirect effect of the COVID-19 pandemic on parents and their children. “Pregnancy is a period of life which shapes much of our subsequent development, and exposure to adversity in pregnancy can leave long-lasting biological footprints.”
Dr. Provenzi, who was not involved in the study, added in the release that the findings reinforce “evidence of epigenetic alterations in infants born from mothers exposed to pandemic-related stress during pregnancy.
“It shows we need more large-scale, international research to allow us to understand the developmental effects of this health emergency and to deliver better quality of care to parents and infants.”
The study was funded by the Spanish Ministry of Economy and Competitiveness, Instituto de Salud Carlos III through the University of Barcelona multicenter project and the Government of Cantabria. No relevant financial relationships were declared.
A version of this article first appeared on Medscape.com.
FROM EPA 2022
Panitumumab beats bevacizumab in left-sided mCRC
A suspicion from retrospective data has now been confirmed by a prospective clinical trial: Adding panitumumab (Vectibix) to standard chemotherapy in left-sided RAS wild-type metastatic colorectal cancer (mCRC) is more effective than adding bevacizumab (Avastin).
Patients treated with panitumumab alongside chemotherapy saw a 16% improvement in overall survival versus those given bevacizumab after a median follow-up of over 5 years.
The overall survival benefit rose to 18% in those with left-sided tumors.
However, there was no difference in overall survival between the two treatment groups in the small subgroup of patients with right-sided primary tumors.
These findings come from the PARADIGM trial conducted in Japan.
The results were presented during a plenary session at the annual meeting of the American Society of Clinical Oncology.
“If gene testing shows that a tumor is RAS wild-type, the choice of initial treatment with panitumumab plus mFOLFOX6 chemotherapy is superior ... for those people with left-sided tumors,” said lead researcher Takayuki Yoshino, MD, PhD, department of gastrointestinal oncology, National Cancer Center Hospital East, Chiba, Japan, in an ASCO press release.
“It has long been believed that the sequence of metastatic colorectal cancer treatment does not matter as long as patients had access to the drugs at some point, which has now been disproven,” he noted.
Dr. Yoshino added in a press conference about the trial that the results establish “a standard first-line combination regimen for patients with RAS wild-type, left-sided mCRC.”
commented Cathy Eng, MD, ASCO Expert in gastrointestinal cancers.
The findings “emphasize the importance of taking into account sidedness, as well as including comprehensive biomarker testing,” she said.
Dr. Eng underlined that this is especially the case for RAS gene status testing, “which is critical for all colorectal cancer patients at the time of diagnosis of metastatic disease.”
These results are of particular relevance in the United States, where the choice between an anti-EGFR or anti-VEGF antibody for the treatment of mCRC has been an area of “controversy” because of the lack of supporting data.
Panitumumab is a human monoclonal antibody that targets EGFR. It was approved in 2006 for use in mCRC by the U.S. Food and Drug Administration and also approved in 2014 for use in combination with FOLFOX for the first-line treatment of patients with wild-type KRAS (exon 2 in codons 12 or 13) mCRC, having previously been shown to be equally effective as cetuximab (another EGFR inhibitor) in this population.
In contrast, bevacizumab is a monoclonal antibody that targets the VEGF receptor. It was approved by the FDA for use in mCRC in 2004 in combination with intravenous 5-fluorouracil–based chemotherapy.
Dr. Yoshino explained that around 36% of patients with CRC have metastatic tumors at diagnosis and that adding an anti-EGFR or anti-VEGF antibody to chemotherapy improves overall survival in these patients by up to 30 months.
There has been “accumulating” evidence from retrospective studies suggesting that patients with RAS wild-type mCRC whose primary tumor is on the left side, which accounts for approximately 35% of mCRC cases, have a longer survival benefit with an anti-EGFR antibody, he commented.
Despite this, both antibody types continue to be used in these patients, he added.
PARADIGM was the first prospective trial to compare the two antibody types. Patients were randomized to receive either panitumumab or bevacizumab plus the combination chemotherapy regimen modified FOLFOX6 (mFOLFOX6).
The trial involved 823 Japanese patients with previously untreated wild-type mCRC with unresectable disease. Most patients had left-sided primary tumors (312 of 400 patients in the panitumumab group, and 292 of 402 patients in the bevacizumab group).
After a median follow-up of 61 months, panitumumab was associated with a significant improvement in overall survival in the overall study population, at a hazard ratio of 0.84 (P = .030, with the boundary of significance set at P < .05).
In addition, panitumumab was associated with a significant improvement in overall survival in the large subgroup of patients with left-sided primary tumors, at 37.9 versus 34.3 months, or a hazard ratio of 0.82 (P = .031).
However, there was no significant difference in overall survival between the two treatment groups in the smaller subgroup of patients with right-sided tumors, at a hazard ratio of 1.09.
Median progression-free survival was no different between the panitumumab and bevacizumab groups, at 13.7 versus 13.2 months in patients with a left-sided tumor and 12.9 versus 12.0 months in the overall cohort.
There was, however, a difference in response rates in left-sided patients between those receiving the two antibodies, at 80.2% with panitumumab versus 68.6% with bevacizumab, and in curative resection rates, at 18.3% and 11.6%, respectively.
These results demonstrate the “superiority of first-line panitumumab versus bevacizumab in combination with mFOLFOX6 in the left-sided and overall populations,” Dr. Yoshino concluded.
He also highlighted that the team has undertaken a large-scale biomarker analysis of pre- and posttreatment plasma and tissue samples from patients in the PARADIGM study to identify potential biomarkers of treatment response.
At the plenary session, discussant for this abstract Chiara Cremolini, MD, PhD, professor of medical oncology, Pisa (Italy) University Hospital, commented that “location matters” when it comes to mCRC tumors.
Dr. Cremolini pointed out that the separation of the survival curves at 28 months suggests that the 40% of patients with left-sided tumors who survived only up until that time point receive an equal benefit from panitumumab and bevacizumab.
In contrast, the remainder who survived for longer showed better outcomes with panitumumab.
Overall, she said, in her opinion and based on the findings from other studies, the current results support the use of panitumumab plus mFOLFOX6 as first-line therapy in patients with microsatellite stable RAS wild-type and with BRAF wild-type left-sided mCRC.
Dr. Cremolini emphasized that patients should be warned that, if they opt for doublet chemotherapy plus bevacizumab, they could face a median 3.6-month loss in overall survival, as well as poorer treatment activity.
However, patients with high microsatellite instability should receive immunotherapy up front, she added, while those with BRAF mutations should be given FOLFOX upfront plus bevacizumab, followed by encorafenib plus cetuximab in the case of progression.
Dr. Cremolini ended by noting that there has, as yet, been no prospective comparison of doublet chemotherapy plus an anti-EGFR antibody with triplet chemotherapy plus bevacizumab in this population.
The study was funded by Takeda. Dr. Yoshino has reported relationships with Bayer Yakuhin, Chugai Pharmaceutical, Merck, and MSD. Dr. Eng has reported relationships with Bayer Health, Gilead/Forty Seven, GlaxoSmithKline, Hookipa Biotech, Mirati Therapeutics, Natera, Pfizer, Elevar, Fruquitinib, Merck, and Pfizer.
A version of this article first appeared on Medscape.com.
A suspicion from retrospective data has now been confirmed by a prospective clinical trial: Adding panitumumab (Vectibix) to standard chemotherapy in left-sided RAS wild-type metastatic colorectal cancer (mCRC) is more effective than adding bevacizumab (Avastin).
Patients treated with panitumumab alongside chemotherapy saw a 16% improvement in overall survival versus those given bevacizumab after a median follow-up of over 5 years.
The overall survival benefit rose to 18% in those with left-sided tumors.
However, there was no difference in overall survival between the two treatment groups in the small subgroup of patients with right-sided primary tumors.
These findings come from the PARADIGM trial conducted in Japan.
The results were presented during a plenary session at the annual meeting of the American Society of Clinical Oncology.
“If gene testing shows that a tumor is RAS wild-type, the choice of initial treatment with panitumumab plus mFOLFOX6 chemotherapy is superior ... for those people with left-sided tumors,” said lead researcher Takayuki Yoshino, MD, PhD, department of gastrointestinal oncology, National Cancer Center Hospital East, Chiba, Japan, in an ASCO press release.
“It has long been believed that the sequence of metastatic colorectal cancer treatment does not matter as long as patients had access to the drugs at some point, which has now been disproven,” he noted.
Dr. Yoshino added in a press conference about the trial that the results establish “a standard first-line combination regimen for patients with RAS wild-type, left-sided mCRC.”
commented Cathy Eng, MD, ASCO Expert in gastrointestinal cancers.
The findings “emphasize the importance of taking into account sidedness, as well as including comprehensive biomarker testing,” she said.
Dr. Eng underlined that this is especially the case for RAS gene status testing, “which is critical for all colorectal cancer patients at the time of diagnosis of metastatic disease.”
These results are of particular relevance in the United States, where the choice between an anti-EGFR or anti-VEGF antibody for the treatment of mCRC has been an area of “controversy” because of the lack of supporting data.
Panitumumab is a human monoclonal antibody that targets EGFR. It was approved in 2006 for use in mCRC by the U.S. Food and Drug Administration and also approved in 2014 for use in combination with FOLFOX for the first-line treatment of patients with wild-type KRAS (exon 2 in codons 12 or 13) mCRC, having previously been shown to be equally effective as cetuximab (another EGFR inhibitor) in this population.
In contrast, bevacizumab is a monoclonal antibody that targets the VEGF receptor. It was approved by the FDA for use in mCRC in 2004 in combination with intravenous 5-fluorouracil–based chemotherapy.
Dr. Yoshino explained that around 36% of patients with CRC have metastatic tumors at diagnosis and that adding an anti-EGFR or anti-VEGF antibody to chemotherapy improves overall survival in these patients by up to 30 months.
There has been “accumulating” evidence from retrospective studies suggesting that patients with RAS wild-type mCRC whose primary tumor is on the left side, which accounts for approximately 35% of mCRC cases, have a longer survival benefit with an anti-EGFR antibody, he commented.
Despite this, both antibody types continue to be used in these patients, he added.
PARADIGM was the first prospective trial to compare the two antibody types. Patients were randomized to receive either panitumumab or bevacizumab plus the combination chemotherapy regimen modified FOLFOX6 (mFOLFOX6).
The trial involved 823 Japanese patients with previously untreated wild-type mCRC with unresectable disease. Most patients had left-sided primary tumors (312 of 400 patients in the panitumumab group, and 292 of 402 patients in the bevacizumab group).
After a median follow-up of 61 months, panitumumab was associated with a significant improvement in overall survival in the overall study population, at a hazard ratio of 0.84 (P = .030, with the boundary of significance set at P < .05).
In addition, panitumumab was associated with a significant improvement in overall survival in the large subgroup of patients with left-sided primary tumors, at 37.9 versus 34.3 months, or a hazard ratio of 0.82 (P = .031).
However, there was no significant difference in overall survival between the two treatment groups in the smaller subgroup of patients with right-sided tumors, at a hazard ratio of 1.09.
Median progression-free survival was no different between the panitumumab and bevacizumab groups, at 13.7 versus 13.2 months in patients with a left-sided tumor and 12.9 versus 12.0 months in the overall cohort.
There was, however, a difference in response rates in left-sided patients between those receiving the two antibodies, at 80.2% with panitumumab versus 68.6% with bevacizumab, and in curative resection rates, at 18.3% and 11.6%, respectively.
These results demonstrate the “superiority of first-line panitumumab versus bevacizumab in combination with mFOLFOX6 in the left-sided and overall populations,” Dr. Yoshino concluded.
He also highlighted that the team has undertaken a large-scale biomarker analysis of pre- and posttreatment plasma and tissue samples from patients in the PARADIGM study to identify potential biomarkers of treatment response.
At the plenary session, discussant for this abstract Chiara Cremolini, MD, PhD, professor of medical oncology, Pisa (Italy) University Hospital, commented that “location matters” when it comes to mCRC tumors.
Dr. Cremolini pointed out that the separation of the survival curves at 28 months suggests that the 40% of patients with left-sided tumors who survived only up until that time point receive an equal benefit from panitumumab and bevacizumab.
In contrast, the remainder who survived for longer showed better outcomes with panitumumab.
Overall, she said, in her opinion and based on the findings from other studies, the current results support the use of panitumumab plus mFOLFOX6 as first-line therapy in patients with microsatellite stable RAS wild-type and with BRAF wild-type left-sided mCRC.
Dr. Cremolini emphasized that patients should be warned that, if they opt for doublet chemotherapy plus bevacizumab, they could face a median 3.6-month loss in overall survival, as well as poorer treatment activity.
However, patients with high microsatellite instability should receive immunotherapy up front, she added, while those with BRAF mutations should be given FOLFOX upfront plus bevacizumab, followed by encorafenib plus cetuximab in the case of progression.
Dr. Cremolini ended by noting that there has, as yet, been no prospective comparison of doublet chemotherapy plus an anti-EGFR antibody with triplet chemotherapy plus bevacizumab in this population.
The study was funded by Takeda. Dr. Yoshino has reported relationships with Bayer Yakuhin, Chugai Pharmaceutical, Merck, and MSD. Dr. Eng has reported relationships with Bayer Health, Gilead/Forty Seven, GlaxoSmithKline, Hookipa Biotech, Mirati Therapeutics, Natera, Pfizer, Elevar, Fruquitinib, Merck, and Pfizer.
A version of this article first appeared on Medscape.com.
A suspicion from retrospective data has now been confirmed by a prospective clinical trial: Adding panitumumab (Vectibix) to standard chemotherapy in left-sided RAS wild-type metastatic colorectal cancer (mCRC) is more effective than adding bevacizumab (Avastin).
Patients treated with panitumumab alongside chemotherapy saw a 16% improvement in overall survival versus those given bevacizumab after a median follow-up of over 5 years.
The overall survival benefit rose to 18% in those with left-sided tumors.
However, there was no difference in overall survival between the two treatment groups in the small subgroup of patients with right-sided primary tumors.
These findings come from the PARADIGM trial conducted in Japan.
The results were presented during a plenary session at the annual meeting of the American Society of Clinical Oncology.
“If gene testing shows that a tumor is RAS wild-type, the choice of initial treatment with panitumumab plus mFOLFOX6 chemotherapy is superior ... for those people with left-sided tumors,” said lead researcher Takayuki Yoshino, MD, PhD, department of gastrointestinal oncology, National Cancer Center Hospital East, Chiba, Japan, in an ASCO press release.
“It has long been believed that the sequence of metastatic colorectal cancer treatment does not matter as long as patients had access to the drugs at some point, which has now been disproven,” he noted.
Dr. Yoshino added in a press conference about the trial that the results establish “a standard first-line combination regimen for patients with RAS wild-type, left-sided mCRC.”
commented Cathy Eng, MD, ASCO Expert in gastrointestinal cancers.
The findings “emphasize the importance of taking into account sidedness, as well as including comprehensive biomarker testing,” she said.
Dr. Eng underlined that this is especially the case for RAS gene status testing, “which is critical for all colorectal cancer patients at the time of diagnosis of metastatic disease.”
These results are of particular relevance in the United States, where the choice between an anti-EGFR or anti-VEGF antibody for the treatment of mCRC has been an area of “controversy” because of the lack of supporting data.
Panitumumab is a human monoclonal antibody that targets EGFR. It was approved in 2006 for use in mCRC by the U.S. Food and Drug Administration and also approved in 2014 for use in combination with FOLFOX for the first-line treatment of patients with wild-type KRAS (exon 2 in codons 12 or 13) mCRC, having previously been shown to be equally effective as cetuximab (another EGFR inhibitor) in this population.
