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Antibiotic prescribing: How to manage patient pressures
Inappropriate antibiotic prescribing in the face of growing microbial resistance is a global public health problem, and a major cause is perceived patient pressure.
At the annual meeting of the European Society for Paediatric Infectious Diseases, held virtually this year, Tanya Stivers, PhD, professor of sociology at the University of California, Los Angeles, presented some of her team’s work studying patterns of clinical prescription.
It is widely appreciated that inappropriate prescribing is a common problem that the medical community seems powerless to stop, particularly in primary care. Already, clinicians are running out of effective antibiotics to treat a range of serious infections. Dr. Stivers began by saying that this problem isn’t caused by a lack of understanding about disease causation and microbial resistance or patients overtly demanding antibiotics, which occurs in less than 2% of cases. Instead, the cause appears to lie in doctor-patient interactions during consultations.
In pediatric practice, physicians have previously been found to prescribe antibiotics for a clinically diagnosed respiratory viral infection in 62% of cases when they perceive that this diagnosis was expected by parents, compared with 7% in the absence of such perception. Similarly, associated ear infections were diagnosed three times more often, and sinus infections seven times more often, leading to increased prescribing.
In adult practice, Dr. Stivers reported that patients can exert subtle pressure to prescribe through:
- Priming. Patients help their physician to see the problem as relatively severe (e.g., a sore throat that “feels like a knife”).
- Nudging. Patients redirect physicians back to a bacterial problem (e.g., “I’ve tried all these medicines, and nothing worked”). Nudging was found to occur in 41% of encounters.
- Resisting. Patients contest diagnosis or treatment in 40% of consultations (e.g., “there was pus yesterday”).
Priming or nudging resulted in antibiotic prescribing in 60% of patients without signs of a bacterial infection, compared with 30% where this was not a feature (P < 0.05).
But how can these pressures be countered? Dr. Stivers offered advice based on her original data from 570 video recordings of pediatric encounters. The current findings come from an analysis of 68 adult primary care visits for upper respiratory tract infections in Southern California. Inappropriate prescribing was identified in 37%.
When researching the antibiotic prescribing problem, it is helpful to explore a typical primary care consultation. The acute medical visit structure is a stepwise process involving opening, establishing the problem, gathering information, counseling, and then closing the consultation. It is important is to recognize that patients shape prescribing decisions, and effective communication is vital in influencing the outcome. In Dr. Stivers’ experience, priming, nudging, and resisting result in antibiotic prescribing in 60% of cases in whom clinical signs of bacterial illness are absent, compared with 30% where patient pressure is not a feature.
How can we change practice? Global experience suggests that printed material aimed at physicians is only of marginal benefit. By comparison, patient education does work but needs to be repeated, and there’s always a reason why this consultation should be “special.”
Try a 3-prong communication plan
To counteract these pressures, Dr. Stivers recommends a three-prong communication plan to influence the consultation:
- Foreshadowing, where suggesting that the cause of the patient’s symptoms is likely to be viral is introduced early in the consultation. This approach was found to reduce antibiotic prescribing to 33%, compared with 59% without foreshadowing (P < .05). Resistance may also be reduced.
- Affirmative nonantibiotic treatment plans, where specific positive recommendations given early (e.g., “I’m going to put you on some medicine to try to dry that out”) are less likely to be resisted than is vague negative advice at the end of a consultation.
- Persuasion, which involves explaining the diagnosis and nature of a cough and cold, educating about viral and bacterial differences, and presenting the risks of antibiotics. When persuasion is employed, antibiotic prescribing is reduced to 33%, compared with 63% (P < .05) without persuasion. In general, effective foreshadowing and affirmation should avoid the need for persuasion.
Dr. Stivers’ research suggests that these techniques work, but to do so, they should be delivered naturally as part of routine practice. Interestingly, her data showed that physicians rarely foreshadowed, and when they encountered resistance, they adopted persuasion in 53% of cases. By comparison, affirmative recommendations were used in 89% of cases, but their effects were reduced by the physician being vague and nonspecific.
In conclusion, Dr. Stivers said that addressing inappropriate prescribing requires awareness but that is not enough. The challenge is to reconsider health policies and ways of communicating about antibiotics. There is no downside to foreshadowing a likely viral origin, delivering affirmation, or using persuasion. She added, “If we can make even a 5%-10% reduction [in prescribing], wouldn’t it be worth it?”
Questions answered
A question-and-answer session followed Dr. Stivers’ presentation, and points raised included:
- Physicians have a desire to please. Dr. Stivers countered this point by saying that satisfaction is not tied to antibiotic prescription, and that physicians often misjudge what patients want. It’s important to communicate other treatment options because patients often just want “something they can do.”
- Decision fatigue is often a factor. Evidence shows that antibiotic prescription is more frequent toward the end of a shift. Doctors should avoid negotiation because it increases consultation time. Here, foreshadowing early on may help. Setting may also be important – prescription is more frequent in the ED.
- Vaccine-resistant parents often want active treatment. Here, conversations can be challenging. Trying to persuade may be a less successful than giving positive instruction (e.g., “we’ll give you a vaccine today.”) Resistance is likely to be lower.
- Concern was expressed about manipulating patients ahead of a firm diagnosis. Could this lead to missing a serious bacterial infection? Dr. Stivers acknowledged that this was a gamble. She recommended a “neutral” early foreshadowing statement such as “we are seeing a lot of viral infections at the present.”
- Cultural differences can have an effect. In China, for example, the argument between parents and physicians no longer focuses on antibiotics versus nonantibiotics but rather on oral versus intravenous administration.
- Litigation is a factor in prescribing, especially in the United States. Dr. Stivers stated that her proposed approach to prescribing should not interfere with appropriate management. The clinical picture can change, and antibiotics should be prescribed where needed.
- Audits improve prescribing in the short term. These results were based on recorded consultations, and that factor may have influenced management. In unrecorded consultations, inappropriate antibiotic prescription would be higher.
- Increased point-of-care testing can reduce unnecessary prescribing. This has been documented in countries such as Sweden. Evidence from China suggests that many patients will still receive antibiotics even if a bacterial cause is excluded.
When patients dictate treatment, sometimes we must tell them what is best. Dr. Stivers closed her presentation by emphasizing that, “how you say things will matter.”
Louis Bont, MD, PhD, chair of this session and pediatric infectious diseases specialist at the University Medical Center Utrecht (the Netherlands), commented: “Antimicrobial resistance is a global health threat which jeopardizes sustainable health goals. The World Health Organization has declared that antimicrobial resistance is one of the top 10 global public health threats facing humanity. Resistance to ciprofloxacin varies from 8%-93% in Escherichia coli and 4%-80% in Klebsiella pneumoniae. Colistin is the only last-resort treatment for life-threatening infections caused by carbapenem-resistant enterobacteriaceae.”
Dr. Stivers stated that she has nothing to disclose.
Inappropriate antibiotic prescribing in the face of growing microbial resistance is a global public health problem, and a major cause is perceived patient pressure.
At the annual meeting of the European Society for Paediatric Infectious Diseases, held virtually this year, Tanya Stivers, PhD, professor of sociology at the University of California, Los Angeles, presented some of her team’s work studying patterns of clinical prescription.
It is widely appreciated that inappropriate prescribing is a common problem that the medical community seems powerless to stop, particularly in primary care. Already, clinicians are running out of effective antibiotics to treat a range of serious infections. Dr. Stivers began by saying that this problem isn’t caused by a lack of understanding about disease causation and microbial resistance or patients overtly demanding antibiotics, which occurs in less than 2% of cases. Instead, the cause appears to lie in doctor-patient interactions during consultations.
In pediatric practice, physicians have previously been found to prescribe antibiotics for a clinically diagnosed respiratory viral infection in 62% of cases when they perceive that this diagnosis was expected by parents, compared with 7% in the absence of such perception. Similarly, associated ear infections were diagnosed three times more often, and sinus infections seven times more often, leading to increased prescribing.
In adult practice, Dr. Stivers reported that patients can exert subtle pressure to prescribe through:
- Priming. Patients help their physician to see the problem as relatively severe (e.g., a sore throat that “feels like a knife”).
- Nudging. Patients redirect physicians back to a bacterial problem (e.g., “I’ve tried all these medicines, and nothing worked”). Nudging was found to occur in 41% of encounters.
- Resisting. Patients contest diagnosis or treatment in 40% of consultations (e.g., “there was pus yesterday”).
Priming or nudging resulted in antibiotic prescribing in 60% of patients without signs of a bacterial infection, compared with 30% where this was not a feature (P < 0.05).
But how can these pressures be countered? Dr. Stivers offered advice based on her original data from 570 video recordings of pediatric encounters. The current findings come from an analysis of 68 adult primary care visits for upper respiratory tract infections in Southern California. Inappropriate prescribing was identified in 37%.
When researching the antibiotic prescribing problem, it is helpful to explore a typical primary care consultation. The acute medical visit structure is a stepwise process involving opening, establishing the problem, gathering information, counseling, and then closing the consultation. It is important is to recognize that patients shape prescribing decisions, and effective communication is vital in influencing the outcome. In Dr. Stivers’ experience, priming, nudging, and resisting result in antibiotic prescribing in 60% of cases in whom clinical signs of bacterial illness are absent, compared with 30% where patient pressure is not a feature.
How can we change practice? Global experience suggests that printed material aimed at physicians is only of marginal benefit. By comparison, patient education does work but needs to be repeated, and there’s always a reason why this consultation should be “special.”
Try a 3-prong communication plan
To counteract these pressures, Dr. Stivers recommends a three-prong communication plan to influence the consultation:
- Foreshadowing, where suggesting that the cause of the patient’s symptoms is likely to be viral is introduced early in the consultation. This approach was found to reduce antibiotic prescribing to 33%, compared with 59% without foreshadowing (P < .05). Resistance may also be reduced.