In contrast, bevacizumab is a monoclonal antibody that targets the VEGF receptor. It was approved by the FDA for use in mCRC in 2004 in combination with intravenous 5-fluorouracil–based chemotherapy.
Dr. Yoshino explained that around 36% of patients with CRC have metastatic tumors at diagnosis and that adding an anti-EGFR or anti-VEGF antibody to chemotherapy improves overall survival in these patients by up to 30 months.
There has been “accumulating” evidence from retrospective studies suggesting that patients with RAS wild-type mCRC whose primary tumor is on the left side, which accounts for approximately 35% of mCRC cases, have a longer survival benefit with an anti-EGFR antibody, he commented.
Despite this, both antibody types continue to be used in these patients, he added.
PARADIGM was the first prospective trial to compare the two antibody types. Patients were randomized to receive either panitumumab or bevacizumab plus the combination chemotherapy regimen modified FOLFOX6 (mFOLFOX6).
The trial involved 823 Japanese patients with previously untreated wild-type mCRC with unresectable disease. Most patients had left-sided primary tumors (312 of 400 patients in the panitumumab group, and 292 of 402 patients in the bevacizumab group).
After a median follow-up of 61 months, panitumumab was associated with a significant improvement in overall survival in the overall study population, at a hazard ratio of 0.84 (P = .030, with the boundary of significance set at P < .05).
In addition, panitumumab was associated with a significant improvement in overall survival in the large subgroup of patients with left-sided primary tumors, at 37.9 versus 34.3 months, or a hazard ratio of 0.82 (P = .031).
However, there was no significant difference in overall survival between the two treatment groups in the smaller subgroup of patients with right-sided tumors, at a hazard ratio of 1.09.
Median progression-free survival was no different between the panitumumab and bevacizumab groups, at 13.7 versus 13.2 months in patients with a left-sided tumor and 12.9 versus 12.0 months in the overall cohort.
There was, however, a difference in response rates in left-sided patients between those receiving the two antibodies, at 80.2% with panitumumab versus 68.6% with bevacizumab, and in curative resection rates, at 18.3% and 11.6%, respectively.
These results demonstrate the “superiority of first-line panitumumab versus bevacizumab in combination with mFOLFOX6 in the left-sided and overall populations,” Dr. Yoshino concluded.
He also highlighted that the team has undertaken a large-scale biomarker analysis of pre- and posttreatment plasma and tissue samples from patients in the PARADIGM study to identify potential biomarkers of treatment response.
At the plenary session, discussant for this abstract Chiara Cremolini, MD, PhD, professor of medical oncology, Pisa (Italy) University Hospital, commented that “location matters” when it comes to mCRC tumors.
Dr. Cremolini pointed out that the separation of the survival curves at 28 months suggests that the 40% of patients with left-sided tumors who survived only up until that time point receive an equal benefit from panitumumab and bevacizumab.
In contrast, the remainder who survived for longer showed better outcomes with panitumumab.
Overall, she said, in her opinion and based on the findings from other studies, the current results support the use of panitumumab plus mFOLFOX6 as first-line therapy in patients with microsatellite stable RAS wild-type and with BRAF wild-type left-sided mCRC.
Dr. Cremolini emphasized that patients should be warned that, if they opt for doublet chemotherapy plus bevacizumab, they could face a median 3.6-month loss in overall survival, as well as poorer treatment activity.
However, patients with high microsatellite instability should receive immunotherapy up front, she added, while those with BRAF mutations should be given FOLFOX upfront plus bevacizumab, followed by encorafenib plus cetuximab in the case of progression.
Dr. Cremolini ended by noting that there has, as yet, been no prospective comparison of doublet chemotherapy plus an anti-EGFR antibody with triplet chemotherapy plus bevacizumab in this population.
The study was funded by Takeda. Dr. Yoshino has reported relationships with Bayer Yakuhin, Chugai Pharmaceutical, Merck, and MSD. Dr. Eng has reported relationships with Bayer Health, Gilead/Forty Seven, GlaxoSmithKline, Hookipa Biotech, Mirati Therapeutics, Natera, Pfizer, Elevar, Fruquitinib, Merck, and Pfizer.
A version of this article first appeared on Medscape.com.
FROM ASCO 2022
Improved survival in subset of advanced pancreatic cancer
, offering hope of a clinical advance in a cancer that remains very difficult to treat.
The drug is nimotuzumab, developed as a joint Chinese-Cuban venture, a monoclonal antibody that targets the epidermal growth factor receptor (EGFR), inhibiting tumor cells that overexpress EGFR.
When nimotuzumab was added to gemcitabine, it significantly improved overall survival, compared with gemcitabine alone, in a trial conducted in China in 92 patients with advanced pancreatic cancer who had KRAS wild-type tumors.
One-year survival rates were 43.6% with nimotuzumab versus 26.8% with placebo, while 3-year survival rates were 13.9% versus 2.7%.
The results were presented at the annual meeting of the American Society of Clinical Oncology and highlighted at a press briefing.
“We believe our NOTABLE trial will be a breakthrough in the field of pancreatic cancer,” co-lead author Shukui Qin, MD, department of medical oncology, Cancer Center, Jinling Hospital, Nanjing, China, commented in an ASCO press release.
“The outcomes in this trial may bring new hope to patients with KRAS wild-type pancreatic cancer,” he added.
“To see any survival benefit in a trial for metastatic pancreatic cancer is of interest,” commented Cathy Eng, MD, an ASCO expert in gastrointestinal cancers.
However, she pointed out that the subgroup of patients who may benefit is small – KRAS wild-type tumors are found in fewer than 10% of patients with pancreatic cancer.
“Additional studies in comparison with the combination of gemcitabine/nab-paclitaxel would be of interest,” Dr. Eng added, to validate “any potential advances to make a true difference in the lives of all patients with pancreatic cancer.”
Already marketed in China
Nimotuzumab is already marketed in China: It was approved in 2008 by the Chinese National Medical Products Administration for the treatment of nasopharyngeal carcinoma and is currently being investigated in head and neck, cervical, esophageal, and other cancers.
Julie R. Gralow, MD, ASCO chief medical officer and executive vice president, commented in an interview that it will be “interesting to see the U.S. Food and Drug Administration’s response to the current data.”
She explained that the FDA has recently rejected drugs developed and tested in China, mostly notably sintilimab in non–small cell lung cancer, because the clinical data submitted were from China and not “reflective of the U.S. cancer population” and also because in this case there were already a number of other similar drugs available in this therapeutic area.
However, pancreatic cancer represents an unmet clinical need, which is a different situation, and there may be some consideration for an accelerated approval while awaiting a U.S. clinical trial, she speculated.
This trial showed an interesting proof of principle, she added – it showed that an EGRF inhibitor was active in KRAS wild-type advanced pancreatic cancer. This opens the door for exploration with other drugs that also act as EGFR blockers, as well as drugs with other actions such as BRAF antagonists, MAP kinase inhibitors, and/or immunotherapy.
Study details
The phase 3 NOTABLE trial involved 92 Chinese patients with locally advanced or metastatic KRAS wild-type pancreatic cancer randomized to nimotuzumab weekly or placebo plus gemcitabine until progression or unacceptable toxicity.
Median overall survival was significantly longer with nimotuzumab, at 10.9 versus 8.5 months with placebo, at a hazard ratio of 0.50.
The results showed that median progression-free survival (PFS) was also significantly longer among patients given nimotuzumab, at 4.2 versus 3.6 months in the placebo group, or a hazard ratio of 0.56.
Patients were then stratified based on whether they needed surgery to remove bile duct obstructions prior to chemotherapy, as those not requiring surgery tend to have better liver function and so may better tolerate chemotherapy.
The overall survival benefit with nimotuzumab was greater among patients with no surgical history, at 15.8 versus 6.0 months with placebo, at a hazard ratio of 0.40, compared with 11.9 versus 8.5 months among those with biliary obstruction, at a hazard ratio of 0.54.
Patients who did not receive treatment for biliary obstruction had a significantly longer PFS than those who underwent surgery, at 5.5 versus 3.4 months (P = .008).
The researchers report that the incidence of adverse events in the nimotuzumab group was similar to that among patients given placebo.
The most common grade 3 treatment-related adverse events with the combination therapy were neutropenia, in 11.1% of patients, leukopenia (8.9%), and thrombocytopenia (6.7%). There were no grade 4 adverse events.
The study was sponsored by Biotech Pharmaceutical. Dr. Qin has disclosed no relevant financial relationships. Dr. Eng has disclosed relationships with Bayer Health, Gilead/Forty Seven, GlaxoSmithKline, Hookipa Biotech, Mirati Therapeutics, Natera, Pfizer, Elevar, Fruquitinib, Merck, and Pfizer. Dr. Gralow has disclosed relationships with Genentech, AstraZeneca, Hexal, Puma Biotechnology, Roche, Novartis, Seagen, and Genomic Health.
A version of this article first appeared on Medscape.com.
, offering hope of a clinical advance in a cancer that remains very difficult to treat.
The drug is nimotuzumab, developed as a joint Chinese-Cuban venture, a monoclonal antibody that targets the epidermal growth factor receptor (EGFR), inhibiting tumor cells that overexpress EGFR.
When nimotuzumab was added to gemcitabine, it significantly improved overall survival, compared with gemcitabine alone, in a trial conducted in China in 92 patients with advanced pancreatic cancer who had KRAS wild-type tumors.
One-year survival rates were 43.6% with nimotuzumab versus 26.8% with placebo, while 3-year survival rates were 13.9% versus 2.7%.
The results were presented at the annual meeting of the American Society of Clinical Oncology and highlighted at a press briefing.
“We believe our NOTABLE trial will be a breakthrough in the field of pancreatic cancer,” co-lead author Shukui Qin, MD, department of medical oncology, Cancer Center, Jinling Hospital, Nanjing, China, commented in an ASCO press release.
“The outcomes in this trial may bring new hope to patients with KRAS wild-type pancreatic cancer,” he added.
“To see any survival benefit in a trial for metastatic pancreatic cancer is of interest,” commented Cathy Eng, MD, an ASCO expert in gastrointestinal cancers.
However, she pointed out that the subgroup of patients who may benefit is small – KRAS wild-type tumors are found in fewer than 10% of patients with pancreatic cancer.
“Additional studies in comparison with the combination of gemcitabine/nab-paclitaxel would be of interest,” Dr. Eng added, to validate “any potential advances to make a true difference in the lives of all patients with pancreatic cancer.”
Already marketed in China
Nimotuzumab is already marketed in China: It was approved in 2008 by the Chinese National Medical Products Administration for the treatment of nasopharyngeal carcinoma and is currently being investigated in head and neck, cervical, esophageal, and other cancers.
Julie R. Gralow, MD, ASCO chief medical officer and executive vice president, commented in an interview that it will be “interesting to see the U.S. Food and Drug Administration’s response to the current data.”
She explained that the FDA has recently rejected drugs developed and tested in China, mostly notably sintilimab in non–small cell lung cancer, because the clinical data submitted were from China and not “reflective of the U.S. cancer population” and also because in this case there were already a number of other similar drugs available in this therapeutic area.
However, pancreatic cancer represents an unmet clinical need, which is a different situation, and there may be some consideration for an accelerated approval while awaiting a U.S. clinical trial, she speculated.
This trial showed an interesting proof of principle, she added – it showed that an EGRF inhibitor was active in KRAS wild-type advanced pancreatic cancer. This opens the door for exploration with other drugs that also act as EGFR blockers, as well as drugs with other actions such as BRAF antagonists, MAP kinase inhibitors, and/or immunotherapy.
Study details
The phase 3 NOTABLE trial involved 92 Chinese patients with locally advanced or metastatic KRAS wild-type pancreatic cancer randomized to nimotuzumab weekly or placebo plus gemcitabine until progression or unacceptable toxicity.
Median overall survival was significantly longer with nimotuzumab, at 10.9 versus 8.5 months with placebo, at a hazard ratio of 0.50.
The results showed that median progression-free survival (PFS) was also significantly longer among patients given nimotuzumab, at 4.2 versus 3.6 months in the placebo group, or a hazard ratio of 0.56.
Patients were then stratified based on whether they needed surgery to remove bile duct obstructions prior to chemotherapy, as those not requiring surgery tend to have better liver function and so may better tolerate chemotherapy.
The overall survival benefit with nimotuzumab was greater among patients with no surgical history, at 15.8 versus 6.0 months with placebo, at a hazard ratio of 0.40, compared with 11.9 versus 8.5 months among those with biliary obstruction, at a hazard ratio of 0.54.
Patients who did not receive treatment for biliary obstruction had a significantly longer PFS than those who underwent surgery, at 5.5 versus 3.4 months (P = .008).
The researchers report that the incidence of adverse events in the nimotuzumab group was similar to that among patients given placebo.
The most common grade 3 treatment-related adverse events with the combination therapy were neutropenia, in 11.1% of patients, leukopenia (8.9%), and thrombocytopenia (6.7%). There were no grade 4 adverse events.
The study was sponsored by Biotech Pharmaceutical. Dr. Qin has disclosed no relevant financial relationships. Dr. Eng has disclosed relationships with Bayer Health, Gilead/Forty Seven, GlaxoSmithKline, Hookipa Biotech, Mirati Therapeutics, Natera, Pfizer, Elevar, Fruquitinib, Merck, and Pfizer. Dr. Gralow has disclosed relationships with Genentech, AstraZeneca, Hexal, Puma Biotechnology, Roche, Novartis, Seagen, and Genomic Health.
A version of this article first appeared on Medscape.com.
, offering hope of a clinical advance in a cancer that remains very difficult to treat.
The drug is nimotuzumab, developed as a joint Chinese-Cuban venture, a monoclonal antibody that targets the epidermal growth factor receptor (EGFR), inhibiting tumor cells that overexpress EGFR.
When nimotuzumab was added to gemcitabine, it significantly improved overall survival, compared with gemcitabine alone, in a trial conducted in China in 92 patients with advanced pancreatic cancer who had KRAS wild-type tumors.
One-year survival rates were 43.6% with nimotuzumab versus 26.8% with placebo, while 3-year survival rates were 13.9% versus 2.7%.
The results were presented at the annual meeting of the American Society of Clinical Oncology and highlighted at a press briefing.
“We believe our NOTABLE trial will be a breakthrough in the field of pancreatic cancer,” co-lead author Shukui Qin, MD, department of medical oncology, Cancer Center, Jinling Hospital, Nanjing, China, commented in an ASCO press release.
“The outcomes in this trial may bring new hope to patients with KRAS wild-type pancreatic cancer,” he added.
“To see any survival benefit in a trial for metastatic pancreatic cancer is of interest,” commented Cathy Eng, MD, an ASCO expert in gastrointestinal cancers.
However, she pointed out that the subgroup of patients who may benefit is small – KRAS wild-type tumors are found in fewer than 10% of patients with pancreatic cancer.
“Additional studies in comparison with the combination of gemcitabine/nab-paclitaxel would be of interest,” Dr. Eng added, to validate “any potential advances to make a true difference in the lives of all patients with pancreatic cancer.”
Already marketed in China
Nimotuzumab is already marketed in China: It was approved in 2008 by the Chinese National Medical Products Administration for the treatment of nasopharyngeal carcinoma and is currently being investigated in head and neck, cervical, esophageal, and other cancers.
Julie R. Gralow, MD, ASCO chief medical officer and executive vice president, commented in an interview that it will be “interesting to see the U.S. Food and Drug Administration’s response to the current data.”
She explained that the FDA has recently rejected drugs developed and tested in China, mostly notably sintilimab in non–small cell lung cancer, because the clinical data submitted were from China and not “reflective of the U.S. cancer population” and also because in this case there were already a number of other similar drugs available in this therapeutic area.
However, pancreatic cancer represents an unmet clinical need, which is a different situation, and there may be some consideration for an accelerated approval while awaiting a U.S. clinical trial, she speculated.
This trial showed an interesting proof of principle, she added – it showed that an EGRF inhibitor was active in KRAS wild-type advanced pancreatic cancer. This opens the door for exploration with other drugs that also act as EGFR blockers, as well as drugs with other actions such as BRAF antagonists, MAP kinase inhibitors, and/or immunotherapy.
Study details
The phase 3 NOTABLE trial involved 92 Chinese patients with locally advanced or metastatic KRAS wild-type pancreatic cancer randomized to nimotuzumab weekly or placebo plus gemcitabine until progression or unacceptable toxicity.
Median overall survival was significantly longer with nimotuzumab, at 10.9 versus 8.5 months with placebo, at a hazard ratio of 0.50.
The results showed that median progression-free survival (PFS) was also significantly longer among patients given nimotuzumab, at 4.2 versus 3.6 months in the placebo group, or a hazard ratio of 0.56.
Patients were then stratified based on whether they needed surgery to remove bile duct obstructions prior to chemotherapy, as those not requiring surgery tend to have better liver function and so may better tolerate chemotherapy.
The overall survival benefit with nimotuzumab was greater among patients with no surgical history, at 15.8 versus 6.0 months with placebo, at a hazard ratio of 0.40, compared with 11.9 versus 8.5 months among those with biliary obstruction, at a hazard ratio of 0.54.
Patients who did not receive treatment for biliary obstruction had a significantly longer PFS than those who underwent surgery, at 5.5 versus 3.4 months (P = .008).
The researchers report that the incidence of adverse events in the nimotuzumab group was similar to that among patients given placebo.
The most common grade 3 treatment-related adverse events with the combination therapy were neutropenia, in 11.1% of patients, leukopenia (8.9%), and thrombocytopenia (6.7%). There were no grade 4 adverse events.
The study was sponsored by Biotech Pharmaceutical. Dr. Qin has disclosed no relevant financial relationships. Dr. Eng has disclosed relationships with Bayer Health, Gilead/Forty Seven, GlaxoSmithKline, Hookipa Biotech, Mirati Therapeutics, Natera, Pfizer, Elevar, Fruquitinib, Merck, and Pfizer. Dr. Gralow has disclosed relationships with Genentech, AstraZeneca, Hexal, Puma Biotechnology, Roche, Novartis, Seagen, and Genomic Health.
A version of this article first appeared on Medscape.com.
FROM ASCO 2022
'New benchmark' set in phase-3 blood cancer study
The phase 3 SHINE study was conducted in 520 older patients (aged ≥ 65 years) with newly diagnosed mantle cell lymphoma who were randomized to receive ibrutinib or placebo plus bendamustine-rituximab (BR) and rituximab maintenance.
After 7 years of follow-up, median PFS was 80.6 months with the ibrutinib combination versus 52.9 years with placebo, offering patients an additional 2.3 years of disease-free life.
Complete response rates were higher with ibrutinib versus placebo, and importantly, there were no new safety signals with the combination.
“We believe this phase 3 clinical trial sets a new benchmark for patients with newly diagnosed mantle cell lymphoma and the elderly,” commented lead investigator Dr. Michael Wang, department of lymphoma & myeloma, University of Texas MD Anderson Cancer Center, Houston.
He was speaking during a press briefing at the annual meeting of the American Society of Clinical Oncology, where the study was presented. It was also simultaneously published in the New England Journal of Medicine.
These results “bring new hope to newly diagnosed, older patients with this rare cancer, who have had too few treatment options” and are “generally underrepresented in clinical trials,” commented Dr. Julie R. Gralow, ASCO chief medical officer.
She described the difference in PFS between the two treatment groups as “profound” and “clinically meaningful,” and said the combination can be considered a “new standard of care as initial treatment of older patients with mantle cell lymphoma.”
Some lymphoma experts not impressed
The study got pushback from several lymphoma experts commenting on Twitter.
Lymphoma specialist and consultant hematologist Toby Eyre, MBChB, from Oxford University, London, highlighted the fact that although there was a PFS benefit, there was no overall survival benefit and more toxicity.
“I hope no one implements this regimen,” replied “Papa Heme” Dr. Aaron Goodman, a hematologist at UC San Diego Health, California.
“The authors should be congratulated on completing a large RCT in this space. As far as the result adding ibrutinib added about 28 mos to PFS. This is actually the median DoR of BTK inhibitors in the 2nd line. So big question is, whether the extra tox is worth it,” commented another lymphoma specialist, Dr. Tim Fenske, MD, of the Medical College of Wisconsin, Milwaukee, replying in the same Twitter thread.
“I don’t see a benefit in adding continuous ibrutinib upfront to BR, based on these results. Added toxicity + less treatment free interval make this a tough pill to swallow (pun intended),” commented Dr. Alan Skarbnik, MD, of Novant Health, Charlotte, N.C.
Potential for first-line use
Ibrutinib is already approved for use in mantle cell lymphoma, but in patients who have received at least one prior therapy; this is an accelerated approval, based on overall response rate.
These new data could lead to approval for first-line use of the drug.
“There is an urgent need to improve outcomes for older patients with mantle cell lymphoma,” Dr. Wang commented in a company press release. “Given the median progression-free survival of 6.7 years, the ibrutinib combination demonstrated the potential to be a first-line treatment in this population.”
Mantle cell lymphoma, a form of non-Hodgkin’s lymphoma, affects men more than women and is more common in people aged over 65 years. Older patients often cannot tolerate intensive chemotherapy or stem cell transplants, so they often have poor outcomes, Dr. Wang explained during the press briefing.
He noted that SHINE is the first phase 3 study to examine ibrutinib plus BR as a first-line therapy in mantle cell lymphoma and involved patients with previously untreated stage II-IV disease aged ≥ 65 years not planning to undergo stem cell transplant.
Participants were a median age of 71 years, and 68%-71% were male. Most were White (76%-79%), and median time from initial diagnosis to randomization was 1.4-1.5 months.
At the data cut-off of June 30, 2021, median follow-up was 84.7 months. Disease progression or death had occurred in 44.4% of patients given ibrutinib and 58.0% of those given placebo.
Dr. Wang noted that the PFS curves “separated early, indicating the benefit that was achieved early within the first year and also that those benefits remained durable” throughout follow-up.
The percentage of patients with a complete response was 65.5% among patients treated with ibrutinib and 57.6% among those in the placebo group.
At the current analysis, there was no significant difference in overall survival between the two treatment arms, with a hazard ratio of 1.07 (P = .06).
Dr. Wang explained that “even though the study has been going on for 10 years, we don’t have enough deaths ... to evaluate overall survival yet.”
Furthermore, the median age of patients at enrollment was 71 years and is currently 78 years, with “half of them over 80 years,” so they are more likely to die of “other causes” than from mantle cell lymphoma, he commented.
He added that if the study had been designed to assess overall survival, it would have been “very different,” requiring 1,500 patients and a follow-up of 15-20 years.
The safety profile of the novel combination was “no surprise,” Dr. Wang said, and “consistent with what we’re seeing in daily practice.”
Grade 3/4 treatment-related adverse events were seen in 81.5% of patients treated with ibrutinib and 77.3% of those given placebo, and 47.1% and 48.1%, respectively, experienced grade 3/4 neutropenia.
In the post-presentation discussion, Dr. Wang said that approximately 40% of the patients in the placebo group received a BTK inhibitor at progression, and most were given ibrutinib.
He cautioned that the current results cannot be generalized to “other subtypes of lymphoma,” as they are “very different,” with different prognostic factors and different underlying biologies.
The study was funded by Janssen Pharmaceuticals and Pharmacyclics, an AbbVie Company. Dr. Wang has reported relationships with multiple companies, as listed in the article. Dr. Gralow has reported relationships with Genentech, AstraZeneca, Hexal, Puma Biotechnology, Roche, Novartis, Seagen, and Genomic Health.
A version of this article first appeared on Medscape.com.
The phase 3 SHINE study was conducted in 520 older patients (aged ≥ 65 years) with newly diagnosed mantle cell lymphoma who were randomized to receive ibrutinib or placebo plus bendamustine-rituximab (BR) and rituximab maintenance.
After 7 years of follow-up, median PFS was 80.6 months with the ibrutinib combination versus 52.9 years with placebo, offering patients an additional 2.3 years of disease-free life.
Complete response rates were higher with ibrutinib versus placebo, and importantly, there were no new safety signals with the combination.
“We believe this phase 3 clinical trial sets a new benchmark for patients with newly diagnosed mantle cell lymphoma and the elderly,” commented lead investigator Dr. Michael Wang, department of lymphoma & myeloma, University of Texas MD Anderson Cancer Center, Houston.
He was speaking during a press briefing at the annual meeting of the American Society of Clinical Oncology, where the study was presented. It was also simultaneously published in the New England Journal of Medicine.
These results “bring new hope to newly diagnosed, older patients with this rare cancer, who have had too few treatment options” and are “generally underrepresented in clinical trials,” commented Dr. Julie R. Gralow, ASCO chief medical officer.
She described the difference in PFS between the two treatment groups as “profound” and “clinically meaningful,” and said the combination can be considered a “new standard of care as initial treatment of older patients with mantle cell lymphoma.”
Some lymphoma experts not impressed
The study got pushback from several lymphoma experts commenting on Twitter.
Lymphoma specialist and consultant hematologist Toby Eyre, MBChB, from Oxford University, London, highlighted the fact that although there was a PFS benefit, there was no overall survival benefit and more toxicity.
“I hope no one implements this regimen,” replied “Papa Heme” Dr. Aaron Goodman, a hematologist at UC San Diego Health, California.
“The authors should be congratulated on completing a large RCT in this space. As far as the result adding ibrutinib added about 28 mos to PFS. This is actually the median DoR of BTK inhibitors in the 2nd line. So big question is, whether the extra tox is worth it,” commented another lymphoma specialist, Dr. Tim Fenske, MD, of the Medical College of Wisconsin, Milwaukee, replying in the same Twitter thread.
“I don’t see a benefit in adding continuous ibrutinib upfront to BR, based on these results. Added toxicity + less treatment free interval make this a tough pill to swallow (pun intended),” commented Dr. Alan Skarbnik, MD, of Novant Health, Charlotte, N.C.
Potential for first-line use
Ibrutinib is already approved for use in mantle cell lymphoma, but in patients who have received at least one prior therapy; this is an accelerated approval, based on overall response rate.
These new data could lead to approval for first-line use of the drug.
“There is an urgent need to improve outcomes for older patients with mantle cell lymphoma,” Dr. Wang commented in a company press release. “Given the median progression-free survival of 6.7 years, the ibrutinib combination demonstrated the potential to be a first-line treatment in this population.”
Mantle cell lymphoma, a form of non-Hodgkin’s lymphoma, affects men more than women and is more common in people aged over 65 years. Older patients often cannot tolerate intensive chemotherapy or stem cell transplants, so they often have poor outcomes, Dr. Wang explained during the press briefing.
He noted that SHINE is the first phase 3 study to examine ibrutinib plus BR as a first-line therapy in mantle cell lymphoma and involved patients with previously untreated stage II-IV disease aged ≥ 65 years not planning to undergo stem cell transplant.
Participants were a median age of 71 years, and 68%-71% were male. Most were White (76%-79%), and median time from initial diagnosis to randomization was 1.4-1.5 months.
At the data cut-off of June 30, 2021, median follow-up was 84.7 months. Disease progression or death had occurred in 44.4% of patients given ibrutinib and 58.0% of those given placebo.
Dr. Wang noted that the PFS curves “separated early, indicating the benefit that was achieved early within the first year and also that those benefits remained durable” throughout follow-up.
The percentage of patients with a complete response was 65.5% among patients treated with ibrutinib and 57.6% among those in the placebo group.
At the current analysis, there was no significant difference in overall survival between the two treatment arms, with a hazard ratio of 1.07 (P = .06).
Dr. Wang explained that “even though the study has been going on for 10 years, we don’t have enough deaths ... to evaluate overall survival yet.”
Furthermore, the median age of patients at enrollment was 71 years and is currently 78 years, with “half of them over 80 years,” so they are more likely to die of “other causes” than from mantle cell lymphoma, he commented.
He added that if the study had been designed to assess overall survival, it would have been “very different,” requiring 1,500 patients and a follow-up of 15-20 years.
The safety profile of the novel combination was “no surprise,” Dr. Wang said, and “consistent with what we’re seeing in daily practice.”
Grade 3/4 treatment-related adverse events were seen in 81.5% of patients treated with ibrutinib and 77.3% of those given placebo, and 47.1% and 48.1%, respectively, experienced grade 3/4 neutropenia.
In the post-presentation discussion, Dr. Wang said that approximately 40% of the patients in the placebo group received a BTK inhibitor at progression, and most were given ibrutinib.
He cautioned that the current results cannot be generalized to “other subtypes of lymphoma,” as they are “very different,” with different prognostic factors and different underlying biologies.
The study was funded by Janssen Pharmaceuticals and Pharmacyclics, an AbbVie Company. Dr. Wang has reported relationships with multiple companies, as listed in the article. Dr. Gralow has reported relationships with Genentech, AstraZeneca, Hexal, Puma Biotechnology, Roche, Novartis, Seagen, and Genomic Health.
A version of this article first appeared on Medscape.com.
The phase 3 SHINE study was conducted in 520 older patients (aged ≥ 65 years) with newly diagnosed mantle cell lymphoma who were randomized to receive ibrutinib or placebo plus bendamustine-rituximab (BR) and rituximab maintenance.
After 7 years of follow-up, median PFS was 80.6 months with the ibrutinib combination versus 52.9 years with placebo, offering patients an additional 2.3 years of disease-free life.
Complete response rates were higher with ibrutinib versus placebo, and importantly, there were no new safety signals with the combination.
“We believe this phase 3 clinical trial sets a new benchmark for patients with newly diagnosed mantle cell lymphoma and the elderly,” commented lead investigator Dr. Michael Wang, department of lymphoma & myeloma, University of Texas MD Anderson Cancer Center, Houston.
He was speaking during a press briefing at the annual meeting of the American Society of Clinical Oncology, where the study was presented. It was also simultaneously published in the New England Journal of Medicine.
These results “bring new hope to newly diagnosed, older patients with this rare cancer, who have had too few treatment options” and are “generally underrepresented in clinical trials,” commented Dr. Julie R. Gralow, ASCO chief medical officer.
She described the difference in PFS between the two treatment groups as “profound” and “clinically meaningful,” and said the combination can be considered a “new standard of care as initial treatment of older patients with mantle cell lymphoma.”
Some lymphoma experts not impressed
The study got pushback from several lymphoma experts commenting on Twitter.
Lymphoma specialist and consultant hematologist Toby Eyre, MBChB, from Oxford University, London, highlighted the fact that although there was a PFS benefit, there was no overall survival benefit and more toxicity.
“I hope no one implements this regimen,” replied “Papa Heme” Dr. Aaron Goodman, a hematologist at UC San Diego Health, California.
“The authors should be congratulated on completing a large RCT in this space. As far as the result adding ibrutinib added about 28 mos to PFS. This is actually the median DoR of BTK inhibitors in the 2nd line. So big question is, whether the extra tox is worth it,” commented another lymphoma specialist, Dr. Tim Fenske, MD, of the Medical College of Wisconsin, Milwaukee, replying in the same Twitter thread.
“I don’t see a benefit in adding continuous ibrutinib upfront to BR, based on these results. Added toxicity + less treatment free interval make this a tough pill to swallow (pun intended),” commented Dr. Alan Skarbnik, MD, of Novant Health, Charlotte, N.C.