- Affirmative nonantibiotic treatment plans, where specific positive recommendations given early (e.g., “I’m going to put you on some medicine to try to dry that out”) are less likely to be resisted than is vague negative advice at the end of a consultation.
- Persuasion, which involves explaining the diagnosis and nature of a cough and cold, educating about viral and bacterial differences, and presenting the risks of antibiotics. When persuasion is employed, antibiotic prescribing is reduced to 33%, compared with 63% (P < .05) without persuasion. In general, effective foreshadowing and affirmation should avoid the need for persuasion.
Dr. Stivers’ research suggests that these techniques work, but to do so, they should be delivered naturally as part of routine practice. Interestingly, her data showed that physicians rarely foreshadowed, and when they encountered resistance, they adopted persuasion in 53% of cases. By comparison, affirmative recommendations were used in 89% of cases, but their effects were reduced by the physician being vague and nonspecific.
In conclusion, Dr. Stivers said that addressing inappropriate prescribing requires awareness but that is not enough. The challenge is to reconsider health policies and ways of communicating about antibiotics. There is no downside to foreshadowing a likely viral origin, delivering affirmation, or using persuasion. She added, “If we can make even a 5%-10% reduction [in prescribing], wouldn’t it be worth it?”
Questions answered
A question-and-answer session followed Dr. Stivers’ presentation, and points raised included:
- Physicians have a desire to please. Dr. Stivers countered this point by saying that satisfaction is not tied to antibiotic prescription, and that physicians often misjudge what patients want. It’s important to communicate other treatment options because patients often just want “something they can do.”
- Decision fatigue is often a factor. Evidence shows that antibiotic prescription is more frequent toward the end of a shift. Doctors should avoid negotiation because it increases consultation time. Here, foreshadowing early on may help. Setting may also be important – prescription is more frequent in the ED.
- Vaccine-resistant parents often want active treatment. Here, conversations can be challenging. Trying to persuade may be a less successful than giving positive instruction (e.g., “we’ll give you a vaccine today.”) Resistance is likely to be lower.
- Concern was expressed about manipulating patients ahead of a firm diagnosis. Could this lead to missing a serious bacterial infection? Dr. Stivers acknowledged that this was a gamble. She recommended a “neutral” early foreshadowing statement such as “we are seeing a lot of viral infections at the present.”
- Cultural differences can have an effect. In China, for example, the argument between parents and physicians no longer focuses on antibiotics versus nonantibiotics but rather on oral versus intravenous administration.
- Litigation is a factor in prescribing, especially in the United States. Dr. Stivers stated that her proposed approach to prescribing should not interfere with appropriate management. The clinical picture can change, and antibiotics should be prescribed where needed.
- Audits improve prescribing in the short term. These results were based on recorded consultations, and that factor may have influenced management. In unrecorded consultations, inappropriate antibiotic prescription would be higher.
- Increased point-of-care testing can reduce unnecessary prescribing. This has been documented in countries such as Sweden. Evidence from China suggests that many patients will still receive antibiotics even if a bacterial cause is excluded.
When patients dictate treatment, sometimes we must tell them what is best. Dr. Stivers closed her presentation by emphasizing that, “how you say things will matter.”
Louis Bont, MD, PhD, chair of this session and pediatric infectious diseases specialist at the University Medical Center Utrecht (the Netherlands), commented: “Antimicrobial resistance is a global health threat which jeopardizes sustainable health goals. The World Health Organization has declared that antimicrobial resistance is one of the top 10 global public health threats facing humanity. Resistance to ciprofloxacin varies from 8%-93% in Escherichia coli and 4%-80% in Klebsiella pneumoniae. Colistin is the only last-resort treatment for life-threatening infections caused by carbapenem-resistant enterobacteriaceae.”
Dr. Stivers stated that she has nothing to disclose.
Inappropriate antibiotic prescribing in the face of growing microbial resistance is a global public health problem, and a major cause is perceived patient pressure.
At the annual meeting of the European Society for Paediatric Infectious Diseases, held virtually this year, Tanya Stivers, PhD, professor of sociology at the University of California, Los Angeles, presented some of her team’s work studying patterns of clinical prescription.
It is widely appreciated that inappropriate prescribing is a common problem that the medical community seems powerless to stop, particularly in primary care. Already, clinicians are running out of effective antibiotics to treat a range of serious infections. Dr. Stivers began by saying that this problem isn’t caused by a lack of understanding about disease causation and microbial resistance or patients overtly demanding antibiotics, which occurs in less than 2% of cases. Instead, the cause appears to lie in doctor-patient interactions during consultations.
In pediatric practice, physicians have previously been found to prescribe antibiotics for a clinically diagnosed respiratory viral infection in 62% of cases when they perceive that this diagnosis was expected by parents, compared with 7% in the absence of such perception. Similarly, associated ear infections were diagnosed three times more often, and sinus infections seven times more often, leading to increased prescribing.
In adult practice, Dr. Stivers reported that patients can exert subtle pressure to prescribe through:
- Priming. Patients help their physician to see the problem as relatively severe (e.g., a sore throat that “feels like a knife”).
- Nudging. Patients redirect physicians back to a bacterial problem (e.g., “I’ve tried all these medicines, and nothing worked”). Nudging was found to occur in 41% of encounters.
- Resisting. Patients contest diagnosis or treatment in 40% of consultations (e.g., “there was pus yesterday”).
Priming or nudging resulted in antibiotic prescribing in 60% of patients without signs of a bacterial infection, compared with 30% where this was not a feature (P < 0.05).
But how can these pressures be countered? Dr. Stivers offered advice based on her original data from 570 video recordings of pediatric encounters. The current findings come from an analysis of 68 adult primary care visits for upper respiratory tract infections in Southern California. Inappropriate prescribing was identified in 37%.
When researching the antibiotic prescribing problem, it is helpful to explore a typical primary care consultation. The acute medical visit structure is a stepwise process involving opening, establishing the problem, gathering information, counseling, and then closing the consultation. It is important is to recognize that patients shape prescribing decisions, and effective communication is vital in influencing the outcome. In Dr. Stivers’ experience, priming, nudging, and resisting result in antibiotic prescribing in 60% of cases in whom clinical signs of bacterial illness are absent, compared with 30% where patient pressure is not a feature.
How can we change practice? Global experience suggests that printed material aimed at physicians is only of marginal benefit. By comparison, patient education does work but needs to be repeated, and there’s always a reason why this consultation should be “special.”
Try a 3-prong communication plan
To counteract these pressures, Dr. Stivers recommends a three-prong communication plan to influence the consultation:
- Foreshadowing, where suggesting that the cause of the patient’s symptoms is likely to be viral is introduced early in the consultation. This approach was found to reduce antibiotic prescribing to 33%, compared with 59% without foreshadowing (P < .05). Resistance may also be reduced.
- Affirmative nonantibiotic treatment plans, where specific positive recommendations given early (e.g., “I’m going to put you on some medicine to try to dry that out”) are less likely to be resisted than is vague negative advice at the end of a consultation.
- Persuasion, which involves explaining the diagnosis and nature of a cough and cold, educating about viral and bacterial differences, and presenting the risks of antibiotics. When persuasion is employed, antibiotic prescribing is reduced to 33%, compared with 63% (P < .05) without persuasion. In general, effective foreshadowing and affirmation should avoid the need for persuasion.
Dr. Stivers’ research suggests that these techniques work, but to do so, they should be delivered naturally as part of routine practice. Interestingly, her data showed that physicians rarely foreshadowed, and when they encountered resistance, they adopted persuasion in 53% of cases. By comparison, affirmative recommendations were used in 89% of cases, but their effects were reduced by the physician being vague and nonspecific.
In conclusion, Dr. Stivers said that addressing inappropriate prescribing requires awareness but that is not enough. The challenge is to reconsider health policies and ways of communicating about antibiotics. There is no downside to foreshadowing a likely viral origin, delivering affirmation, or using persuasion. She added, “If we can make even a 5%-10% reduction [in prescribing], wouldn’t it be worth it?”
Questions answered
A question-and-answer session followed Dr. Stivers’ presentation, and points raised included:
- Physicians have a desire to please. Dr. Stivers countered this point by saying that satisfaction is not tied to antibiotic prescription, and that physicians often misjudge what patients want. It’s important to communicate other treatment options because patients often just want “something they can do.”
- Decision fatigue is often a factor. Evidence shows that antibiotic prescription is more frequent toward the end of a shift. Doctors should avoid negotiation because it increases consultation time. Here, foreshadowing early on may help. Setting may also be important – prescription is more frequent in the ED.
- Vaccine-resistant parents often want active treatment. Here, conversations can be challenging. Trying to persuade may be a less successful than giving positive instruction (e.g., “we’ll give you a vaccine today.”) Resistance is likely to be lower.
- Concern was expressed about manipulating patients ahead of a firm diagnosis. Could this lead to missing a serious bacterial infection? Dr. Stivers acknowledged that this was a gamble. She recommended a “neutral” early foreshadowing statement such as “we are seeing a lot of viral infections at the present.”
- Cultural differences can have an effect. In China, for example, the argument between parents and physicians no longer focuses on antibiotics versus nonantibiotics but rather on oral versus intravenous administration.
- Litigation is a factor in prescribing, especially in the United States. Dr. Stivers stated that her proposed approach to prescribing should not interfere with appropriate management. The clinical picture can change, and antibiotics should be prescribed where needed.
- Audits improve prescribing in the short term. These results were based on recorded consultations, and that factor may have influenced management. In unrecorded consultations, inappropriate antibiotic prescription would be higher.
- Increased point-of-care testing can reduce unnecessary prescribing. This has been documented in countries such as Sweden. Evidence from China suggests that many patients will still receive antibiotics even if a bacterial cause is excluded.
When patients dictate treatment, sometimes we must tell them what is best. Dr. Stivers closed her presentation by emphasizing that, “how you say things will matter.”
Louis Bont, MD, PhD, chair of this session and pediatric infectious diseases specialist at the University Medical Center Utrecht (the Netherlands), commented: “Antimicrobial resistance is a global health threat which jeopardizes sustainable health goals. The World Health Organization has declared that antimicrobial resistance is one of the top 10 global public health threats facing humanity. Resistance to ciprofloxacin varies from 8%-93% in Escherichia coli and 4%-80% in Klebsiella pneumoniae. Colistin is the only last-resort treatment for life-threatening infections caused by carbapenem-resistant enterobacteriaceae.”
Dr. Stivers stated that she has nothing to disclose.
FROM ESPID 2020
Hand hygiene in pediatric ICUs: Identifying areas for improvement
A multidisciplinary team seeking to measure compliance with hand hygiene (HH) practices in pediatric ICUs across Europe found compliance was comparable and relatively high among unit doctors and nurses, but not as high in nonunit doctors and nurses.
Ioannis Kopsidas, MD, presented these results from the RANIN-KIDS Network during the annual meeting of the European Society for Paediatric Infectious Diseases, held virtually this year. RANIN-KIDS (Reducing Antimicrobial Use and Nosocomial Infections in Kids) is a European network with the aim of preventing hospital-associated infections and promoting judicial antimicrobial use in pediatric patients using a common sustainable methodology across Europe.
Infections kill. This is especially the case in pediatric ICUs, where young age and an immunocompromised status make patients particularly vulnerable to infections. Poor HH is a major cause for disease transmission. To reduce the risk, the World Health Organization recommends attention to five moments of hand hygiene and nine steps for hand washing. Various tools are available to improve adherence, but whether these measures are being followed is unclear. The researchers sought to assess the degree of compliance with HH practices in pediatric ICUs and to identify targets for improvement.
Dr. Kopsidas, of the Center of Clinical Epidemiology and Outcomes Research, the National and Kapodistrian University of Athens, and colleagues examined practices in nine pediatric ICUs across six European countries (Estonia, Germany, Greece, Italy, Spain, and Switzerland) by means of prospective observational study. All organizations were part of the RANIN-KIDS network. Over a 6-month period starting in March 2019, observations were conducted in every unit by observers using a data collection tool developed based on WHO guidelines. Training for observers was provided using a self-paced teaching kit comprising PowerPoint and video presentations, followed by the completion of a test observation form after observing staged hand hygiene exercises. Results were then compared with WHO guidance, and irregularities were explained in order to achieve interrater reliability.
Researchers observed 1,715 HH opportunities. Across all pediatric ICUs, the median HH compliance rate was 82% (interquartile range, 72%-95%). Stratified by type of professional, median compliance was comparable among unit doctors (90%) and nurses (87%), but lower for nonunit doctors and nurses (81%) and also for nondoctors and nonnurses (67%). Alcohol-based hand rub was substantially preferred to soap and water, being used in 84% of the observations (IQR, 69%-87%). Cleaning and drying technique was considered appropriate in a median of 93% of observations (IQR, 86%-96%).
Compliance to moment 5 (after touching patient surroundings) was the lowest across hospitals (median 71%), compared with a median 100% for moment 2 (before clean/aseptic procedures) and a median 93% for moment 3 (after body fluid exposure/risk). For moment 1, median compliance was 87% (before touching a patient), and for moment 4, median compliance was 82% (after touching a patient).
Dr. Kopsidas concluded that the overall level of HH compliance among doctors and nurses working in European pediatric ICUs appears to be high, with moment 5 being the most frequently missed opportunity. Nonunit doctors and nurses and other personnel show lower WHO guidelines adherence. He stated that “these results will be used to design tailor-made interventions in participating units with the aim of reducing HAIs [health care–associated infections] and spread of multidrug resistant infections.”
He also said that “unified surveillance in Europe is possible and achievable, and allows for benchmarking among countries, institutions and wards.”
For some units, improving HH is a missed opportunity. The next stop for the RANIN-KIDS network is to look at the effects of interventions on reducing spread.
Dr. Kopsidas had no relevant financial disclosures.
A multidisciplinary team seeking to measure compliance with hand hygiene (HH) practices in pediatric ICUs across Europe found compliance was comparable and relatively high among unit doctors and nurses, but not as high in nonunit doctors and nurses.
Ioannis Kopsidas, MD, presented these results from the RANIN-KIDS Network during the annual meeting of the European Society for Paediatric Infectious Diseases, held virtually this year. RANIN-KIDS (Reducing Antimicrobial Use and Nosocomial Infections in Kids) is a European network with the aim of preventing hospital-associated infections and promoting judicial antimicrobial use in pediatric patients using a common sustainable methodology across Europe.
Infections kill. This is especially the case in pediatric ICUs, where young age and an immunocompromised status make patients particularly vulnerable to infections. Poor HH is a major cause for disease transmission. To reduce the risk, the World Health Organization recommends attention to five moments of hand hygiene and nine steps for hand washing. Various tools are available to improve adherence, but whether these measures are being followed is unclear. The researchers sought to assess the degree of compliance with HH practices in pediatric ICUs and to identify targets for improvement.
Dr. Kopsidas, of the Center of Clinical Epidemiology and Outcomes Research, the National and Kapodistrian University of Athens, and colleagues examined practices in nine pediatric ICUs across six European countries (Estonia, Germany, Greece, Italy, Spain, and Switzerland) by means of prospective observational study. All organizations were part of the RANIN-KIDS network. Over a 6-month period starting in March 2019, observations were conducted in every unit by observers using a data collection tool developed based on WHO guidelines. Training for observers was provided using a self-paced teaching kit comprising PowerPoint and video presentations, followed by the completion of a test observation form after observing staged hand hygiene exercises. Results were then compared with WHO guidance, and irregularities were explained in order to achieve interrater reliability.
Researchers observed 1,715 HH opportunities. Across all pediatric ICUs, the median HH compliance rate was 82% (interquartile range, 72%-95%). Stratified by type of professional, median compliance was comparable among unit doctors (90%) and nurses (87%), but lower for nonunit doctors and nurses (81%) and also for nondoctors and nonnurses (67%). Alcohol-based hand rub was substantially preferred to soap and water, being used in 84% of the observations (IQR, 69%-87%). Cleaning and drying technique was considered appropriate in a median of 93% of observations (IQR, 86%-96%).
Compliance to moment 5 (after touching patient surroundings) was the lowest across hospitals (median 71%), compared with a median 100% for moment 2 (before clean/aseptic procedures) and a median 93% for moment 3 (after body fluid exposure/risk). For moment 1, median compliance was 87% (before touching a patient), and for moment 4, median compliance was 82% (after touching a patient).
Dr. Kopsidas concluded that the overall level of HH compliance among doctors and nurses working in European pediatric ICUs appears to be high, with moment 5 being the most frequently missed opportunity. Nonunit doctors and nurses and other personnel show lower WHO guidelines adherence. He stated that “these results will be used to design tailor-made interventions in participating units with the aim of reducing HAIs [health care–associated infections] and spread of multidrug resistant infections.”
He also said that “unified surveillance in Europe is possible and achievable, and allows for benchmarking among countries, institutions and wards.”
For some units, improving HH is a missed opportunity. The next stop for the RANIN-KIDS network is to look at the effects of interventions on reducing spread.
Dr. Kopsidas had no relevant financial disclosures.
A multidisciplinary team seeking to measure compliance with hand hygiene (HH) practices in pediatric ICUs across Europe found compliance was comparable and relatively high among unit doctors and nurses, but not as high in nonunit doctors and nurses.
Ioannis Kopsidas, MD, presented these results from the RANIN-KIDS Network during the annual meeting of the European Society for Paediatric Infectious Diseases, held virtually this year. RANIN-KIDS (Reducing Antimicrobial Use and Nosocomial Infections in Kids) is a European network with the aim of preventing hospital-associated infections and promoting judicial antimicrobial use in pediatric patients using a common sustainable methodology across Europe.
Infections kill. This is especially the case in pediatric ICUs, where young age and an immunocompromised status make patients particularly vulnerable to infections. Poor HH is a major cause for disease transmission. To reduce the risk, the World Health Organization recommends attention to five moments of hand hygiene and nine steps for hand washing. Various tools are available to improve adherence, but whether these measures are being followed is unclear. The researchers sought to assess the degree of compliance with HH practices in pediatric ICUs and to identify targets for improvement.
Dr. Kopsidas, of the Center of Clinical Epidemiology and Outcomes Research, the National and Kapodistrian University of Athens, and colleagues examined practices in nine pediatric ICUs across six European countries (Estonia, Germany, Greece, Italy, Spain, and Switzerland) by means of prospective observational study. All organizations were part of the RANIN-KIDS network. Over a 6-month period starting in March 2019, observations were conducted in every unit by observers using a data collection tool developed based on WHO guidelines. Training for observers was provided using a self-paced teaching kit comprising PowerPoint and video presentations, followed by the completion of a test observation form after observing staged hand hygiene exercises. Results were then compared with WHO guidance, and irregularities were explained in order to achieve interrater reliability.
Researchers observed 1,715 HH opportunities. Across all pediatric ICUs, the median HH compliance rate was 82% (interquartile range, 72%-95%). Stratified by type of professional, median compliance was comparable among unit doctors (90%) and nurses (87%), but lower for nonunit doctors and nurses (81%) and also for nondoctors and nonnurses (67%). Alcohol-based hand rub was substantially preferred to soap and water, being used in 84% of the observations (IQR, 69%-87%). Cleaning and drying technique was considered appropriate in a median of 93% of observations (IQR, 86%-96%).
Compliance to moment 5 (after touching patient surroundings) was the lowest across hospitals (median 71%), compared with a median 100% for moment 2 (before clean/aseptic procedures) and a median 93% for moment 3 (after body fluid exposure/risk). For moment 1, median compliance was 87% (before touching a patient), and for moment 4, median compliance was 82% (after touching a patient).