Potential for first-line use
Ibrutinib is already approved for use in mantle cell lymphoma, but in patients who have received at least one prior therapy; this is an accelerated approval, based on overall response rate.
These new data could lead to approval for first-line use of the drug.
“There is an urgent need to improve outcomes for older patients with mantle cell lymphoma,” Dr. Wang commented in a company press release. “Given the median progression-free survival of 6.7 years, the ibrutinib combination demonstrated the potential to be a first-line treatment in this population.”
Mantle cell lymphoma, a form of non-Hodgkin’s lymphoma, affects men more than women and is more common in people aged over 65 years. Older patients often cannot tolerate intensive chemotherapy or stem cell transplants, so they often have poor outcomes, Dr. Wang explained during the press briefing.
He noted that SHINE is the first phase 3 study to examine ibrutinib plus BR as a first-line therapy in mantle cell lymphoma and involved patients with previously untreated stage II-IV disease aged ≥ 65 years not planning to undergo stem cell transplant.
Participants were a median age of 71 years, and 68%-71% were male. Most were White (76%-79%), and median time from initial diagnosis to randomization was 1.4-1.5 months.
At the data cut-off of June 30, 2021, median follow-up was 84.7 months. Disease progression or death had occurred in 44.4% of patients given ibrutinib and 58.0% of those given placebo.
Dr. Wang noted that the PFS curves “separated early, indicating the benefit that was achieved early within the first year and also that those benefits remained durable” throughout follow-up.
The percentage of patients with a complete response was 65.5% among patients treated with ibrutinib and 57.6% among those in the placebo group.
At the current analysis, there was no significant difference in overall survival between the two treatment arms, with a hazard ratio of 1.07 (P = .06).
Dr. Wang explained that “even though the study has been going on for 10 years, we don’t have enough deaths ... to evaluate overall survival yet.”
Furthermore, the median age of patients at enrollment was 71 years and is currently 78 years, with “half of them over 80 years,” so they are more likely to die of “other causes” than from mantle cell lymphoma, he commented.
He added that if the study had been designed to assess overall survival, it would have been “very different,” requiring 1,500 patients and a follow-up of 15-20 years.
The safety profile of the novel combination was “no surprise,” Dr. Wang said, and “consistent with what we’re seeing in daily practice.”
Grade 3/4 treatment-related adverse events were seen in 81.5% of patients treated with ibrutinib and 77.3% of those given placebo, and 47.1% and 48.1%, respectively, experienced grade 3/4 neutropenia.
In the post-presentation discussion, Dr. Wang said that approximately 40% of the patients in the placebo group received a BTK inhibitor at progression, and most were given ibrutinib.
He cautioned that the current results cannot be generalized to “other subtypes of lymphoma,” as they are “very different,” with different prognostic factors and different underlying biologies.
The study was funded by Janssen Pharmaceuticals and Pharmacyclics, an AbbVie Company. Dr. Wang has reported relationships with multiple companies, as listed in the article. Dr. Gralow has reported relationships with Genentech, AstraZeneca, Hexal, Puma Biotechnology, Roche, Novartis, Seagen, and Genomic Health.
A version of this article first appeared on Medscape.com.
FROM ASCO 2022
LDL lowering to specific targets may offset risk from high Lp(a)
MILAN – The increased risk for atherosclerotic cardiovascular disease events caused by elevated lipoprotein(a) levels can potentially be precisely offset by lowering LDL cholesterol to specific levels, suggests a novel study that underscores the importance or early intervention.
The results, derived from an analysis of data on Lp(a) and LDL cholesterol levels and associated genetic risk scores in almost 500,000 individuals from the United Kingdom, have been used to develop a series of age-related targets for lowering LDL cholesterol levels to counter the risk associated with lifetime Lp(a) exposure.
Measuring Lp(a) levels can “substantially refine individual estimates of absolute risk of atherosclerotic cardiovascular disease,” said study presenter Brian A. Ference, MD, Centre for Naturally Randomized Trials, University of Cambridge (England).
This can “directly inform treatment decisions about the intensity of LDL lowering or other risk-factor modification needed to overcome the increased risk caused by Lp(a).”
Dr. Ference said this will allow clinicians to personalize the prevention of atherosclerotic cardiovascular disease and identify people “who may benefit from potent Lp(a)-lowering therapies when they become available.”
The research was presented at the European Atherosclerosis Society (EAS) 2022 congress on May 24.
In addition to producing a tabular version of the intensification of LDL-cholesterol reduction needed to overcome the increased cardiovascular risk at different levels of Lp(a), stratified by age, Dr. Ference is working with the EAS to develop an app to further deliver on that personalized prevention.
It will display an individual’s lifetime risk for myocardial infarction or stroke, with and without the inclusion of Lp(a) levels, and determine not only the percentage of increased risk caused by Lp(a), but also the amount by which LDL cholesterol needs to be lowered to overcome that risk.
“The whole rationale for this study was to say, how can we give practical advice on how to use Lp(a) to inform clinical decisions about how to individualize personal risk reduction,” Dr. Ference told this news organization.
“What the app will do is make it very easy for clinicians to, first, understand how much Lp(a) increases risk, but specifically how they can use that information to directly inform their treatment decisions.”
In addition, Dr. Ference said that it will “show patients why it’s important for them” to intensify LDL lowering to overcome their particular level of Lp(a).
Other key takeaways from the results is the importance of intervention as early as possible to minimize the impact of lifetime exposure to increased Lp(a), and that the reduction in LDL cholesterol required to achieve that remains relatively modest.
For Dr. Ference, this means ideally beginning comprehensive health checks at 30 years of age and starting lipid-lowering interventions immediately for those at risk.
“The good thing about LDL and other causes of atherosclerotic cardiovascular disease is it doesn’t really matter how you lower it,” he said, noting that it could be with diet, lifestyle interventions, or medication.
Handy tool
The new app could be a “handy tool to counsel patients,” Florian Kronenberg, MD, Institute of Genetic Epidemiology, Medical University of Innsbruck, Austria, told this news organization.
“We can say, look, you have high Lp(a),” he said. “This is coming from nature, from your genetics, but here we have a point where we can act on your high risk by lowering LDL further. This is important to explain to the patient,” said Dr. Kronenberg, who was not involved in the study.
He emphasized that it is crucial to get across the idea of an individual’s global risk, with not just Lp(a) or cholesterol levels influencing their likelihood of cardiovascular events, but also their age, blood pressure, smoking status, and underlying genetic risk.
Dr. Kronenberg said the current data will be helpful in explaining to clinicians why they should lower LDL-cholesterol levels when a patients had high Lp(a), again centered on the idea of lowering their global risk.
During his presentation, Dr. Ference noted that an increase in Lp(a) levels is associated with a log-linear increase in atherosclerotic cardiovascular disease that is proportional to the absolute, rather than relative, magnitude of Lp(a) increase.
“Unfortunately, unlike other proteins,” he continued, diet and exercise do not affect levels, and there are currently no effective therapies to lower the risks associated with increased Lp(a) concentrations.
“For that reason,” he said, the 2019 ESC/EAS guidelines for the management of dyslipidemias, on which Dr. Ference was a coauthor, “recommend that we intensify life risk-factor modification in persons with elevated risks.”
However, he added, “this guidance is not specific enough to be useful, and that has created a great deal of inertia among clinicians,” with some concluding that they don’t need to measure Lp(a) “because there’s nothing they can do for it.”
Until the development of novel therapies that directly target Lp(a), the authors sought to quantify the amount of LDL lowering needed to “overcome the increased risk caused by Lp(a),” he said.
They studied data on 455,765 individuals from the UK Biobank who did not have a history of cardiovascular events, diabetes, or any cancer before the age of 30. They also had LDL cholesterol levels below 5 mmol/L at the time of enrollment to exclude people with presumed familial hypercholesterolemia.
The researchers used an Lp(a) genetic risk score based on the variants rs10455872 and rs3798220 and an LDL instrumental variable genetic score comprised of 100 variants to randomly categorize individuals with average Lp(a) levels, higher Lp(a) levels, or higher Lp(a) and lower LDL-cholesterol levels.
The data showed that, with elevated absolute levels of measured Lp(a) and with elevated genetic risk scores, there was a progressive increase in the lifetime risk for major coronary events.
When looking at the combination of both increased Lp(a) levels and lower LDL-cholesterol levels, they found that the increase in risk for major coronary events at Lp(a) of 123 nmol/L could be offset by a reduction in LDL-cholesterol levels of 19.5 mg/dL.
For people with an Lp(a) level of 251 nmol/L, the increase in risk for major coronary events was offset by a reduction in LDL-cholesterol levels of 36.1 mg/dL.
Furthermore, the researchers found that the magnitude of intensification of LDL-cholesterol lowering needed to overcome the risk caused by elevated Lp(a) levels varied by age.
For example, in individuals with an Lp(a) level of 220 nmol/L, the reduction in LDL-cholesterol levels needed to offset the risk for major coronary events was calculated to be 0.8 mmol/L if lipid-lowering was started at 30 years of age, rising to 0.9 mmol/L if started at 40 years, 1.2 mmol/L if started at 50 years, and 1.5 mmol/L if started at 60 years.
This, Dr. Ference said, suggests that “diet and lifestyle modification is unlikely to be an effective strategy if started later.”
No funding was declared. Dr. Ference declared relationships with Amgen, Novartis, Merck, Esperion Therapeutics, Pfizer, Regeneron, Sanofi, AstraZeneca, Eli Lilly, Novo Nordisk, The Medicines Company, Mylan, Daiichi Sankyo, Viatris, Ionis Pharmaceuticals, dalCOR, CiVi Pharma, and KrKa Pharmaceuticals. Dr. Kronenberg declared relationships with Amgen, Novartis, and Kaneka.
A version of this article first appeared on Medscape.com.
MILAN – The increased risk for atherosclerotic cardiovascular disease events caused by elevated lipoprotein(a) levels can potentially be precisely offset by lowering LDL cholesterol to specific levels, suggests a novel study that underscores the importance or early intervention.
The results, derived from an analysis of data on Lp(a) and LDL cholesterol levels and associated genetic risk scores in almost 500,000 individuals from the United Kingdom, have been used to develop a series of age-related targets for lowering LDL cholesterol levels to counter the risk associated with lifetime Lp(a) exposure.
Measuring Lp(a) levels can “substantially refine individual estimates of absolute risk of atherosclerotic cardiovascular disease,” said study presenter Brian A. Ference, MD, Centre for Naturally Randomized Trials, University of Cambridge (England).
This can “directly inform treatment decisions about the intensity of LDL lowering or other risk-factor modification needed to overcome the increased risk caused by Lp(a).”
Dr. Ference said this will allow clinicians to personalize the prevention of atherosclerotic cardiovascular disease and identify people “who may benefit from potent Lp(a)-lowering therapies when they become available.”
The research was presented at the European Atherosclerosis Society (EAS) 2022 congress on May 24.
In addition to producing a tabular version of the intensification of LDL-cholesterol reduction needed to overcome the increased cardiovascular risk at different levels of Lp(a), stratified by age, Dr. Ference is working with the EAS to develop an app to further deliver on that personalized prevention.
It will display an individual’s lifetime risk for myocardial infarction or stroke, with and without the inclusion of Lp(a) levels, and determine not only the percentage of increased risk caused by Lp(a), but also the amount by which LDL cholesterol needs to be lowered to overcome that risk.
“The whole rationale for this study was to say, how can we give practical advice on how to use Lp(a) to inform clinical decisions about how to individualize personal risk reduction,” Dr. Ference told this news organization.
“What the app will do is make it very easy for clinicians to, first, understand how much Lp(a) increases risk, but specifically how they can use that information to directly inform their treatment decisions.”
In addition, Dr. Ference said that it will “show patients why it’s important for them” to intensify LDL lowering to overcome their particular level of Lp(a).
Other key takeaways from the results is the importance of intervention as early as possible to minimize the impact of lifetime exposure to increased Lp(a), and that the reduction in LDL cholesterol required to achieve that remains relatively modest.
For Dr. Ference, this means ideally beginning comprehensive health checks at 30 years of age and starting lipid-lowering interventions immediately for those at risk.
“The good thing about LDL and other causes of atherosclerotic cardiovascular disease is it doesn’t really matter how you lower it,” he said, noting that it could be with diet, lifestyle interventions, or medication.
Handy tool
The new app could be a “handy tool to counsel patients,” Florian Kronenberg, MD, Institute of Genetic Epidemiology, Medical University of Innsbruck, Austria, told this news organization.
“We can say, look, you have high Lp(a),” he said. “This is coming from nature, from your genetics, but here we have a point where we can act on your high risk by lowering LDL further. This is important to explain to the patient,” said Dr. Kronenberg, who was not involved in the study.
He emphasized that it is crucial to get across the idea of an individual’s global risk, with not just Lp(a) or cholesterol levels influencing their likelihood of cardiovascular events, but also their age, blood pressure, smoking status, and underlying genetic risk.
Dr. Kronenberg said the current data will be helpful in explaining to clinicians why they should lower LDL-cholesterol levels when a patients had high Lp(a), again centered on the idea of lowering their global risk.
During his presentation, Dr. Ference noted that an increase in Lp(a) levels is associated with a log-linear increase in atherosclerotic cardiovascular disease that is proportional to the absolute, rather than relative, magnitude of Lp(a) increase.
“Unfortunately, unlike other proteins,” he continued, diet and exercise do not affect levels, and there are currently no effective therapies to lower the risks associated with increased Lp(a) concentrations.
“For that reason,” he said, the 2019 ESC/EAS guidelines for the management of dyslipidemias, on which Dr. Ference was a coauthor, “recommend that we intensify life risk-factor modification in persons with elevated risks.”
However, he added, “this guidance is not specific enough to be useful, and that has created a great deal of inertia among clinicians,” with some concluding that they don’t need to measure Lp(a) “because there’s nothing they can do for it.”
Until the development of novel therapies that directly target Lp(a), the authors sought to quantify the amount of LDL lowering needed to “overcome the increased risk caused by Lp(a),” he said.
They studied data on 455,765 individuals from the UK Biobank who did not have a history of cardiovascular events, diabetes, or any cancer before the age of 30. They also had LDL cholesterol levels below 5 mmol/L at the time of enrollment to exclude people with presumed familial hypercholesterolemia.
The researchers used an Lp(a) genetic risk score based on the variants rs10455872 and rs3798220 and an LDL instrumental variable genetic score comprised of 100 variants to randomly categorize individuals with average Lp(a) levels, higher Lp(a) levels, or higher Lp(a) and lower LDL-cholesterol levels.
The data showed that, with elevated absolute levels of measured Lp(a) and with elevated genetic risk scores, there was a progressive increase in the lifetime risk for major coronary events.
When looking at the combination of both increased Lp(a) levels and lower LDL-cholesterol levels, they found that the increase in risk for major coronary events at Lp(a) of 123 nmol/L could be offset by a reduction in LDL-cholesterol levels of 19.5 mg/dL.
For people with an Lp(a) level of 251 nmol/L, the increase in risk for major coronary events was offset by a reduction in LDL-cholesterol levels of 36.1 mg/dL.
Furthermore, the researchers found that the magnitude of intensification of LDL-cholesterol lowering needed to overcome the risk caused by elevated Lp(a) levels varied by age.
For example, in individuals with an Lp(a) level of 220 nmol/L, the reduction in LDL-cholesterol levels needed to offset the risk for major coronary events was calculated to be 0.8 mmol/L if lipid-lowering was started at 30 years of age, rising to 0.9 mmol/L if started at 40 years, 1.2 mmol/L if started at 50 years, and 1.5 mmol/L if started at 60 years.