Dr. Kopsidas concluded that the overall level of HH compliance among doctors and nurses working in European pediatric ICUs appears to be high, with moment 5 being the most frequently missed opportunity. Nonunit doctors and nurses and other personnel show lower WHO guidelines adherence. He stated that “these results will be used to design tailor-made interventions in participating units with the aim of reducing HAIs [health care–associated infections] and spread of multidrug resistant infections.”
He also said that “unified surveillance in Europe is possible and achievable, and allows for benchmarking among countries, institutions and wards.”
For some units, improving HH is a missed opportunity. The next stop for the RANIN-KIDS network is to look at the effects of interventions on reducing spread.
Dr. Kopsidas had no relevant financial disclosures.
FROM ESPID 2020
Consider C. difficile early in children with cancer with GI symptoms
Children with cancer are at increased risk of potentially life-threatening Clostridioides difficile infections (CDI), and Brianna Murphy, DO, reported at the annual meeting of the European Society for Paediatric Infectious Diseases, held virtually this year.
CDI are characterized by diarrhea, fever, and loss of appetite. The clinical features are caused by the release of toxins A and B by this gram-positive bacterium. In pediatric groups, CDI are a leading cause of antibiotic-associated gastric illness. This in turn can lead to a protracted stay in hospital and increases risk of mortality. The rising incidence in the United States over the last 2 decades prompted Dr. Murphy, a pediatric hematology oncology fellow working at the department of pediatric research at the University of Texas MD Anderson Cancer Center, Houston, to investigate further. A search of the literature found limited information regarding CDI and pediatric oncology patients.
Recognized factors for contracting CDI include the presence of other illnesses, a weakened immune system because of drugs or disease, enteral nutrition, usage of medicines such as proton pump inhibitors which decrease gastric acid production, and classically, treatment with broad spectrum antibiotics.
Dr. Murphy’s study included patients aged 1-18 years, all of whom had a cancer diagnosis and a positive stool culture for C. difficile. Presenting symptoms were three or more loose stools per day or acute onset ileus. The study evaluated data for the years 2000-2017 and included 11,366 children; 207 CDI (0.98%) cases were identified among pediatric oncology patients during the study period. This compares with historical data showing an incidence of 0.14% among hospitalized children in general.
Malignancy data were then subdivided into three groups: hematologic, nonneural solid tumors (NNST), and neural tumors. Hematologic malignancies had a CDI prevalence higher than the average for oncologic patients at 5.4%. Inside this group those suffering with acute myeloid leukemia had a rate of 10.5%. In the NNST and neural tumor groups, CDI rates were lower and closer to the overall average.
Dr. Murphy then looked at her patient population in more detail. Poor clinical outcomes (PCOs) were defined as severe, refractory, recurrent, or multiple infections. Severe CDI included features such as toxic megacolon, gastrointestinal perforation, or need for surgical intervention. Refractory CDI were defined as continuation of symptoms beyond 7 days of appropriate therapy, and recurrent CDI were classed as reinfection within 8 weeks of a previous CDI. Ultimately, 51% of patients in this study died. Patients with severe CDI experienced increased mortality (P = .02). There was no difference shown when looking at the type of cancer, age, gender, or patient ethnicity.
Next, Dr. Murphy looked for associations. Hematologic and biochemical testing identified that elevated creatinine was statistically associated with the likelihood of PCOs, compared with leukocytosis and neutropenia, particularly in the NNST group. Treatment modality also was studied. Here radiation therapy was the only treatment shown to increase PCOs in patients with CDI. One-fifth (22%) of radiation therapy recipients experienced multiple CDI, compared with 12% of the total population.
In commenting on her paper, Louis Bent, MD, from the Netherlands raised the issue of deaths in septic patients. What was the origin of the responsible organism, for example from the GI tract or from central lines, and were patients receiving appropriate antibiotic treatment?
Dr. Kelly responded that sepsis was generally believed to occur as a result of infection with mixed bacterial translocation through the bowel wall, notably Escherichia coli. Patients were usually on a cocktail of antibiotics targeting CDI, but also other infections illustrating the serious nature of the situation.
Dr. Murphy had no financial conflicts of interest to declare.
Children with cancer are at increased risk of potentially life-threatening Clostridioides difficile infections (CDI), and Brianna Murphy, DO, reported at the annual meeting of the European Society for Paediatric Infectious Diseases, held virtually this year.
CDI are characterized by diarrhea, fever, and loss of appetite. The clinical features are caused by the release of toxins A and B by this gram-positive bacterium. In pediatric groups, CDI are a leading cause of antibiotic-associated gastric illness. This in turn can lead to a protracted stay in hospital and increases risk of mortality. The rising incidence in the United States over the last 2 decades prompted Dr. Murphy, a pediatric hematology oncology fellow working at the department of pediatric research at the University of Texas MD Anderson Cancer Center, Houston, to investigate further. A search of the literature found limited information regarding CDI and pediatric oncology patients.
Recognized factors for contracting CDI include the presence of other illnesses, a weakened immune system because of drugs or disease, enteral nutrition, usage of medicines such as proton pump inhibitors which decrease gastric acid production, and classically, treatment with broad spectrum antibiotics.
Dr. Murphy’s study included patients aged 1-18 years, all of whom had a cancer diagnosis and a positive stool culture for C. difficile. Presenting symptoms were three or more loose stools per day or acute onset ileus. The study evaluated data for the years 2000-2017 and included 11,366 children; 207 CDI (0.98%) cases were identified among pediatric oncology patients during the study period. This compares with historical data showing an incidence of 0.14% among hospitalized children in general.
Malignancy data were then subdivided into three groups: hematologic, nonneural solid tumors (NNST), and neural tumors. Hematologic malignancies had a CDI prevalence higher than the average for oncologic patients at 5.4%. Inside this group those suffering with acute myeloid leukemia had a rate of 10.5%. In the NNST and neural tumor groups, CDI rates were lower and closer to the overall average.
Dr. Murphy then looked at her patient population in more detail. Poor clinical outcomes (PCOs) were defined as severe, refractory, recurrent, or multiple infections. Severe CDI included features such as toxic megacolon, gastrointestinal perforation, or need for surgical intervention. Refractory CDI were defined as continuation of symptoms beyond 7 days of appropriate therapy, and recurrent CDI were classed as reinfection within 8 weeks of a previous CDI. Ultimately, 51% of patients in this study died. Patients with severe CDI experienced increased mortality (P = .02). There was no difference shown when looking at the type of cancer, age, gender, or patient ethnicity.
Next, Dr. Murphy looked for associations. Hematologic and biochemical testing identified that elevated creatinine was statistically associated with the likelihood of PCOs, compared with leukocytosis and neutropenia, particularly in the NNST group. Treatment modality also was studied. Here radiation therapy was the only treatment shown to increase PCOs in patients with CDI. One-fifth (22%) of radiation therapy recipients experienced multiple CDI, compared with 12% of the total population.
In commenting on her paper, Louis Bent, MD, from the Netherlands raised the issue of deaths in septic patients. What was the origin of the responsible organism, for example from the GI tract or from central lines, and were patients receiving appropriate antibiotic treatment?
Dr. Kelly responded that sepsis was generally believed to occur as a result of infection with mixed bacterial translocation through the bowel wall, notably Escherichia coli. Patients were usually on a cocktail of antibiotics targeting CDI, but also other infections illustrating the serious nature of the situation.
Dr. Murphy had no financial conflicts of interest to declare.
Children with cancer are at increased risk of potentially life-threatening Clostridioides difficile infections (CDI), and Brianna Murphy, DO, reported at the annual meeting of the European Society for Paediatric Infectious Diseases, held virtually this year.
CDI are characterized by diarrhea, fever, and loss of appetite. The clinical features are caused by the release of toxins A and B by this gram-positive bacterium. In pediatric groups, CDI are a leading cause of antibiotic-associated gastric illness. This in turn can lead to a protracted stay in hospital and increases risk of mortality. The rising incidence in the United States over the last 2 decades prompted Dr. Murphy, a pediatric hematology oncology fellow working at the department of pediatric research at the University of Texas MD Anderson Cancer Center, Houston, to investigate further. A search of the literature found limited information regarding CDI and pediatric oncology patients.
Recognized factors for contracting CDI include the presence of other illnesses, a weakened immune system because of drugs or disease, enteral nutrition, usage of medicines such as proton pump inhibitors which decrease gastric acid production, and classically, treatment with broad spectrum antibiotics.
Dr. Murphy’s study included patients aged 1-18 years, all of whom had a cancer diagnosis and a positive stool culture for C. difficile. Presenting symptoms were three or more loose stools per day or acute onset ileus. The study evaluated data for the years 2000-2017 and included 11,366 children; 207 CDI (0.98%) cases were identified among pediatric oncology patients during the study period. This compares with historical data showing an incidence of 0.14% among hospitalized children in general.
Malignancy data were then subdivided into three groups: hematologic, nonneural solid tumors (NNST), and neural tumors. Hematologic malignancies had a CDI prevalence higher than the average for oncologic patients at 5.4%. Inside this group those suffering with acute myeloid leukemia had a rate of 10.5%. In the NNST and neural tumor groups, CDI rates were lower and closer to the overall average.
Dr. Murphy then looked at her patient population in more detail. Poor clinical outcomes (PCOs) were defined as severe, refractory, recurrent, or multiple infections. Severe CDI included features such as toxic megacolon, gastrointestinal perforation, or need for surgical intervention. Refractory CDI were defined as continuation of symptoms beyond 7 days of appropriate therapy, and recurrent CDI were classed as reinfection within 8 weeks of a previous CDI. Ultimately, 51% of patients in this study died. Patients with severe CDI experienced increased mortality (P = .02). There was no difference shown when looking at the type of cancer, age, gender, or patient ethnicity.