This, Dr. Ference said, suggests that “diet and lifestyle modification is unlikely to be an effective strategy if started later.”
No funding was declared. Dr. Ference declared relationships with Amgen, Novartis, Merck, Esperion Therapeutics, Pfizer, Regeneron, Sanofi, AstraZeneca, Eli Lilly, Novo Nordisk, The Medicines Company, Mylan, Daiichi Sankyo, Viatris, Ionis Pharmaceuticals, dalCOR, CiVi Pharma, and KrKa Pharmaceuticals. Dr. Kronenberg declared relationships with Amgen, Novartis, and Kaneka.
A version of this article first appeared on Medscape.com.
MILAN – The increased risk for atherosclerotic cardiovascular disease events caused by elevated lipoprotein(a) levels can potentially be precisely offset by lowering LDL cholesterol to specific levels, suggests a novel study that underscores the importance or early intervention.
The results, derived from an analysis of data on Lp(a) and LDL cholesterol levels and associated genetic risk scores in almost 500,000 individuals from the United Kingdom, have been used to develop a series of age-related targets for lowering LDL cholesterol levels to counter the risk associated with lifetime Lp(a) exposure.
Measuring Lp(a) levels can “substantially refine individual estimates of absolute risk of atherosclerotic cardiovascular disease,” said study presenter Brian A. Ference, MD, Centre for Naturally Randomized Trials, University of Cambridge (England).
This can “directly inform treatment decisions about the intensity of LDL lowering or other risk-factor modification needed to overcome the increased risk caused by Lp(a).”
Dr. Ference said this will allow clinicians to personalize the prevention of atherosclerotic cardiovascular disease and identify people “who may benefit from potent Lp(a)-lowering therapies when they become available.”
The research was presented at the European Atherosclerosis Society (EAS) 2022 congress on May 24.
In addition to producing a tabular version of the intensification of LDL-cholesterol reduction needed to overcome the increased cardiovascular risk at different levels of Lp(a), stratified by age, Dr. Ference is working with the EAS to develop an app to further deliver on that personalized prevention.
It will display an individual’s lifetime risk for myocardial infarction or stroke, with and without the inclusion of Lp(a) levels, and determine not only the percentage of increased risk caused by Lp(a), but also the amount by which LDL cholesterol needs to be lowered to overcome that risk.
“The whole rationale for this study was to say, how can we give practical advice on how to use Lp(a) to inform clinical decisions about how to individualize personal risk reduction,” Dr. Ference told this news organization.
“What the app will do is make it very easy for clinicians to, first, understand how much Lp(a) increases risk, but specifically how they can use that information to directly inform their treatment decisions.”
In addition, Dr. Ference said that it will “show patients why it’s important for them” to intensify LDL lowering to overcome their particular level of Lp(a).
Other key takeaways from the results is the importance of intervention as early as possible to minimize the impact of lifetime exposure to increased Lp(a), and that the reduction in LDL cholesterol required to achieve that remains relatively modest.
For Dr. Ference, this means ideally beginning comprehensive health checks at 30 years of age and starting lipid-lowering interventions immediately for those at risk.
“The good thing about LDL and other causes of atherosclerotic cardiovascular disease is it doesn’t really matter how you lower it,” he said, noting that it could be with diet, lifestyle interventions, or medication.
Handy tool
The new app could be a “handy tool to counsel patients,” Florian Kronenberg, MD, Institute of Genetic Epidemiology, Medical University of Innsbruck, Austria, told this news organization.
“We can say, look, you have high Lp(a),” he said. “This is coming from nature, from your genetics, but here we have a point where we can act on your high risk by lowering LDL further. This is important to explain to the patient,” said Dr. Kronenberg, who was not involved in the study.
He emphasized that it is crucial to get across the idea of an individual’s global risk, with not just Lp(a) or cholesterol levels influencing their likelihood of cardiovascular events, but also their age, blood pressure, smoking status, and underlying genetic risk.
Dr. Kronenberg said the current data will be helpful in explaining to clinicians why they should lower LDL-cholesterol levels when a patients had high Lp(a), again centered on the idea of lowering their global risk.
During his presentation, Dr. Ference noted that an increase in Lp(a) levels is associated with a log-linear increase in atherosclerotic cardiovascular disease that is proportional to the absolute, rather than relative, magnitude of Lp(a) increase.
“Unfortunately, unlike other proteins,” he continued, diet and exercise do not affect levels, and there are currently no effective therapies to lower the risks associated with increased Lp(a) concentrations.
“For that reason,” he said, the 2019 ESC/EAS guidelines for the management of dyslipidemias, on which Dr. Ference was a coauthor, “recommend that we intensify life risk-factor modification in persons with elevated risks.”
However, he added, “this guidance is not specific enough to be useful, and that has created a great deal of inertia among clinicians,” with some concluding that they don’t need to measure Lp(a) “because there’s nothing they can do for it.”
Until the development of novel therapies that directly target Lp(a), the authors sought to quantify the amount of LDL lowering needed to “overcome the increased risk caused by Lp(a),” he said.
They studied data on 455,765 individuals from the UK Biobank who did not have a history of cardiovascular events, diabetes, or any cancer before the age of 30. They also had LDL cholesterol levels below 5 mmol/L at the time of enrollment to exclude people with presumed familial hypercholesterolemia.
The researchers used an Lp(a) genetic risk score based on the variants rs10455872 and rs3798220 and an LDL instrumental variable genetic score comprised of 100 variants to randomly categorize individuals with average Lp(a) levels, higher Lp(a) levels, or higher Lp(a) and lower LDL-cholesterol levels.
The data showed that, with elevated absolute levels of measured Lp(a) and with elevated genetic risk scores, there was a progressive increase in the lifetime risk for major coronary events.
When looking at the combination of both increased Lp(a) levels and lower LDL-cholesterol levels, they found that the increase in risk for major coronary events at Lp(a) of 123 nmol/L could be offset by a reduction in LDL-cholesterol levels of 19.5 mg/dL.
For people with an Lp(a) level of 251 nmol/L, the increase in risk for major coronary events was offset by a reduction in LDL-cholesterol levels of 36.1 mg/dL.
Furthermore, the researchers found that the magnitude of intensification of LDL-cholesterol lowering needed to overcome the risk caused by elevated Lp(a) levels varied by age.
For example, in individuals with an Lp(a) level of 220 nmol/L, the reduction in LDL-cholesterol levels needed to offset the risk for major coronary events was calculated to be 0.8 mmol/L if lipid-lowering was started at 30 years of age, rising to 0.9 mmol/L if started at 40 years, 1.2 mmol/L if started at 50 years, and 1.5 mmol/L if started at 60 years.
This, Dr. Ference said, suggests that “diet and lifestyle modification is unlikely to be an effective strategy if started later.”
No funding was declared. Dr. Ference declared relationships with Amgen, Novartis, Merck, Esperion Therapeutics, Pfizer, Regeneron, Sanofi, AstraZeneca, Eli Lilly, Novo Nordisk, The Medicines Company, Mylan, Daiichi Sankyo, Viatris, Ionis Pharmaceuticals, dalCOR, CiVi Pharma, and KrKa Pharmaceuticals. Dr. Kronenberg declared relationships with Amgen, Novartis, and Kaneka.
A version of this article first appeared on Medscape.com.
AT EAS 2022
PPIs should be used ‘judiciously’ in patients with cirrhosis
In a retrospective study to evaluate the impact of proton pump inhibitors (PPIs) on all-cause mortality in patients with cirrhosis, researchers found reduced mortality only in those hospitalized for gastrointestinal bleeding. They reported increased liver-related mortality associated with PPIs in all other patients with cirrhosis.
Patients on PPIs had an 18% reduction in all-cause mortality versus other patients if they had gastrointestinal bleeding. But in those without bleeding, PPIs were associated with a 23% increase in liver-related mortality.
Further analysis suggested that the mortality increase could be related to a 21% increased risk for severe infection with PPI exposure in patients with cirrhosis, as well as a 64% increased risk for decompensation.
“My takeaway from this study is that there should be a nuanced understanding of PPIs and cirrhosis,” corresponding author Nadim Mahmud, MD, MS, University of Pennsylvania, Philadelphia, said in an interview, adding that, if they are to be used in this setting, there should be “a very compelling indication.”
Based on the new analysis, Dr. Mahmud explained, in a patient with cirrhosis hospitalized with a potentially ulcer-related upper gastrointestinal bleed, “we shouldn’t be afraid” to use PPIs “out of fear of potential infection or decompensation because our data demonstrate pretty strongly that that sort of patient may have a mortality benefit.”
In contrast, patients with cirrhosis and “vague abdominal discomfort” are often started on a PPI “just to see if that helps,” Dr. Mahmud said, and they may stay on the medication “in perpetuity, just because they’re so ubiquitously prescribed.”
“In that patient, we should recognize that there is a potential risk of increased infection and decompensation,” he said. There “should be an active effort to deprescribe the PPI or at the very least reduce it to the minimum dose needed for efficacy, if it’s treating a symptom.”
The research was published online in Gastroenterology.
Looking at the big picture of PPIs in people with cirrhosis
The authors noted that the half-life of PPIs is “prolonged in patients with cirrhosis” and that alterations in the gastrointestinal microbiota as a result of gastric acid suppression “may allow for bacterial overgrowth and translocation,” thus increasing the risk for infections.
However, studies of the impact of PPIs on adverse outcomes in patients with cirrhosis have often been hampered by numerous limitations, such as small sample sizes, a “limited ability to control for complex confounding,” or a “narrow focus” on hospitalized patients.
To overcome these problems, the team retrospectively examined data from the Veterans Outcomes and Costs Associated with Liver Diseases cohort, including all adults with incident cirrhosis between January 2008 and June 2021.
They excluded patients with Fibrosis-4 scores less than 1.45 at baseline, as well as those with prior liver transplantation, decompensated cirrhosis at baseline, a diagnosis of hepatocellular carcinoma within 6 months of the index date, and less than 6 months of follow-up.
In all, 76,251 patients with incident cirrhosis met the inclusion criteria, 21% of whom were on a PPI at baseline. The most commonly used PPIs were omeprazole (76.7%), followed by pantoprazole (22.2%) and lansoprazole (0.1%).
Those taking the drugs were more likely than other patients to be White, have metabolic and cardiovascular comorbidities, have a higher median body mass index, and were more likely to have cirrhosis because of alcohol-related liver disease or metabolic-associated fatty liver disease.
Over 49 months of follow-up, all-cause mortality was recorded for 37.5% of patients, of whom 59% experienced non–liver-related death and 41% liver-related mortality.
Multivariate analysis revealed that PPI exposure was not associated with all-cause mortality overall but was significantly associated with reduced all-cause mortality in patients with hospitalization for gastrointestinal bleeding, at a hazard ratio of 0.88.
However, PPI exposure in patients without gastrointestinal bleeding was associated with an increased risk for liver-related mortality (HR, 1.23), but a reduced risk for non–liver-related mortality (HR, 0.88).
Dr. Mahmud and colleagues found that PPI exposure was significantly associated with severe infection (HR, 1.21) and cirrhosis decompensation (HR, 1.64).
The authors suggested that these increased risks “may mediate the observed increased in liver-related mortality.”
Large study suggests limited protective PPI indication
Nancy S. Reau, MD, chair of hepatology at Rush Medical College, Chicago, said that “multiple studies” point to a link between PPI exposure and infection in cirrhosis.
“Although this is a retrospective study, it is very large so we should give credit to the associations,” she said in an interview. She was not involved with the current study.
“The most important message is that we need to be judicious with our therapy,” Dr. Reau added, qualifying that “everything is a risk-benefit ratio.”
“PPI use in cirrhosis has a role but should not overstep its boundary,” she explained. “More simply, if the PPI is indicated, you should not avoid it in a patient with cirrhosis. On the other hand, if you have a patient with advanced liver disease who is chronically taking a PPI, you should question its indication.
Paul Martin, MD, chief of the division of hepatology, University of Miami Health Systems, said in an interview that, when it comes to PPI use in patients with cirrhosis, “judicious is the right word. They should be clearly used if there’s a bona fide indication ... and probably for a finite period of time.”
In a common scenario, “a patient is put on a PPI after they’ve undergone endoscopy with obliteration of varices, and the thought is that PPIs help the ulcers induced by the banding to heal,” said Dr. Martin, who was not associated with the research. “This paper didn’t specifically tease out whether that’s beneficial or not, but it certainly suggests, in patients with a history of gastrointestinal bleeding, that PPIs are still beneficial.”
Dr. Mahmud is supported by the National Institute of Diabetes and Digestive and Kidney Diseases. One coauthor is supported by a National Institutes of Health K23 grant; another is supported by a VA Merit Grant and by a National Cancer Institute R01; a third has received unrelated support from Gilead, Glycotest, and Bayer and also is supported by VA Merit Grants. Dr. Reau and Dr. Martin disclosed no relevant financial relationships.
A version of this article first appeared on Medscape.com.
In a retrospective study to evaluate the impact of proton pump inhibitors (PPIs) on all-cause mortality in patients with cirrhosis, researchers found reduced mortality only in those hospitalized for gastrointestinal bleeding. They reported increased liver-related mortality associated with PPIs in all other patients with cirrhosis.
Patients on PPIs had an 18% reduction in all-cause mortality versus other patients if they had gastrointestinal bleeding. But in those without bleeding, PPIs were associated with a 23% increase in liver-related mortality.
Further analysis suggested that the mortality increase could be related to a 21% increased risk for severe infection with PPI exposure in patients with cirrhosis, as well as a 64% increased risk for decompensation.
“My takeaway from this study is that there should be a nuanced understanding of PPIs and cirrhosis,” corresponding author Nadim Mahmud, MD, MS, University of Pennsylvania, Philadelphia, said in an interview, adding that, if they are to be used in this setting, there should be “a very compelling indication.”
Based on the new analysis, Dr. Mahmud explained, in a patient with cirrhosis hospitalized with a potentially ulcer-related upper gastrointestinal bleed, “we shouldn’t be afraid” to use PPIs “out of fear of potential infection or decompensation because our data demonstrate pretty strongly that that sort of patient may have a mortality benefit.”
In contrast, patients with cirrhosis and “vague abdominal discomfort” are often started on a PPI “just to see if that helps,” Dr. Mahmud said, and they may stay on the medication “in perpetuity, just because they’re so ubiquitously prescribed.”
“In that patient, we should recognize that there is a potential risk of increased infection and decompensation,” he said. There “should be an active effort to deprescribe the PPI or at the very least reduce it to the minimum dose needed for efficacy, if it’s treating a symptom.”
The research was published online in Gastroenterology.
Looking at the big picture of PPIs in people with cirrhosis
The authors noted that the half-life of PPIs is “prolonged in patients with cirrhosis” and that alterations in the gastrointestinal microbiota as a result of gastric acid suppression “may allow for bacterial overgrowth and translocation,” thus increasing the risk for infections.
However, studies of the impact of PPIs on adverse outcomes in patients with cirrhosis have often been hampered by numerous limitations, such as small sample sizes, a “limited ability to control for complex confounding,” or a “narrow focus” on hospitalized patients.
To overcome these problems, the team retrospectively examined data from the Veterans Outcomes and Costs Associated with Liver Diseases cohort, including all adults with incident cirrhosis between January 2008 and June 2021.
They excluded patients with Fibrosis-4 scores less than 1.45 at baseline, as well as those with prior liver transplantation, decompensated cirrhosis at baseline, a diagnosis of hepatocellular carcinoma within 6 months of the index date, and less than 6 months of follow-up.
In all, 76,251 patients with incident cirrhosis met the inclusion criteria, 21% of whom were on a PPI at baseline. The most commonly used PPIs were omeprazole (76.7%), followed by pantoprazole (22.2%) and lansoprazole (0.1%).
Those taking the drugs were more likely than other patients to be White, have metabolic and cardiovascular comorbidities, have a higher median body mass index, and were more likely to have cirrhosis because of alcohol-related liver disease or metabolic-associated fatty liver disease.
Over 49 months of follow-up, all-cause mortality was recorded for 37.5% of patients, of whom 59% experienced non–liver-related death and 41% liver-related mortality.
Multivariate analysis revealed that PPI exposure was not associated with all-cause mortality overall but was significantly associated with reduced all-cause mortality in patients with hospitalization for gastrointestinal bleeding, at a hazard ratio of 0.88.
However, PPI exposure in patients without gastrointestinal bleeding was associated with an increased risk for liver-related mortality (HR, 1.23), but a reduced risk for non–liver-related mortality (HR, 0.88).
Dr. Mahmud and colleagues found that PPI exposure was significantly associated with severe infection (HR, 1.21) and cirrhosis decompensation (HR, 1.64).
The authors suggested that these increased risks “may mediate the observed increased in liver-related mortality.”
Large study suggests limited protective PPI indication
Nancy S. Reau, MD, chair of hepatology at Rush Medical College, Chicago, said that “multiple studies” point to a link between PPI exposure and infection in cirrhosis.
“Although this is a retrospective study, it is very large so we should give credit to the associations,” she said in an interview. She was not involved with the current study.
“The most important message is that we need to be judicious with our therapy,” Dr. Reau added, qualifying that “everything is a risk-benefit ratio.”
“PPI use in cirrhosis has a role but should not overstep its boundary,” she explained. “More simply, if the PPI is indicated, you should not avoid it in a patient with cirrhosis. On the other hand, if you have a patient with advanced liver disease who is chronically taking a PPI, you should question its indication.
Paul Martin, MD, chief of the division of hepatology, University of Miami Health Systems, said in an interview that, when it comes to PPI use in patients with cirrhosis, “judicious is the right word. They should be clearly used if there’s a bona fide indication ... and probably for a finite period of time.”
In a common scenario, “a patient is put on a PPI after they’ve undergone endoscopy with obliteration of varices, and the thought is that PPIs help the ulcers induced by the banding to heal,” said Dr. Martin, who was not associated with the research. “This paper didn’t specifically tease out whether that’s beneficial or not, but it certainly suggests, in patients with a history of gastrointestinal bleeding, that PPIs are still beneficial.”
Dr. Mahmud is supported by the National Institute of Diabetes and Digestive and Kidney Diseases. One coauthor is supported by a National Institutes of Health K23 grant; another is supported by a VA Merit Grant and by a National Cancer Institute R01; a third has received unrelated support from Gilead, Glycotest, and Bayer and also is supported by VA Merit Grants. Dr. Reau and Dr. Martin disclosed no relevant financial relationships.
A version of this article first appeared on Medscape.com.
In a retrospective study to evaluate the impact of proton pump inhibitors (PPIs) on all-cause mortality in patients with cirrhosis, researchers found reduced mortality only in those hospitalized for gastrointestinal bleeding. They reported increased liver-related mortality associated with PPIs in all other patients with cirrhosis.
Patients on PPIs had an 18% reduction in all-cause mortality versus other patients if they had gastrointestinal bleeding. But in those without bleeding, PPIs were associated with a 23% increase in liver-related mortality.
Further analysis suggested that the mortality increase could be related to a 21% increased risk for severe infection with PPI exposure in patients with cirrhosis, as well as a 64% increased risk for decompensation.
“My takeaway from this study is that there should be a nuanced understanding of PPIs and cirrhosis,” corresponding author Nadim Mahmud, MD, MS, University of Pennsylvania, Philadelphia, said in an interview, adding that, if they are to be used in this setting, there should be “a very compelling indication.”
Based on the new analysis, Dr. Mahmud explained, in a patient with cirrhosis hospitalized with a potentially ulcer-related upper gastrointestinal bleed, “we shouldn’t be afraid” to use PPIs “out of fear of potential infection or decompensation because our data demonstrate pretty strongly that that sort of patient may have a mortality benefit.”
In contrast, patients with cirrhosis and “vague abdominal discomfort” are often started on a PPI “just to see if that helps,” Dr. Mahmud said, and they may stay on the medication “in perpetuity, just because they’re so ubiquitously prescribed.”
“In that patient, we should recognize that there is a potential risk of increased infection and decompensation,” he said. There “should be an active effort to deprescribe the PPI or at the very least reduce it to the minimum dose needed for efficacy, if it’s treating a symptom.”
The research was published online in Gastroenterology.
Looking at the big picture of PPIs in people with cirrhosis
The authors noted that the half-life of PPIs is “prolonged in patients with cirrhosis” and that alterations in the gastrointestinal microbiota as a result of gastric acid suppression “may allow for bacterial overgrowth and translocation,” thus increasing the risk for infections.
However, studies of the impact of PPIs on adverse outcomes in patients with cirrhosis have often been hampered by numerous limitations, such as small sample sizes, a “limited ability to control for complex confounding,” or a “narrow focus” on hospitalized patients.
To overcome these problems, the team retrospectively examined data from the Veterans Outcomes and Costs Associated with Liver Diseases cohort, including all adults with incident cirrhosis between January 2008 and June 2021.
They excluded patients with Fibrosis-4 scores less than 1.45 at baseline, as well as those with prior liver transplantation, decompensated cirrhosis at baseline, a diagnosis of hepatocellular carcinoma within 6 months of the index date, and less than 6 months of follow-up.
In all, 76,251 patients with incident cirrhosis met the inclusion criteria, 21% of whom were on a PPI at baseline. The most commonly used PPIs were omeprazole (76.7%), followed by pantoprazole (22.2%) and lansoprazole (0.1%).
Those taking the drugs were more likely than other patients to be White, have metabolic and cardiovascular comorbidities, have a higher median body mass index, and were more likely to have cirrhosis because of alcohol-related liver disease or metabolic-associated fatty liver disease.
Over 49 months of follow-up, all-cause mortality was recorded for 37.5% of patients, of whom 59% experienced non–liver-related death and 41% liver-related mortality.
Multivariate analysis revealed that PPI exposure was not associated with all-cause mortality overall but was significantly associated with reduced all-cause mortality in patients with hospitalization for gastrointestinal bleeding, at a hazard ratio of 0.88.
However, PPI exposure in patients without gastrointestinal bleeding was associated with an increased risk for liver-related mortality (HR, 1.23), but a reduced risk for non–liver-related mortality (HR, 0.88).
Dr. Mahmud and colleagues found that PPI exposure was significantly associated with severe infection (HR, 1.21) and cirrhosis decompensation (HR, 1.64).
The authors suggested that these increased risks “may mediate the observed increased in liver-related mortality.”
Large study suggests limited protective PPI indication
Nancy S. Reau, MD, chair of hepatology at Rush Medical College, Chicago, said that “multiple studies” point to a link between PPI exposure and infection in cirrhosis.
“Although this is a retrospective study, it is very large so we should give credit to the associations,” she said in an interview. She was not involved with the current study.
“The most important message is that we need to be judicious with our therapy,” Dr. Reau added, qualifying that “everything is a risk-benefit ratio.”
“PPI use in cirrhosis has a role but should not overstep its boundary,” she explained. “More simply, if the PPI is indicated, you should not avoid it in a patient with cirrhosis. On the other hand, if you have a patient with advanced liver disease who is chronically taking a PPI, you should question its indication.
Paul Martin, MD, chief of the division of hepatology, University of Miami Health Systems, said in an interview that, when it comes to PPI use in patients with cirrhosis, “judicious is the right word. They should be clearly used if there’s a bona fide indication ... and probably for a finite period of time.”
In a common scenario, “a patient is put on a PPI after they’ve undergone endoscopy with obliteration of varices, and the thought is that PPIs help the ulcers induced by the banding to heal,” said Dr. Martin, who was not associated with the research. “This paper didn’t specifically tease out whether that’s beneficial or not, but it certainly suggests, in patients with a history of gastrointestinal bleeding, that PPIs are still beneficial.”
Dr. Mahmud is supported by the National Institute of Diabetes and Digestive and Kidney Diseases. One coauthor is supported by a National Institutes of Health K23 grant; another is supported by a VA Merit Grant and by a National Cancer Institute R01; a third has received unrelated support from Gilead, Glycotest, and Bayer and also is supported by VA Merit Grants. Dr. Reau and Dr. Martin disclosed no relevant financial relationships.
A version of this article first appeared on Medscape.com.
FROM GASTROENTEROLOGY
Misconceptions remain on gene signature use in breast cancer
BERLIN – , a European survey suggests.
The authors found, for instance, that while most specialists agreed that molecular intrinsic subtypes had clinical utility for understanding prognosis in early-stage hormone receptor (HR)–positive disease and for identifying patients for whom chemotherapy could be safely avoided, about 1 in 4 experts either disagreed or felt neutral about the use of signatures in these settings.
Similarly, almost 75% of respondents felt that these signatures were not useful in the triple-negative or metastatic setting, but a small percentage believed they were, and about 10% were neutral.
“Considering that breast cancer multigene signatures were developed in the post menopausal HR+/HER2- early breast cancer setting, the fact that some experts consider [them] useful in triple-negative, HER2+ breast cancer or in the metastatic setting corroborates a misunderstanding on how to interpret the results,” study author Giuseppe Curigliano, MD, PhD, associate professor of medical oncology at the University of Milan, and colleagues wrote.
Dr. Curigliano, who is also head of the Division of Early Drug Development at the European Institute of Oncology, presented the survey findings on May 4 at the European Society for Medical Oncology (ESMO BCC) Breast Cancer Congress.
Although several breast cancer multigene signatures are available to profile early breast cancer, little information exists on how these signatures should be used in clinical practice.
To investigate, Dr. Curigliano and colleagues convened a scientific committee of eight breast cancer experts to develop a Delphi questionnaire to examine respondents’ opinions and uses of these signatures.
The questionnaire asked about the clinical utility of multigene signatures in breast cancer and recommendations for their use in clinical practice.
In all, 133 breast cancer specialists from 11 European countries completed the questionnaire. Respondents were about 49 years old on average, and most (86.5%) worked in a teaching hospital. More than 72% were medical oncologists; 12% were pathologists.
Consensus was considered to be reached when 70% or more of the respondents were in agreement on a topic.
Participants had “extensive experience in the management of breast cancer patients and have been using breast cancer multigene signatures in clinical practice,” Dr. Curigliano said.
Almost all respondents (93.6%) reported using breast cancer multigene signatures routinely or in selected patients, and 73.4% had more than 5 years of experience with them.
Overall, more than 70% of respondents agreed that identifying tumor intrinsic subtype via gene expression profiling was important in making prognostic and treatment decisions; however, a consensus was not reached on the use of immunohistochemistry.
In addition, most respondents (76%) agreed that identifying breast cancer molecular intrinsic subtypes had clinical utility for prognosis in early-stage HR-positive disease and for identifying patients for whom chemotherapy can be safely avoided (75%). However, in both cases, about one-quarter of respondents either disagreed or felt neutral.
No consensus was reached on the clinical utility of these subtypes for selecting the most appropriate chemotherapy treatment – two-thirds disagreed, while 13% agreed and 17% felt neutral.
When deciding on the use of chemotherapy in the adjuvant setting in early node-negative breast cancer, 88% of respondents felt that breast cancer multigene signatures were important. Moreover, 75% considered such signatures important when deciding whether to use chemotherapy in the adjuvant setting for patients with one to three positive lymph nodes. However, no consensus was reached on the utility of signatures for deciding whether to extend endocrine therapy in either setting.
When examining the usefulness of signatures in more special settings, the authors found that the vast majority (90%) of respondents believed that multigene signatures had clinical utility for postmenopausal early breast cancer patients, and 82% did not consider signatures clinically useful in the early-stage HER2-overexpressed setting.
In addition, 74% thought that breast cancer multigene signatures were not useful in triple-negative disease or in the metastatic setting.
Respondents did not reach a consensus on the clinical utility of multigene signatures in the neoadjuvant setting – only 27% considered them useful, and almost half did not.
The “low percentage” of respondents using the signatures in the neoadjuvant setting and the “misconception regarding the predictive value of these tests on chemotherapy benefits suggest there is still room for training on results interpretation [for breast cancer multigene signatures],” the authors write.
The study was sponsored by Veracyte. Dr. Curigliano has relationships with Pfizer, Novartis, Lilly, Roche, Seattle Genetics, Celltrion, and Veracyte. No other relevant financial relationships were disclosed.
A version of this article first appeared on Medscape.com.
This article was updated 5/9/22.
BERLIN – , a European survey suggests.
The authors found, for instance, that while most specialists agreed that molecular intrinsic subtypes had clinical utility for understanding prognosis in early-stage hormone receptor (HR)–positive disease and for identifying patients for whom chemotherapy could be safely avoided, about 1 in 4 experts either disagreed or felt neutral about the use of signatures in these settings.
Similarly, almost 75% of respondents felt that these signatures were not useful in the triple-negative or metastatic setting, but a small percentage believed they were, and about 10% were neutral.
“Considering that breast cancer multigene signatures were developed in the post menopausal HR+/HER2- early breast cancer setting, the fact that some experts consider [them] useful in triple-negative, HER2+ breast cancer or in the metastatic setting corroborates a misunderstanding on how to interpret the results,” study author Giuseppe Curigliano, MD, PhD, associate professor of medical oncology at the University of Milan, and colleagues wrote.
Dr. Curigliano, who is also head of the Division of Early Drug Development at the European Institute of Oncology, presented the survey findings on May 4 at the European Society for Medical Oncology (ESMO BCC) Breast Cancer Congress.
Although several breast cancer multigene signatures are available to profile early breast cancer, little information exists on how these signatures should be used in clinical practice.
To investigate, Dr. Curigliano and colleagues convened a scientific committee of eight breast cancer experts to develop a Delphi questionnaire to examine respondents’ opinions and uses of these signatures.
The questionnaire asked about the clinical utility of multigene signatures in breast cancer and recommendations for their use in clinical practice.
In all, 133 breast cancer specialists from 11 European countries completed the questionnaire. Respondents were about 49 years old on average, and most (86.5%) worked in a teaching hospital. More than 72% were medical oncologists; 12% were pathologists.
Consensus was considered to be reached when 70% or more of the respondents were in agreement on a topic.
Participants had “extensive experience in the management of breast cancer patients and have been using breast cancer multigene signatures in clinical practice,” Dr. Curigliano said.
Almost all respondents (93.6%) reported using breast cancer multigene signatures routinely or in selected patients, and 73.4% had more than 5 years of experience with them.
Overall, more than 70% of respondents agreed that identifying tumor intrinsic subtype via gene expression profiling was important in making prognostic and treatment decisions; however, a consensus was not reached on the use of immunohistochemistry.
In addition, most respondents (76%) agreed that identifying breast cancer molecular intrinsic subtypes had clinical utility for prognosis in early-stage HR-positive disease and for identifying patients for whom chemotherapy can be safely avoided (75%). However, in both cases, about one-quarter of respondents either disagreed or felt neutral.
No consensus was reached on the clinical utility of these subtypes for selecting the most appropriate chemotherapy treatment – two-thirds disagreed, while 13% agreed and 17% felt neutral.
When deciding on the use of chemotherapy in the adjuvant setting in early node-negative breast cancer, 88% of respondents felt that breast cancer multigene signatures were important. Moreover, 75% considered such signatures important when deciding whether to use chemotherapy in the adjuvant setting for patients with one to three positive lymph nodes. However, no consensus was reached on the utility of signatures for deciding whether to extend endocrine therapy in either setting.