Next, Dr. Murphy looked for associations. Hematologic and biochemical testing identified that elevated creatinine was statistically associated with the likelihood of PCOs, compared with leukocytosis and neutropenia, particularly in the NNST group. Treatment modality also was studied. Here radiation therapy was the only treatment shown to increase PCOs in patients with CDI. One-fifth (22%) of radiation therapy recipients experienced multiple CDI, compared with 12% of the total population.
In commenting on her paper, Louis Bent, MD, from the Netherlands raised the issue of deaths in septic patients. What was the origin of the responsible organism, for example from the GI tract or from central lines, and were patients receiving appropriate antibiotic treatment?
Dr. Kelly responded that sepsis was generally believed to occur as a result of infection with mixed bacterial translocation through the bowel wall, notably Escherichia coli. Patients were usually on a cocktail of antibiotics targeting CDI, but also other infections illustrating the serious nature of the situation.
Dr. Murphy had no financial conflicts of interest to declare.
FROM ESPID 2020
Encouraging results for new epilepsy drug
Post hoc analyses from an open-label study showed that seizure frequency was significantly reduced and the seizure-freedom rate was significantly improved among 240 adult participants who received cenobamate. The patients’ use of concomitant antiseizure medications was also reduced, with no effect on efficacy.
These results are “fascinating” and “very, very exciting,” said lead author William E. Rosenfeld, MD, director, Comprehensive Epilepsy Care Center for Children and Adults, St. Louis, Mo. Although responder rates were impressive, at 50% or greater and 75% or greater, “what patients really want is to have seizure freedom, or at least a 90% reduction in seizures,” Dr. Rosenfeld said.
The findings were presented at the annual meeting of the American Epilepsy Society, held online this year.
Adverse events
Cenobamate reduces seizures by inhibiting sodium current or affecting the GABAA channel, or potentially through a combination of these two mechanisms, said Dr. Rosenfeld. The drug was approved by the U.S. Food and Drug Administration in November 2019 for the treatment of uncontrolled partial-onset seizures in adults, which represent about 60% of all epileptic seizures. It has been on the market since May 2020.
During the drug’s development, three cases of drug reaction with eosinophilia and systemic symptoms (DRESS) occurred. This condition typically involves a skin rash, fever, swollen lymph nodes, and characteristic blood abnormalities, including a high level of eosinophils. However, an open-label study, published earlier this year in Epilepsia, that assessed safety and pharmacokinetics in 1,347 patients aged 18-70 years who received stable doses of one to three antiseizure medications showed that, with “slow and low titration” of cenobamate, there were no cases of DRESS, Dr. Rosenfeld said.
In that safety study, investigators administered increasing daily doses of cenobamate at 12.5, 25, 50, 100, 150, and 200 mg/day at 2-week intervals. If necessary, the dose could be increased to 400 mg/day via 50-mg/day increments every other week.
The researchers presented post hoc analyses regarding 240 patients from 10 U.S. sites who participated in the safety study. Dr. Rosenfeld noted, “These are all good epilepsy centers, and they all kept seizure records.” Of these participants, 177 continued taking the drug as they had at their last visit for a mean of more than 30 months; for some, it was up to 44 months.
“So we had a 73.8% retention rate over the course of the open label, which is the maintenance phase of the study,” Dr. Rosenfeld said.
Among the entire group of 240 patients, 25.8% had been seizure free for more than 12 months at their last visit. Of the 177 who continued to take cenobamate, 33.9% were seizure free for an average of 23.5 months.
“We have never seen those kinds of numbers in the past,” said Dr. Rosenfeld, adding, “it’s so important for patients to get seizure freedom.” These promising results may be related to the fact that the drug works on more than one mechanism of seizure, he speculated.
For some patients, the drug will “make a big difference” by providing them with the best quality of life and allow them to resume normal activities, Dr. Rosenfeld noted. In addition, the drug was well tolerated. The most common adverse events were dizziness/diplopia and sleepiness/drowsiness.
Concomitant drug reductions
Another post hoc analysis of the 240 patients showed that many patients were able to reduce use of other antiseizure medications. At study outset, about 41% were taking lacosamide, 35.7% were taking levetiracetam, and 27.7% were taking lamotrigine. Among patients who continued to take cenobamate, 22.7% of concomitant baseline antiseizure medications were discontinued. Carbamazepine was discontinued by 31.3%, oxcarbazepine by 26.7%, lacosamide by 23.4%, eslicarbazepine by 23.1%, clobazam by 26.7%, lamotrigine by 14.6%, and levetiracetam by 20.3%.
“We found that the patients who stayed in the study the longest had greater reductions in their concomitant antiepileptic mediation,” said Dr. Rosenfeld. Lowering concomitant medications did not reduce efficacy at a target dose of 200 mg/day.
The investigators hope to test the drug in children and in patients with different seizure types.
Promising, with caveats
Commenting on the research, Jong Woo Lee, MD, PhD, associate professor of neurology, the Edward B. Bromfield Epilepsy Program, Brigham and Women’s Hospital, Boston, said cenobamate “has certainly given new hope” to some of his patients. He noted that a few of these patients had been experiencing daily or nearly daily seizures and had been taking three or more medications for many years.
“The chances of another medication being effective for these patients is very low,” said Dr. Lee, who was not involved with the research. “But several of these patients responded to cenobamate, and some of them achieved complete seizure freedom.”
However, as with all new promising medications, there are some caveats. “The concern is for long-term efficacy for more than 5 years and, of course, unforeseen side effects,” Dr. Lee said.
The studies were funded by SK Life Science. Dr. Rosenfeld has been a consultant for SK Life Science. Dr. Lee has disclosed no relevant financial relationships.
A version of this article first appeared on Medscape.com.
Post hoc analyses from an open-label study showed that seizure frequency was significantly reduced and the seizure-freedom rate was significantly improved among 240 adult participants who received cenobamate. The patients’ use of concomitant antiseizure medications was also reduced, with no effect on efficacy.
These results are “fascinating” and “very, very exciting,” said lead author William E. Rosenfeld, MD, director, Comprehensive Epilepsy Care Center for Children and Adults, St. Louis, Mo. Although responder rates were impressive, at 50% or greater and 75% or greater, “what patients really want is to have seizure freedom, or at least a 90% reduction in seizures,” Dr. Rosenfeld said.
The findings were presented at the annual meeting of the American Epilepsy Society, held online this year.
Adverse events
Cenobamate reduces seizures by inhibiting sodium current or affecting the GABAA channel, or potentially through a combination of these two mechanisms, said Dr. Rosenfeld. The drug was approved by the U.S. Food and Drug Administration in November 2019 for the treatment of uncontrolled partial-onset seizures in adults, which represent about 60% of all epileptic seizures. It has been on the market since May 2020.
During the drug’s development, three cases of drug reaction with eosinophilia and systemic symptoms (DRESS) occurred. This condition typically involves a skin rash, fever, swollen lymph nodes, and characteristic blood abnormalities, including a high level of eosinophils. However, an open-label study, published earlier this year in Epilepsia, that assessed safety and pharmacokinetics in 1,347 patients aged 18-70 years who received stable doses of one to three antiseizure medications showed that, with “slow and low titration” of cenobamate, there were no cases of DRESS, Dr. Rosenfeld said.
In that safety study, investigators administered increasing daily doses of cenobamate at 12.5, 25, 50, 100, 150, and 200 mg/day at 2-week intervals. If necessary, the dose could be increased to 400 mg/day via 50-mg/day increments every other week.
The researchers presented post hoc analyses regarding 240 patients from 10 U.S. sites who participated in the safety study. Dr. Rosenfeld noted, “These are all good epilepsy centers, and they all kept seizure records.” Of these participants, 177 continued taking the drug as they had at their last visit for a mean of more than 30 months; for some, it was up to 44 months.
“So we had a 73.8% retention rate over the course of the open label, which is the maintenance phase of the study,” Dr. Rosenfeld said.
Among the entire group of 240 patients, 25.8% had been seizure free for more than 12 months at their last visit. Of the 177 who continued to take cenobamate, 33.9% were seizure free for an average of 23.5 months.
“We have never seen those kinds of numbers in the past,” said Dr. Rosenfeld, adding, “it’s so important for patients to get seizure freedom.” These promising results may be related to the fact that the drug works on more than one mechanism of seizure, he speculated.
For some patients, the drug will “make a big difference” by providing them with the best quality of life and allow them to resume normal activities, Dr. Rosenfeld noted. In addition, the drug was well tolerated. The most common adverse events were dizziness/diplopia and sleepiness/drowsiness.
Concomitant drug reductions
Another post hoc analysis of the 240 patients showed that many patients were able to reduce use of other antiseizure medications. At study outset, about 41% were taking lacosamide, 35.7% were taking levetiracetam, and 27.7% were taking lamotrigine. Among patients who continued to take cenobamate, 22.7% of concomitant baseline antiseizure medications were discontinued. Carbamazepine was discontinued by 31.3%, oxcarbazepine by 26.7%, lacosamide by 23.4%, eslicarbazepine by 23.1%, clobazam by 26.7%, lamotrigine by 14.6%, and levetiracetam by 20.3%.
“We found that the patients who stayed in the study the longest had greater reductions in their concomitant antiepileptic mediation,” said Dr. Rosenfeld. Lowering concomitant medications did not reduce efficacy at a target dose of 200 mg/day.
The investigators hope to test the drug in children and in patients with different seizure types.
Promising, with caveats
Commenting on the research, Jong Woo Lee, MD, PhD, associate professor of neurology, the Edward B. Bromfield Epilepsy Program, Brigham and Women’s Hospital, Boston, said cenobamate “has certainly given new hope” to some of his patients. He noted that a few of these patients had been experiencing daily or nearly daily seizures and had been taking three or more medications for many years.
“The chances of another medication being effective for these patients is very low,” said Dr. Lee, who was not involved with the research. “But several of these patients responded to cenobamate, and some of them achieved complete seizure freedom.”