When examining the usefulness of signatures in more special settings, the authors found that the vast majority (90%) of respondents believed that multigene signatures had clinical utility for postmenopausal early breast cancer patients, and 82% did not consider signatures clinically useful in the early-stage HER2-overexpressed setting.
In addition, 74% thought that breast cancer multigene signatures were not useful in triple-negative disease or in the metastatic setting.
Respondents did not reach a consensus on the clinical utility of multigene signatures in the neoadjuvant setting – only 27% considered them useful, and almost half did not.
The “low percentage” of respondents using the signatures in the neoadjuvant setting and the “misconception regarding the predictive value of these tests on chemotherapy benefits suggest there is still room for training on results interpretation [for breast cancer multigene signatures],” the authors write.
The study was sponsored by Veracyte. Dr. Curigliano has relationships with Pfizer, Novartis, Lilly, Roche, Seattle Genetics, Celltrion, and Veracyte. No other relevant financial relationships were disclosed.
A version of this article first appeared on Medscape.com.
This article was updated 5/9/22.
BERLIN – , a European survey suggests.
The authors found, for instance, that while most specialists agreed that molecular intrinsic subtypes had clinical utility for understanding prognosis in early-stage hormone receptor (HR)–positive disease and for identifying patients for whom chemotherapy could be safely avoided, about 1 in 4 experts either disagreed or felt neutral about the use of signatures in these settings.
Similarly, almost 75% of respondents felt that these signatures were not useful in the triple-negative or metastatic setting, but a small percentage believed they were, and about 10% were neutral.
“Considering that breast cancer multigene signatures were developed in the post menopausal HR+/HER2- early breast cancer setting, the fact that some experts consider [them] useful in triple-negative, HER2+ breast cancer or in the metastatic setting corroborates a misunderstanding on how to interpret the results,” study author Giuseppe Curigliano, MD, PhD, associate professor of medical oncology at the University of Milan, and colleagues wrote.
Dr. Curigliano, who is also head of the Division of Early Drug Development at the European Institute of Oncology, presented the survey findings on May 4 at the European Society for Medical Oncology (ESMO BCC) Breast Cancer Congress.
Although several breast cancer multigene signatures are available to profile early breast cancer, little information exists on how these signatures should be used in clinical practice.
To investigate, Dr. Curigliano and colleagues convened a scientific committee of eight breast cancer experts to develop a Delphi questionnaire to examine respondents’ opinions and uses of these signatures.
The questionnaire asked about the clinical utility of multigene signatures in breast cancer and recommendations for their use in clinical practice.
In all, 133 breast cancer specialists from 11 European countries completed the questionnaire. Respondents were about 49 years old on average, and most (86.5%) worked in a teaching hospital. More than 72% were medical oncologists; 12% were pathologists.
Consensus was considered to be reached when 70% or more of the respondents were in agreement on a topic.
Participants had “extensive experience in the management of breast cancer patients and have been using breast cancer multigene signatures in clinical practice,” Dr. Curigliano said.
Almost all respondents (93.6%) reported using breast cancer multigene signatures routinely or in selected patients, and 73.4% had more than 5 years of experience with them.
Overall, more than 70% of respondents agreed that identifying tumor intrinsic subtype via gene expression profiling was important in making prognostic and treatment decisions; however, a consensus was not reached on the use of immunohistochemistry.
In addition, most respondents (76%) agreed that identifying breast cancer molecular intrinsic subtypes had clinical utility for prognosis in early-stage HR-positive disease and for identifying patients for whom chemotherapy can be safely avoided (75%). However, in both cases, about one-quarter of respondents either disagreed or felt neutral.
No consensus was reached on the clinical utility of these subtypes for selecting the most appropriate chemotherapy treatment – two-thirds disagreed, while 13% agreed and 17% felt neutral.
When deciding on the use of chemotherapy in the adjuvant setting in early node-negative breast cancer, 88% of respondents felt that breast cancer multigene signatures were important. Moreover, 75% considered such signatures important when deciding whether to use chemotherapy in the adjuvant setting for patients with one to three positive lymph nodes. However, no consensus was reached on the utility of signatures for deciding whether to extend endocrine therapy in either setting.
When examining the usefulness of signatures in more special settings, the authors found that the vast majority (90%) of respondents believed that multigene signatures had clinical utility for postmenopausal early breast cancer patients, and 82% did not consider signatures clinically useful in the early-stage HER2-overexpressed setting.
In addition, 74% thought that breast cancer multigene signatures were not useful in triple-negative disease or in the metastatic setting.
Respondents did not reach a consensus on the clinical utility of multigene signatures in the neoadjuvant setting – only 27% considered them useful, and almost half did not.
The “low percentage” of respondents using the signatures in the neoadjuvant setting and the “misconception regarding the predictive value of these tests on chemotherapy benefits suggest there is still room for training on results interpretation [for breast cancer multigene signatures],” the authors write.
The study was sponsored by Veracyte. Dr. Curigliano has relationships with Pfizer, Novartis, Lilly, Roche, Seattle Genetics, Celltrion, and Veracyte. No other relevant financial relationships were disclosed.
A version of this article first appeared on Medscape.com.
This article was updated 5/9/22.
AT ESMO BCC 2022
High antipsychotic switch rates suggest ‘suboptimal’ prescribing for first-episode psychosis
In a large-scale, real-world analysis of U.K. prescribing patterns, researchers found more than two-thirds of patients who received antipsychotics for FEP switched medication, and almost half switched drugs three times.
Although this is “one of the largest real-world studies examining antipsychotic treatment strategies,” it reflects findings from previous, smaller studies showing “antipsychotic switching in first episode psychosis is high,” said study investigator Aimee Brinn, Institute of Psychiatry, Psychology & Neuroscience at King’s College London.
This may reflect reports of poor efficacy and suggests that first-line prescribing is “suboptimal,” Ms. Brinn noted. In addition, olanzapine remains the most popular antipsychotic for prescribing despite recent guidelines indicating it is “not ideal ... due to its dangerous metabolic side effects,” she added.
The findings were presented at the Congress of the Schizophrenia International Research Society (SIRS) 2022.
Real-world data
The response to, and tolerability of, antipsychotics differs between patients with FEP; and prescribing patterns “reflect clinician and patient-led decisionmaking,” Ms. Brinn told meeting attendees.
Since randomized controlled trials “do not necessarily reflect prescribing practice in real-world clinical settings,” the researchers gathered data from a large mental health care electronic health record dataset.
The investigators examined records from the South London and Maudsley NHS Foundation Trust (SLaM), which has a catchment area of 1.2 million individuals across four boroughs of London. The group sees approximately 37,500 active patients per week.
The team used the Clinical Interactive Record Search tool to extract data on 2,309 adults with FEP who received care from a SLaM early intervention in psychosis service between April 1, 2008, and March 31, 2019.
They found that 12 different antipsychotics were prescribed as first-line treatment. The most common were olanzapine (43.9%), risperidone (24.7%), and aripiprazole (19.9%).
Results showed that over 81,969.5 person-years of follow-up, at a minimum of 24 months per patient, 68.8% had an antipsychotic switch. The most common first treatment switch, in 17.9% of patients, was from olanzapine to aripiprazole.
Of patients who switched to aripiprazole, 48.4% stayed on the drug, 26% switched back to olanzapine, and 25.6% received other treatment. Overall, 44.7% of patients switched medication at least three times.
Among patients with FEP who did not switch, 42.2% were prescribed olanzapine, 26.2% risperidone, 23.3% aripiprazole, 5.6% quetiapine, and 2.7% amisulpride.
During the post-presentation discussion, Ms. Brinn was asked whether the high rate of first-line olanzapine prescribing could be because patients started treatment as inpatients and were then switched once they were moved to community care.
“We found that a lot of patients would be prescribed olanzapine for around 7 days at the start of their prescription and then switch,” Ms. Brinn said, adding it is “likely” they started as inpatients. The investigators are currently examining the differences between inpatient and outpatient prescriptions to verify whether this is indeed the case, she added.
‘Pulling out the big guns too fast?’
Commenting on the findings, Thomas W. Sedlak, MD, PhD, Johns Hopkins University School of Medicine, Baltimore, said the study raises a “number of questions.”
Both olanzapine and risperidone “tend to have higher treatment effect improvements than aripiprazole, so it’s curious that a switch to aripiprazole was common,” said Dr. Sedlak, who was not involved with the research.
“Are we pulling out the ‘big guns’ too fast, or inappropriately, especially as olanzapine and risperidone carry greater risk of weight gain?” he asked. In addition, “now that olanzapine is available with samidorphan to mitigate weight gain, will that shape future patterns, if it can be paid for?”
Dr. Sedlak noted it was unclear why olanzapine was chosen so often as first-line treatment in the study and agreed it is “possible that hospitalized patients had been prescribed a ‘stronger’ medication like olanzapine compared to never-hospitalized patients.”
He also underlined that it is “not clear if patients in this FEP program are representative of all FEP patients.”
“For instance, if the program is well known to inpatient hospital social workers, then the program might be disproportionately filled with patients who have had more severe symptoms,” Dr. Sedlak said.
The study was supported by Janssen-Cilag. The investigators and Dr. Sedlak have disclosed no relevant financial relationships.
A version of this article first appeared on Medscape.com.
In a large-scale, real-world analysis of U.K. prescribing patterns, researchers found more than two-thirds of patients who received antipsychotics for FEP switched medication, and almost half switched drugs three times.
Although this is “one of the largest real-world studies examining antipsychotic treatment strategies,” it reflects findings from previous, smaller studies showing “antipsychotic switching in first episode psychosis is high,” said study investigator Aimee Brinn, Institute of Psychiatry, Psychology & Neuroscience at King’s College London.
This may reflect reports of poor efficacy and suggests that first-line prescribing is “suboptimal,” Ms. Brinn noted. In addition, olanzapine remains the most popular antipsychotic for prescribing despite recent guidelines indicating it is “not ideal ... due to its dangerous metabolic side effects,” she added.
The findings were presented at the Congress of the Schizophrenia International Research Society (SIRS) 2022.
Real-world data
The response to, and tolerability of, antipsychotics differs between patients with FEP; and prescribing patterns “reflect clinician and patient-led decisionmaking,” Ms. Brinn told meeting attendees.
Since randomized controlled trials “do not necessarily reflect prescribing practice in real-world clinical settings,” the researchers gathered data from a large mental health care electronic health record dataset.
The investigators examined records from the South London and Maudsley NHS Foundation Trust (SLaM), which has a catchment area of 1.2 million individuals across four boroughs of London. The group sees approximately 37,500 active patients per week.
The team used the Clinical Interactive Record Search tool to extract data on 2,309 adults with FEP who received care from a SLaM early intervention in psychosis service between April 1, 2008, and March 31, 2019.
They found that 12 different antipsychotics were prescribed as first-line treatment. The most common were olanzapine (43.9%), risperidone (24.7%), and aripiprazole (19.9%).
Results showed that over 81,969.5 person-years of follow-up, at a minimum of 24 months per patient, 68.8% had an antipsychotic switch. The most common first treatment switch, in 17.9% of patients, was from olanzapine to aripiprazole.
Of patients who switched to aripiprazole, 48.4% stayed on the drug, 26% switched back to olanzapine, and 25.6% received other treatment. Overall, 44.7% of patients switched medication at least three times.
Among patients with FEP who did not switch, 42.2% were prescribed olanzapine, 26.2% risperidone, 23.3% aripiprazole, 5.6% quetiapine, and 2.7% amisulpride.
During the post-presentation discussion, Ms. Brinn was asked whether the high rate of first-line olanzapine prescribing could be because patients started treatment as inpatients and were then switched once they were moved to community care.
“We found that a lot of patients would be prescribed olanzapine for around 7 days at the start of their prescription and then switch,” Ms. Brinn said, adding it is “likely” they started as inpatients. The investigators are currently examining the differences between inpatient and outpatient prescriptions to verify whether this is indeed the case, she added.
‘Pulling out the big guns too fast?’
Commenting on the findings, Thomas W. Sedlak, MD, PhD, Johns Hopkins University School of Medicine, Baltimore, said the study raises a “number of questions.”
Both olanzapine and risperidone “tend to have higher treatment effect improvements than aripiprazole, so it’s curious that a switch to aripiprazole was common,” said Dr. Sedlak, who was not involved with the research.
“Are we pulling out the ‘big guns’ too fast, or inappropriately, especially as olanzapine and risperidone carry greater risk of weight gain?” he asked. In addition, “now that olanzapine is available with samidorphan to mitigate weight gain, will that shape future patterns, if it can be paid for?”
Dr. Sedlak noted it was unclear why olanzapine was chosen so often as first-line treatment in the study and agreed it is “possible that hospitalized patients had been prescribed a ‘stronger’ medication like olanzapine compared to never-hospitalized patients.”
He also underlined that it is “not clear if patients in this FEP program are representative of all FEP patients.”
“For instance, if the program is well known to inpatient hospital social workers, then the program might be disproportionately filled with patients who have had more severe symptoms,” Dr. Sedlak said.
The study was supported by Janssen-Cilag. The investigators and Dr. Sedlak have disclosed no relevant financial relationships.
A version of this article first appeared on Medscape.com.
In a large-scale, real-world analysis of U.K. prescribing patterns, researchers found more than two-thirds of patients who received antipsychotics for FEP switched medication, and almost half switched drugs three times.
Although this is “one of the largest real-world studies examining antipsychotic treatment strategies,” it reflects findings from previous, smaller studies showing “antipsychotic switching in first episode psychosis is high,” said study investigator Aimee Brinn, Institute of Psychiatry, Psychology & Neuroscience at King’s College London.
This may reflect reports of poor efficacy and suggests that first-line prescribing is “suboptimal,” Ms. Brinn noted. In addition, olanzapine remains the most popular antipsychotic for prescribing despite recent guidelines indicating it is “not ideal ... due to its dangerous metabolic side effects,” she added.
The findings were presented at the Congress of the Schizophrenia International Research Society (SIRS) 2022.
Real-world data
The response to, and tolerability of, antipsychotics differs between patients with FEP; and prescribing patterns “reflect clinician and patient-led decisionmaking,” Ms. Brinn told meeting attendees.
Since randomized controlled trials “do not necessarily reflect prescribing practice in real-world clinical settings,” the researchers gathered data from a large mental health care electronic health record dataset.
The investigators examined records from the South London and Maudsley NHS Foundation Trust (SLaM), which has a catchment area of 1.2 million individuals across four boroughs of London. The group sees approximately 37,500 active patients per week.
The team used the Clinical Interactive Record Search tool to extract data on 2,309 adults with FEP who received care from a SLaM early intervention in psychosis service between April 1, 2008, and March 31, 2019.
They found that 12 different antipsychotics were prescribed as first-line treatment. The most common were olanzapine (43.9%), risperidone (24.7%), and aripiprazole (19.9%).
Results showed that over 81,969.5 person-years of follow-up, at a minimum of 24 months per patient, 68.8% had an antipsychotic switch. The most common first treatment switch, in 17.9% of patients, was from olanzapine to aripiprazole.
Of patients who switched to aripiprazole, 48.4% stayed on the drug, 26% switched back to olanzapine, and 25.6% received other treatment. Overall, 44.7% of patients switched medication at least three times.
Among patients with FEP who did not switch, 42.2% were prescribed olanzapine, 26.2% risperidone, 23.3% aripiprazole, 5.6% quetiapine, and 2.7% amisulpride.
During the post-presentation discussion, Ms. Brinn was asked whether the high rate of first-line olanzapine prescribing could be because patients started treatment as inpatients and were then switched once they were moved to community care.