However, as with all new promising medications, there are some caveats. “The concern is for long-term efficacy for more than 5 years and, of course, unforeseen side effects,” Dr. Lee said.
The studies were funded by SK Life Science. Dr. Rosenfeld has been a consultant for SK Life Science. Dr. Lee has disclosed no relevant financial relationships.
A version of this article first appeared on Medscape.com.
Post hoc analyses from an open-label study showed that seizure frequency was significantly reduced and the seizure-freedom rate was significantly improved among 240 adult participants who received cenobamate. The patients’ use of concomitant antiseizure medications was also reduced, with no effect on efficacy.
These results are “fascinating” and “very, very exciting,” said lead author William E. Rosenfeld, MD, director, Comprehensive Epilepsy Care Center for Children and Adults, St. Louis, Mo. Although responder rates were impressive, at 50% or greater and 75% or greater, “what patients really want is to have seizure freedom, or at least a 90% reduction in seizures,” Dr. Rosenfeld said.
The findings were presented at the annual meeting of the American Epilepsy Society, held online this year.
Adverse events
Cenobamate reduces seizures by inhibiting sodium current or affecting the GABAA channel, or potentially through a combination of these two mechanisms, said Dr. Rosenfeld. The drug was approved by the U.S. Food and Drug Administration in November 2019 for the treatment of uncontrolled partial-onset seizures in adults, which represent about 60% of all epileptic seizures. It has been on the market since May 2020.
During the drug’s development, three cases of drug reaction with eosinophilia and systemic symptoms (DRESS) occurred. This condition typically involves a skin rash, fever, swollen lymph nodes, and characteristic blood abnormalities, including a high level of eosinophils. However, an open-label study, published earlier this year in Epilepsia, that assessed safety and pharmacokinetics in 1,347 patients aged 18-70 years who received stable doses of one to three antiseizure medications showed that, with “slow and low titration” of cenobamate, there were no cases of DRESS, Dr. Rosenfeld said.
In that safety study, investigators administered increasing daily doses of cenobamate at 12.5, 25, 50, 100, 150, and 200 mg/day at 2-week intervals. If necessary, the dose could be increased to 400 mg/day via 50-mg/day increments every other week.
The researchers presented post hoc analyses regarding 240 patients from 10 U.S. sites who participated in the safety study. Dr. Rosenfeld noted, “These are all good epilepsy centers, and they all kept seizure records.” Of these participants, 177 continued taking the drug as they had at their last visit for a mean of more than 30 months; for some, it was up to 44 months.
“So we had a 73.8% retention rate over the course of the open label, which is the maintenance phase of the study,” Dr. Rosenfeld said.
Among the entire group of 240 patients, 25.8% had been seizure free for more than 12 months at their last visit. Of the 177 who continued to take cenobamate, 33.9% were seizure free for an average of 23.5 months.
“We have never seen those kinds of numbers in the past,” said Dr. Rosenfeld, adding, “it’s so important for patients to get seizure freedom.” These promising results may be related to the fact that the drug works on more than one mechanism of seizure, he speculated.
For some patients, the drug will “make a big difference” by providing them with the best quality of life and allow them to resume normal activities, Dr. Rosenfeld noted. In addition, the drug was well tolerated. The most common adverse events were dizziness/diplopia and sleepiness/drowsiness.
Concomitant drug reductions
Another post hoc analysis of the 240 patients showed that many patients were able to reduce use of other antiseizure medications. At study outset, about 41% were taking lacosamide, 35.7% were taking levetiracetam, and 27.7% were taking lamotrigine. Among patients who continued to take cenobamate, 22.7% of concomitant baseline antiseizure medications were discontinued. Carbamazepine was discontinued by 31.3%, oxcarbazepine by 26.7%, lacosamide by 23.4%, eslicarbazepine by 23.1%, clobazam by 26.7%, lamotrigine by 14.6%, and levetiracetam by 20.3%.
“We found that the patients who stayed in the study the longest had greater reductions in their concomitant antiepileptic mediation,” said Dr. Rosenfeld. Lowering concomitant medications did not reduce efficacy at a target dose of 200 mg/day.
The investigators hope to test the drug in children and in patients with different seizure types.
Promising, with caveats
Commenting on the research, Jong Woo Lee, MD, PhD, associate professor of neurology, the Edward B. Bromfield Epilepsy Program, Brigham and Women’s Hospital, Boston, said cenobamate “has certainly given new hope” to some of his patients. He noted that a few of these patients had been experiencing daily or nearly daily seizures and had been taking three or more medications for many years.
“The chances of another medication being effective for these patients is very low,” said Dr. Lee, who was not involved with the research. “But several of these patients responded to cenobamate, and some of them achieved complete seizure freedom.”
However, as with all new promising medications, there are some caveats. “The concern is for long-term efficacy for more than 5 years and, of course, unforeseen side effects,” Dr. Lee said.
The studies were funded by SK Life Science. Dr. Rosenfeld has been a consultant for SK Life Science. Dr. Lee has disclosed no relevant financial relationships.
A version of this article first appeared on Medscape.com.
FROM AES 2020
Should we use antibiotics to treat sore throats?
The use of antibiotics to treat a sore throat remains contentious, with guidelines from around the world providing contradictory advice. This topic generated a lively debate at the annual meeting of the European Society for Paediatric Infectious Diseases, held virtually this year.
Lauri Ivaska, MD, of the department of pediatrics and adolescent medicine at Turku (Finland) University Hospital, argued for the use of antibiotics, while Borbála Zsigmond, MD, of Heim Pál Children’s Hospital in Budapest, made the case against their use. Interestingly, this debate occurred against the background of a poll conducted before the debate, which found that only 11% of the audience voted in favor of using antibiotics to treat sore throats.
Both speakers began by exploring their approach to the treatment of a recent clinical case involving a 4-year-old girl presenting with sore throat. Dr. Ivaska stressed the difference between a sore throat, pharyngitis, and tonsillitis: the latter two refer to a physical finding, while the former is a subjective symptom.
International guidelines differ on the subject
The debate moved to discussing the international guidelines for treating pharyngitis and tonsillitis. Dr. Zsigmond believes that these are flawed and unhelpful, arguing that they differ depending on what part of the world a physician is practicing in. For example, the 2012 Infectious Diseases Society of America guidelines recommend using best clinical judgment and then backing this up by testing. If testing proves positive for group A Streptococcus pyogenes (GAS), the physician should universally treat. By comparison, the European Society of Clinical Microbiology and Infectious Diseases Sore Throat Guideline Group focuses on severity rather than the cause of the infection. If the case is deemed to be serious, antibiotics can be prescribed without a positive test.
Sore throat is frequently associated with a common cold. In a recent study, more that 80% of students with an acute viral respiratory tract infection had soreness at the beginning of their illness.
Reporting from his own research, Dr. Ivaska argued that viruses can be detected in almost two-thirds of children with pharyngitis using polymerase chain reaction analysis. He thinks antibiotics should be reserved for those 30%-40% of patients with a confirmed GAS infection. The potential role of Fusobacterium necrophorum was raised, but there is no evidence of the benefits of antibiotic treatment in such cases.
There are diagnostic aids for GAS infection
It was suggested that, instead of concentrating on sore throat, the debate should be about whether to use antibiotics to treat GAS infection. But how can the diagnosis be confirmed simply in a clinical setting? Dr. Ivaska recommended adopting diagnostic aids such as Centor, McIsaac, and FeverPAIN, which award scores for several common disease features – the higher the score, the more likely a patient is to be suffering from a GAS infection.
Dr. Zsigmond also likes scoring symptoms but believes they are often inaccurate, especially in young children. She pointed to a report that examined the use of the Centor tool among 441 children attending a pediatric ED. The authors concluded that the Centor criteria were ineffective in predicting a positive GAS culture in throat swabs taken from symptomatic patients.
When are antibiotics warranted?
It is widely accepted that antibiotics should be avoided for viral infections. Returning to the case described at the start of this debate, Dr. Zsigmond calculated that her patient with a 2-day history of sore throat, elevated temperature, pussy tonsils, and enlarged cervical lymph glands but no cough or rhinitis had a FeverPAIN score of 4-5 and a Centor score of 4, meaning that, according to the European guidelines, she should receive antibiotic treatment. However, viral swabs proved positive for adenovirus.
Dr. Ivaska responded with his recent experiences of a similar case, where a 5-year-old boy had a FeverPAIN score of 4-5 and Centor score of 3. Cultures from his throat were GAS positive, illustrating the problem of differentiating between bacterial and viral infections.
But does a GAS-positive pharyngeal culture necessarily mean that antibiotic treatment is indicated? Dr. Ivaska believes it does, citing the importance of preventing serious complications such as rheumatic fever. Dr. Zsigmind countered by pointing out the low levels of acute rheumatic fever in developed nations. In her own country, Hungary, there has not been a case in the last 30 years. Giving antibiotics for historical reasons cannot, in her view, be justified.
Dr. Ivaska responded that perhaps this is because of early treatment in children with sore throats.
Another complication of tonsillitis is quinsy. Dr. Zsigmond cited a study showing that there is no statistically significant evidence demonstrating that antibiotics prevent quinsy. She attributed this to quinsy appearing quickly, typically within 2 days. Delay in seeking help means that the window to treat is often missed. However, should symptoms present early, there is no statistical evidence that prior antibiotic use can prevent quinsy. Also, given the rarity of this condition, prevention would mean excessive use of antibiotics.
Are there other possible benefits of antibiotic treatment in patients with a sore throat? Dr. Ivaska referred to a Cochrane review that found a shortening in duration of throat soreness and fever. Furthermore, compared with placebo, antibiotics reduced the incidence of suppurative complications such as acute otitis media and sinusitis following a sore throat. Other studies have also pointed to the potential benefits of reduced transmission in families where one member with pharyngitis was GAS positive.
As the debate ended, Dr. Zsigmond reported evidence of global antibiotic overprescribing for sore throat ranging from 53% in Europe to 94% in Australia. She also highlighted risks such as altered gut flora, drug resistance, and rashes.
Robin Marlow from the University of Bristol (England), PhD, MBBS, commented that “one of the most enjoyable parts of the ESPID meeting is hearing different viewpoints rationally explained from across the world. As [antibiotic prescription for a sore throat is] a clinical conundrum that faces pediatricians every day, I thought this debate was a really great example of how, despite our different health care systems and ways of working, we are all striving together to improve children’s health using the best evidence available.”
The presenters had no financial conflicts of interest to declare.
The use of antibiotics to treat a sore throat remains contentious, with guidelines from around the world providing contradictory advice. This topic generated a lively debate at the annual meeting of the European Society for Paediatric Infectious Diseases, held virtually this year.
Lauri Ivaska, MD, of the department of pediatrics and adolescent medicine at Turku (Finland) University Hospital, argued for the use of antibiotics, while Borbála Zsigmond, MD, of Heim Pál Children’s Hospital in Budapest, made the case against their use. Interestingly, this debate occurred against the background of a poll conducted before the debate, which found that only 11% of the audience voted in favor of using antibiotics to treat sore throats.
Both speakers began by exploring their approach to the treatment of a recent clinical case involving a 4-year-old girl presenting with sore throat. Dr. Ivaska stressed the difference between a sore throat, pharyngitis, and tonsillitis: the latter two refer to a physical finding, while the former is a subjective symptom.
International guidelines differ on the subject
The debate moved to discussing the international guidelines for treating pharyngitis and tonsillitis. Dr. Zsigmond believes that these are flawed and unhelpful, arguing that they differ depending on what part of the world a physician is practicing in. For example, the 2012 Infectious Diseases Society of America guidelines recommend using best clinical judgment and then backing this up by testing. If testing proves positive for group A Streptococcus pyogenes (GAS), the physician should universally treat. By comparison, the European Society of Clinical Microbiology and Infectious Diseases Sore Throat Guideline Group focuses on severity rather than the cause of the infection. If the case is deemed to be serious, antibiotics can be prescribed without a positive test.
Sore throat is frequently associated with a common cold. In a recent study, more that 80% of students with an acute viral respiratory tract infection had soreness at the beginning of their illness.
Reporting from his own research, Dr. Ivaska argued that viruses can be detected in almost two-thirds of children with pharyngitis using polymerase chain reaction analysis. He thinks antibiotics should be reserved for those 30%-40% of patients with a confirmed GAS infection. The potential role of Fusobacterium necrophorum was raised, but there is no evidence of the benefits of antibiotic treatment in such cases.
There are diagnostic aids for GAS infection
It was suggested that, instead of concentrating on sore throat, the debate should be about whether to use antibiotics to treat GAS infection. But how can the diagnosis be confirmed simply in a clinical setting? Dr. Ivaska recommended adopting diagnostic aids such as Centor, McIsaac, and FeverPAIN, which award scores for several common disease features – the higher the score, the more likely a patient is to be suffering from a GAS infection.
Dr. Zsigmond also likes scoring symptoms but believes they are often inaccurate, especially in young children. She pointed to a report that examined the use of the Centor tool among 441 children attending a pediatric ED. The authors concluded that the Centor criteria were ineffective in predicting a positive GAS culture in throat swabs taken from symptomatic patients.
When are antibiotics warranted?
It is widely accepted that antibiotics should be avoided for viral infections. Returning to the case described at the start of this debate, Dr. Zsigmond calculated that her patient with a 2-day history of sore throat, elevated temperature, pussy tonsils, and enlarged cervical lymph glands but no cough or rhinitis had a FeverPAIN score of 4-5 and a Centor score of 4, meaning that, according to the European guidelines, she should receive antibiotic treatment. However, viral swabs proved positive for adenovirus.
Dr. Ivaska responded with his recent experiences of a similar case, where a 5-year-old boy had a FeverPAIN score of 4-5 and Centor score of 3. Cultures from his throat were GAS positive, illustrating the problem of differentiating between bacterial and viral infections.
But does a GAS-positive pharyngeal culture necessarily mean that antibiotic treatment is indicated? Dr. Ivaska believes it does, citing the importance of preventing serious complications such as rheumatic fever. Dr. Zsigmind countered by pointing out the low levels of acute rheumatic fever in developed nations. In her own country, Hungary, there has not been a case in the last 30 years. Giving antibiotics for historical reasons cannot, in her view, be justified.
Dr. Ivaska responded that perhaps this is because of early treatment in children with sore throats.
Another complication of tonsillitis is quinsy. Dr. Zsigmond cited a study showing that there is no statistically significant evidence demonstrating that antibiotics prevent quinsy. She attributed this to quinsy appearing quickly, typically within 2 days. Delay in seeking help means that the window to treat is often missed. However, should symptoms present early, there is no statistical evidence that prior antibiotic use can prevent quinsy. Also, given the rarity of this condition, prevention would mean excessive use of antibiotics.
Are there other possible benefits of antibiotic treatment in patients with a sore throat? Dr. Ivaska referred to a Cochrane review that found a shortening in duration of throat soreness and fever. Furthermore, compared with placebo, antibiotics reduced the incidence of suppurative complications such as acute otitis media and sinusitis following a sore throat. Other studies have also pointed to the potential benefits of reduced transmission in families where one member with pharyngitis was GAS positive.
As the debate ended, Dr. Zsigmond reported evidence of global antibiotic overprescribing for sore throat ranging from 53% in Europe to 94% in Australia. She also highlighted risks such as altered gut flora, drug resistance, and rashes.
Robin Marlow from the University of Bristol (England), PhD, MBBS, commented that “one of the most enjoyable parts of the ESPID meeting is hearing different viewpoints rationally explained from across the world. As [antibiotic prescription for a sore throat is] a clinical conundrum that faces pediatricians every day, I thought this debate was a really great example of how, despite our different health care systems and ways of working, we are all striving together to improve children’s health using the best evidence available.”
The presenters had no financial conflicts of interest to declare.
The use of antibiotics to treat a sore throat remains contentious, with guidelines from around the world providing contradictory advice. This topic generated a lively debate at the annual meeting of the European Society for Paediatric Infectious Diseases, held virtually this year.
Lauri Ivaska, MD, of the department of pediatrics and adolescent medicine at Turku (Finland) University Hospital, argued for the use of antibiotics, while Borbála Zsigmond, MD, of Heim Pál Children’s Hospital in Budapest, made the case against their use. Interestingly, this debate occurred against the background of a poll conducted before the debate, which found that only 11% of the audience voted in favor of using antibiotics to treat sore throats.
Both speakers began by exploring their approach to the treatment of a recent clinical case involving a 4-year-old girl presenting with sore throat. Dr. Ivaska stressed the difference between a sore throat, pharyngitis, and tonsillitis: the latter two refer to a physical finding, while the former is a subjective symptom.
International guidelines differ on the subject
The debate moved to discussing the international guidelines for treating pharyngitis and tonsillitis. Dr. Zsigmond believes that these are flawed and unhelpful, arguing that they differ depending on what part of the world a physician is practicing in. For example, the 2012 Infectious Diseases Society of America guidelines recommend using best clinical judgment and then backing this up by testing. If testing proves positive for group A Streptococcus pyogenes (GAS), the physician should universally treat. By comparison, the European Society of Clinical Microbiology and Infectious Diseases Sore Throat Guideline Group focuses on severity rather than the cause of the infection. If the case is deemed to be serious, antibiotics can be prescribed without a positive test.
Sore throat is frequently associated with a common cold. In a recent study, more that 80% of students with an acute viral respiratory tract infection had soreness at the beginning of their illness.
Reporting from his own research, Dr. Ivaska argued that viruses can be detected in almost two-thirds of children with pharyngitis using polymerase chain reaction analysis. He thinks antibiotics should be reserved for those 30%-40% of patients with a confirmed GAS infection. The potential role of Fusobacterium necrophorum was raised, but there is no evidence of the benefits of antibiotic treatment in such cases.
There are diagnostic aids for GAS infection
It was suggested that, instead of concentrating on sore throat, the debate should be about whether to use antibiotics to treat GAS infection. But how can the diagnosis be confirmed simply in a clinical setting? Dr. Ivaska recommended adopting diagnostic aids such as Centor, McIsaac, and FeverPAIN, which award scores for several common disease features – the higher the score, the more likely a patient is to be suffering from a GAS infection.
Dr. Zsigmond also likes scoring symptoms but believes they are often inaccurate, especially in young children. She pointed to a report that examined the use of the Centor tool among 441 children attending a pediatric ED. The authors concluded that the Centor criteria were ineffective in predicting a positive GAS culture in throat swabs taken from symptomatic patients.
When are antibiotics warranted?
It is widely accepted that antibiotics should be avoided for viral infections. Returning to the case described at the start of this debate, Dr. Zsigmond calculated that her patient with a 2-day history of sore throat, elevated temperature, pussy tonsils, and enlarged cervical lymph glands but no cough or rhinitis had a FeverPAIN score of 4-5 and a Centor score of 4, meaning that, according to the European guidelines, she should receive antibiotic treatment. However, viral swabs proved positive for adenovirus.
Dr. Ivaska responded with his recent experiences of a similar case, where a 5-year-old boy had a FeverPAIN score of 4-5 and Centor score of 3. Cultures from his throat were GAS positive, illustrating the problem of differentiating between bacterial and viral infections.
But does a GAS-positive pharyngeal culture necessarily mean that antibiotic treatment is indicated? Dr. Ivaska believes it does, citing the importance of preventing serious complications such as rheumatic fever. Dr. Zsigmind countered by pointing out the low levels of acute rheumatic fever in developed nations. In her own country, Hungary, there has not been a case in the last 30 years. Giving antibiotics for historical reasons cannot, in her view, be justified.