“We found that a lot of patients would be prescribed olanzapine for around 7 days at the start of their prescription and then switch,” Ms. Brinn said, adding it is “likely” they started as inpatients. The investigators are currently examining the differences between inpatient and outpatient prescriptions to verify whether this is indeed the case, she added.
‘Pulling out the big guns too fast?’
Commenting on the findings, Thomas W. Sedlak, MD, PhD, Johns Hopkins University School of Medicine, Baltimore, said the study raises a “number of questions.”
Both olanzapine and risperidone “tend to have higher treatment effect improvements than aripiprazole, so it’s curious that a switch to aripiprazole was common,” said Dr. Sedlak, who was not involved with the research.
“Are we pulling out the ‘big guns’ too fast, or inappropriately, especially as olanzapine and risperidone carry greater risk of weight gain?” he asked. In addition, “now that olanzapine is available with samidorphan to mitigate weight gain, will that shape future patterns, if it can be paid for?”
Dr. Sedlak noted it was unclear why olanzapine was chosen so often as first-line treatment in the study and agreed it is “possible that hospitalized patients had been prescribed a ‘stronger’ medication like olanzapine compared to never-hospitalized patients.”
He also underlined that it is “not clear if patients in this FEP program are representative of all FEP patients.”
“For instance, if the program is well known to inpatient hospital social workers, then the program might be disproportionately filled with patients who have had more severe symptoms,” Dr. Sedlak said.
The study was supported by Janssen-Cilag. The investigators and Dr. Sedlak have disclosed no relevant financial relationships.
A version of this article first appeared on Medscape.com.
FROM SIRS 2022
New combination med for severe mental illness tied to less weight gain
, new research suggests. However, at least one expert says the weight difference between the two drugs is of “questionable clinical benefit.”
Last year, the Food and Drug Administration approved the drug for the treatment of adults with schizophrenia or bipolar I disorder, as a maintenance monotherapy or as either monotherapy or an adjunct to lithium or valproate for acute manic or mixed episodes.
In the ENLIGHTEN-Early trial, researchers examined weight-gain profiles of more than 400 patients with early schizophrenia, schizophreniform disorder, or bipolar I disorder.
Results showed those given combination treatment gained just over half the amount of weight as those given monotherapy. They were also 36% less likely to gain at least 10% of their body weight during the 12-week treatment period.
They indicate that the weight-mitigating effects shown with olanzapine plus samidorphan are “consistent, regardless of the stage of illness,” Dr. Kahn added.
He presented the findings at the annual congress of the Schizophrenia International Research Society.
Potential benefit
“Early intervention with antipsychotic treatment is critical in shaping the course of treatment and the disease trajectory,” coinvestigator Christine Graham, PhD, with Alkermes, which manufactures the drug, told this news organization.
Olanzapine is a “highly effective antipsychotic, but it’s really avoided a lot in this population,” Dr. Graham said. Therefore, patients “could really stand to benefit” from a combination that delivers the same amount of antipsychotic effect, but “reduces the propensity” for clinically significant weight gain, she added.
Dr. Kahn noted in his meeting presentation that antipsychotics are the “cornerstone” of the treatment of serious mental illness, but that “many are associated with concerning weight gain and cardiometabolic effects.”
While olanzapine is an effective medication, it has “one of the highest weight gain” profiles of the available antipsychotics and patients early on in their illness are “especially vulnerable,” Dr. Kahn said.
Previous studies have shown the combination of olanzapine plus samidorphan is similarly effective as olanzapine, but is associated with less weight gain.
To determine its impact in recent-onset illness, the current researchers screened patients with schizophrenia, schizophreniform disorder, or bipolar I disorder. The patients were aged 16-39 years and had an initial onset of active phase symptoms less than 4 years previously. They had less than 24 weeks’ cumulative lifetime exposure to antipsychotics.
Participants were randomly assigned to receive olanzapine plus samidorphan or olanzapine alone for 12 weeks, and then followed up for safety assessment for a further 4 weeks.
A total of 426 patients were recruited and 76.5% completed the study. The mean age was 25.8 years, 66.2% were men, 66.4% were White, and 28.2% were Black.
The mean body mass index at baseline was 23.69 kg/m2. The most common diagnosis among the participants was schizophrenia (62.9%) followed by bipolar I disorder (21.6%).
Less weight gain
Results of the 12-week study showed a significant difference in percent change in body weight from baseline between the two treatment groups, with a gain of 4.91% for the olanzapine plus samidorphan group vs. 6.77% for the olanzapine-alone group (between-group difference, 1.87%; P = .012).
Dr. Kahn noted this equates to an average weight gain of 2.8 kg (6.2 pounds) with olanzapine plus samidorphan and a gain of about 5 kg (11pounds) with olanzapine.
“It’s not a huge difference, but it’s certainly a significant one,” he said. “I also think it’s clinically important and significant.”
The reduction in weight gain compared with olanzapine was even maintained in patients assigned to olanzapine plus samidorphan who dropped out and did not complete the study, Dr. Kahn reported. “No one really had a weight gain,” he said.
In contrast, patients in the olanzapine groups who dropped out of the study had weight gain larger than their counterparts who stayed in it.
Further analysis showed the proportion of patients who gained 10% or more of their body weight by week 12 was 21.9% for those receiving olanzapine plus samidorphan vs. 30.4% for those receiving just olanzapine (odds ratio, 0.64; P = .075).
As expected, the improvement in Clinical Global Impression–Severity scale scores was almost identical between the olanzapine + samidorphan and olanzapine-only groups.
For safety, Dr. Kahn said the adverse event rates were “very, very similar” between the two treatment arms, which was a pattern that was repeated for serious AEs. This led him to note that “nothing out of the ordinary” was observed.
Clinical impact 'questionable'
Commenting on the study, Laura LaChance, MD, a psychiatrist at St. Mary’s Hospital Centre, McGill University, Montreal, said the actual amount of weight loss shown in the study “is of questionable clinical significance.”
On the other hand, Dr. LaChance said she has achieved “better results with metformin, which has a great safety profile and is cheap and widely available.
“Cost is always a concern in patients with psychotic disorders,” she concluded.
The study was funded by Alkermes. Dr. Kahn reported having relationships with Alkermes, Angelini, Janssen, Sunovion, Otsuka, Merck, Minerva Neuroscience, Roche, and Teva. Dr. Graham is an employee of Alkermes.
A version of this article first appeared on Medscape.com.
, new research suggests. However, at least one expert says the weight difference between the two drugs is of “questionable clinical benefit.”
Last year, the Food and Drug Administration approved the drug for the treatment of adults with schizophrenia or bipolar I disorder, as a maintenance monotherapy or as either monotherapy or an adjunct to lithium or valproate for acute manic or mixed episodes.
In the ENLIGHTEN-Early trial, researchers examined weight-gain profiles of more than 400 patients with early schizophrenia, schizophreniform disorder, or bipolar I disorder.
Results showed those given combination treatment gained just over half the amount of weight as those given monotherapy. They were also 36% less likely to gain at least 10% of their body weight during the 12-week treatment period.
They indicate that the weight-mitigating effects shown with olanzapine plus samidorphan are “consistent, regardless of the stage of illness,” Dr. Kahn added.
He presented the findings at the annual congress of the Schizophrenia International Research Society.
Potential benefit
“Early intervention with antipsychotic treatment is critical in shaping the course of treatment and the disease trajectory,” coinvestigator Christine Graham, PhD, with Alkermes, which manufactures the drug, told this news organization.
Olanzapine is a “highly effective antipsychotic, but it’s really avoided a lot in this population,” Dr. Graham said. Therefore, patients “could really stand to benefit” from a combination that delivers the same amount of antipsychotic effect, but “reduces the propensity” for clinically significant weight gain, she added.
Dr. Kahn noted in his meeting presentation that antipsychotics are the “cornerstone” of the treatment of serious mental illness, but that “many are associated with concerning weight gain and cardiometabolic effects.”
While olanzapine is an effective medication, it has “one of the highest weight gain” profiles of the available antipsychotics and patients early on in their illness are “especially vulnerable,” Dr. Kahn said.
Previous studies have shown the combination of olanzapine plus samidorphan is similarly effective as olanzapine, but is associated with less weight gain.
To determine its impact in recent-onset illness, the current researchers screened patients with schizophrenia, schizophreniform disorder, or bipolar I disorder. The patients were aged 16-39 years and had an initial onset of active phase symptoms less than 4 years previously. They had less than 24 weeks’ cumulative lifetime exposure to antipsychotics.
Participants were randomly assigned to receive olanzapine plus samidorphan or olanzapine alone for 12 weeks, and then followed up for safety assessment for a further 4 weeks.
A total of 426 patients were recruited and 76.5% completed the study. The mean age was 25.8 years, 66.2% were men, 66.4% were White, and 28.2% were Black.
The mean body mass index at baseline was 23.69 kg/m2. The most common diagnosis among the participants was schizophrenia (62.9%) followed by bipolar I disorder (21.6%).
Less weight gain
Results of the 12-week study showed a significant difference in percent change in body weight from baseline between the two treatment groups, with a gain of 4.91% for the olanzapine plus samidorphan group vs. 6.77% for the olanzapine-alone group (between-group difference, 1.87%; P = .012).
Dr. Kahn noted this equates to an average weight gain of 2.8 kg (6.2 pounds) with olanzapine plus samidorphan and a gain of about 5 kg (11pounds) with olanzapine.
“It’s not a huge difference, but it’s certainly a significant one,” he said. “I also think it’s clinically important and significant.”
The reduction in weight gain compared with olanzapine was even maintained in patients assigned to olanzapine plus samidorphan who dropped out and did not complete the study, Dr. Kahn reported. “No one really had a weight gain,” he said.
In contrast, patients in the olanzapine groups who dropped out of the study had weight gain larger than their counterparts who stayed in it.
Further analysis showed the proportion of patients who gained 10% or more of their body weight by week 12 was 21.9% for those receiving olanzapine plus samidorphan vs. 30.4% for those receiving just olanzapine (odds ratio, 0.64; P = .075).
As expected, the improvement in Clinical Global Impression–Severity scale scores was almost identical between the olanzapine + samidorphan and olanzapine-only groups.
For safety, Dr. Kahn said the adverse event rates were “very, very similar” between the two treatment arms, which was a pattern that was repeated for serious AEs. This led him to note that “nothing out of the ordinary” was observed.
Clinical impact 'questionable'
Commenting on the study, Laura LaChance, MD, a psychiatrist at St. Mary’s Hospital Centre, McGill University, Montreal, said the actual amount of weight loss shown in the study “is of questionable clinical significance.”
On the other hand, Dr. LaChance said she has achieved “better results with metformin, which has a great safety profile and is cheap and widely available.
“Cost is always a concern in patients with psychotic disorders,” she concluded.
The study was funded by Alkermes. Dr. Kahn reported having relationships with Alkermes, Angelini, Janssen, Sunovion, Otsuka, Merck, Minerva Neuroscience, Roche, and Teva. Dr. Graham is an employee of Alkermes.
A version of this article first appeared on Medscape.com.
, new research suggests. However, at least one expert says the weight difference between the two drugs is of “questionable clinical benefit.”
Last year, the Food and Drug Administration approved the drug for the treatment of adults with schizophrenia or bipolar I disorder, as a maintenance monotherapy or as either monotherapy or an adjunct to lithium or valproate for acute manic or mixed episodes.
In the ENLIGHTEN-Early trial, researchers examined weight-gain profiles of more than 400 patients with early schizophrenia, schizophreniform disorder, or bipolar I disorder.
Results showed those given combination treatment gained just over half the amount of weight as those given monotherapy. They were also 36% less likely to gain at least 10% of their body weight during the 12-week treatment period.
They indicate that the weight-mitigating effects shown with olanzapine plus samidorphan are “consistent, regardless of the stage of illness,” Dr. Kahn added.
He presented the findings at the annual congress of the Schizophrenia International Research Society.
Potential benefit
“Early intervention with antipsychotic treatment is critical in shaping the course of treatment and the disease trajectory,” coinvestigator Christine Graham, PhD, with Alkermes, which manufactures the drug, told this news organization.
Olanzapine is a “highly effective antipsychotic, but it’s really avoided a lot in this population,” Dr. Graham said. Therefore, patients “could really stand to benefit” from a combination that delivers the same amount of antipsychotic effect, but “reduces the propensity” for clinically significant weight gain, she added.
Dr. Kahn noted in his meeting presentation that antipsychotics are the “cornerstone” of the treatment of serious mental illness, but that “many are associated with concerning weight gain and cardiometabolic effects.”
While olanzapine is an effective medication, it has “one of the highest weight gain” profiles of the available antipsychotics and patients early on in their illness are “especially vulnerable,” Dr. Kahn said.
Previous studies have shown the combination of olanzapine plus samidorphan is similarly effective as olanzapine, but is associated with less weight gain.
To determine its impact in recent-onset illness, the current researchers screened patients with schizophrenia, schizophreniform disorder, or bipolar I disorder. The patients were aged 16-39 years and had an initial onset of active phase symptoms less than 4 years previously. They had less than 24 weeks’ cumulative lifetime exposure to antipsychotics.
Participants were randomly assigned to receive olanzapine plus samidorphan or olanzapine alone for 12 weeks, and then followed up for safety assessment for a further 4 weeks.
A total of 426 patients were recruited and 76.5% completed the study. The mean age was 25.8 years, 66.2% were men, 66.4% were White, and 28.2% were Black.
The mean body mass index at baseline was 23.69 kg/m2. The most common diagnosis among the participants was schizophrenia (62.9%) followed by bipolar I disorder (21.6%).
Less weight gain
Results of the 12-week study showed a significant difference in percent change in body weight from baseline between the two treatment groups, with a gain of 4.91% for the olanzapine plus samidorphan group vs. 6.77% for the olanzapine-alone group (between-group difference, 1.87%; P = .012).
Dr. Kahn noted this equates to an average weight gain of 2.8 kg (6.2 pounds) with olanzapine plus samidorphan and a gain of about 5 kg (11pounds) with olanzapine.
“It’s not a huge difference, but it’s certainly a significant one,” he said. “I also think it’s clinically important and significant.”
The reduction in weight gain compared with olanzapine was even maintained in patients assigned to olanzapine plus samidorphan who dropped out and did not complete the study, Dr. Kahn reported. “No one really had a weight gain,” he said.
In contrast, patients in the olanzapine groups who dropped out of the study had weight gain larger than their counterparts who stayed in it.
Further analysis showed the proportion of patients who gained 10% or more of their body weight by week 12 was 21.9% for those receiving olanzapine plus samidorphan vs. 30.4% for those receiving just olanzapine (odds ratio, 0.64; P = .075).
As expected, the improvement in Clinical Global Impression–Severity scale scores was almost identical between the olanzapine + samidorphan and olanzapine-only groups.
For safety, Dr. Kahn said the adverse event rates were “very, very similar” between the two treatment arms, which was a pattern that was repeated for serious AEs. This led him to note that “nothing out of the ordinary” was observed.
Clinical impact 'questionable'
Commenting on the study, Laura LaChance, MD, a psychiatrist at St. Mary’s Hospital Centre, McGill University, Montreal, said the actual amount of weight loss shown in the study “is of questionable clinical significance.”
On the other hand, Dr. LaChance said she has achieved “better results with metformin, which has a great safety profile and is cheap and widely available.
“Cost is always a concern in patients with psychotic disorders,” she concluded.
The study was funded by Alkermes. Dr. Kahn reported having relationships with Alkermes, Angelini, Janssen, Sunovion, Otsuka, Merck, Minerva Neuroscience, Roche, and Teva. Dr. Graham is an employee of Alkermes.
A version of this article first appeared on Medscape.com.
FROM SIRS 2022