Dr. Ivaska responded that perhaps this is because of early treatment in children with sore throats.
Another complication of tonsillitis is quinsy. Dr. Zsigmond cited a study showing that there is no statistically significant evidence demonstrating that antibiotics prevent quinsy. She attributed this to quinsy appearing quickly, typically within 2 days. Delay in seeking help means that the window to treat is often missed. However, should symptoms present early, there is no statistical evidence that prior antibiotic use can prevent quinsy. Also, given the rarity of this condition, prevention would mean excessive use of antibiotics.
Are there other possible benefits of antibiotic treatment in patients with a sore throat? Dr. Ivaska referred to a Cochrane review that found a shortening in duration of throat soreness and fever. Furthermore, compared with placebo, antibiotics reduced the incidence of suppurative complications such as acute otitis media and sinusitis following a sore throat. Other studies have also pointed to the potential benefits of reduced transmission in families where one member with pharyngitis was GAS positive.
As the debate ended, Dr. Zsigmond reported evidence of global antibiotic overprescribing for sore throat ranging from 53% in Europe to 94% in Australia. She also highlighted risks such as altered gut flora, drug resistance, and rashes.
Robin Marlow from the University of Bristol (England), PhD, MBBS, commented that “one of the most enjoyable parts of the ESPID meeting is hearing different viewpoints rationally explained from across the world. As [antibiotic prescription for a sore throat is] a clinical conundrum that faces pediatricians every day, I thought this debate was a really great example of how, despite our different health care systems and ways of working, we are all striving together to improve children’s health using the best evidence available.”
The presenters had no financial conflicts of interest to declare.
FROM ESPID 2020
An all-oral option for advanced HR+, HER2– breast cancer?
These results suggest tesetaxel plus capecitabine is “a potential new treatment option” for this patient population, said study investigator Joyce O’Shaughnessy, MD, of Baylor University Medical Center and Texas Oncology, both in Dallas.
“This should launch an oral taxane into the clinical space, which will be a nice addition to the toolbox for treating advanced breast cancer, with real upsides for patients,” said Hal Burstein, MD, PhD, of Dana-Farber Cancer Institute and Harvard Medical School, both in Boston, who was not involved in the trial but commented on the results in an interview.
Another commenter was more critical of CONTESSA’s results, which were presented at the 2020 San Antonio Breast Cancer Symposium.
“Three months’ difference in PFS in this setting is meaningless without overall survival [OS] results,” Fatima Cardoso, MD, of Champalimaud Clinical Center in Lisbon, Portugal, said in a question submitted through the virtual meeting’s chat system.
At this point, the OS data are immature, and mature data won’t be available for another couple of years at least, according to the study’s protocol.
Dr. O’Shaughnessy defended the PFS result as being significant, however, saying it was comparable with outcomes seen previously with docetaxel-capecitabine and paclitaxel-gemcitabine combinations.
Other meeting attendees questioned why the waters had been muddied by testing the effects of tesetaxel in combination with capecitabine, albeit at a reduced dose, versus the approved full dose of capecitabine as monotherapy, particularly as a phase 2 trial had shown that tesetaxel demonstrated “significant activity” as monotherapy.
“The reason for the combination versus a monotherapy is because it was designed as a registration trial,” Dr. O’Shaughnessy explained. The trial was designed to be very similar to early taxane studies where docetaxel was assessed with or without capecitabine, or paclitaxel with or without gemcitabine.
“Probably we’re going to be using a doublet for patients who have virulent disease who really need a response,” Dr. O’Shaughnessy explained. She noted that the objective response rate was much higher with the tesetaxel-capecitabine combination than with capecitabine alone, and that result alone is “probably enough that we would utilize a doublet.”
The key thing is that it now gives patients an all-oral option, Dr. O’Shaughnessy said.
“The data are exciting because it would be terrific to have an orally available taxane chemotherapy,” agreed Dr. Burstein. “It is far more convenient for patients and opens access globally in places that do not have adequate resources for administration of IV therapeutics. Also, the data suggest that tesetaxel has a different side effect profile than IV taxane, with less neuropathy and less alopecia.”
Trial design
CONTESSA is an ongoing randomized, controlled trial that started in 2017 and is projected to end in early 2023. It is investigating the use of tesetaxel plus a reduced dose of capecitabine versus the approved dose of capecitabine alone in 685 women with hormone receptor–positive, HER2-negative locally advanced or metastatic breast cancer who had previously been treated with a taxane.
Being intrinsically orally bioavailable and more soluble than the other taxanes means that tesetaxel has a much longer half-life that allows for a “more convenient treatment experience for patients,” Dr. O’Shaughnessy observed.
Indeed, because tesetaxel only needs to be dosed once every 3 weeks, patients in the trial received tesetaxel at 27 mg/m2 only on the first day of a 21-day treatment cycle. This was combined with a reduced, 825-mg/m2 dose of capecitabine, given orally twice-daily on days 2-14 but once daily on the evening of day 1 and on the morning of day 15.
The combination regimen was compared with the recommended full dose of capecitabine alone, 1,250 mg/m2 given orally twice daily on days 2-14 but once daily on the evening of day 1 and on the morning of day 15.
Efficacy and safety
PFS was 9.8 months with tesetaxel plus capecitabine and 6.9 months with capecitabine alone, representing a 2.9-month improvement with the combination (hazard ratio, 0.716; P = .003).
A similar PFS benefit was seen regardless of multiple predefined subgroups, such as age, baseline performance status, duration of disease-free interval before study entry, and the use of CDK4/6 inhibitors.
The objective response rate was 57% with tesetaxel plus capecitabine and 41% with capecitabine alone (P = .0002). The 24-week disease control rate was 67% and 50%, respectively (P < .0001).
The most frequent treatment-emergent adverse event seen with the tesetaxel-capecitabine combination was neutropenia, occurring in 76.9% of patients, compared with 22.6% of patients in the monotherapy arm. Rates of grade 3-4 neutropenia were much higher in the combination arm (32.6% and 38.3%, respectively) than in the monotherapy arm (7.4% and 0.9%, respectively).
The neutropenia seen was “generally manageable,” Dr. O’Shaughnessy said, primarily with dose reductions and granulocyte colony–stimulating factor as needed.
She pointed out that rates of grade 3 or higher neuropathy and grade 2 alopecia were low, a respective 5.9% and 8%, with the combination.
The dose of capecitabine used in the control arm was noted to be higher than that used in usual practice.
“This was because of the global nature of the study and the regulatory requirements globally,” Dr. O’Shaughnessy said.
“The dose-modification scheme was that patients could have a dose reduction at the first sign of grade 2 toxicity,” she added, giving investigators the flexibility to reduce the dose as soon as possible.
This study was sponsored by Odonate Therapeutics. Dr. O’Shaughnessy disclosed consulting fees from AbbVie, Agendia, AstraZeneca, Bristol-Myers Squibb, Celgene, Eisai, Genentech/Roche, Genomic Health, GRAIL, Heron, Immunomedics, Ipsen, Jounce, Lilly, Novartis, Odonate, Pfizer, Puma, and Seagen. Dr. Burstein and Dr. Cardoso had no relevant disclosures.
SOURCE: O’Shaughnessy J et al. SABCS 2020, Abstract GS4-01.
These results suggest tesetaxel plus capecitabine is “a potential new treatment option” for this patient population, said study investigator Joyce O’Shaughnessy, MD, of Baylor University Medical Center and Texas Oncology, both in Dallas.
“This should launch an oral taxane into the clinical space, which will be a nice addition to the toolbox for treating advanced breast cancer, with real upsides for patients,” said Hal Burstein, MD, PhD, of Dana-Farber Cancer Institute and Harvard Medical School, both in Boston, who was not involved in the trial but commented on the results in an interview.
Another commenter was more critical of CONTESSA’s results, which were presented at the 2020 San Antonio Breast Cancer Symposium.
“Three months’ difference in PFS in this setting is meaningless without overall survival [OS] results,” Fatima Cardoso, MD, of Champalimaud Clinical Center in Lisbon, Portugal, said in a question submitted through the virtual meeting’s chat system.
At this point, the OS data are immature, and mature data won’t be available for another couple of years at least, according to the study’s protocol.
Dr. O’Shaughnessy defended the PFS result as being significant, however, saying it was comparable with outcomes seen previously with docetaxel-capecitabine and paclitaxel-gemcitabine combinations.
Other meeting attendees questioned why the waters had been muddied by testing the effects of tesetaxel in combination with capecitabine, albeit at a reduced dose, versus the approved full dose of capecitabine as monotherapy, particularly as a phase 2 trial had shown that tesetaxel demonstrated “significant activity” as monotherapy.
“The reason for the combination versus a monotherapy is because it was designed as a registration trial,” Dr. O’Shaughnessy explained. The trial was designed to be very similar to early taxane studies where docetaxel was assessed with or without capecitabine, or paclitaxel with or without gemcitabine.
“Probably we’re going to be using a doublet for patients who have virulent disease who really need a response,” Dr. O’Shaughnessy explained. She noted that the objective response rate was much higher with the tesetaxel-capecitabine combination than with capecitabine alone, and that result alone is “probably enough that we would utilize a doublet.”
The key thing is that it now gives patients an all-oral option, Dr. O’Shaughnessy said.
“The data are exciting because it would be terrific to have an orally available taxane chemotherapy,” agreed Dr. Burstein. “It is far more convenient for patients and opens access globally in places that do not have adequate resources for administration of IV therapeutics. Also, the data suggest that tesetaxel has a different side effect profile than IV taxane, with less neuropathy and less alopecia.”
Trial design
CONTESSA is an ongoing randomized, controlled trial that started in 2017 and is projected to end in early 2023. It is investigating the use of tesetaxel plus a reduced dose of capecitabine versus the approved dose of capecitabine alone in 685 women with hormone receptor–positive, HER2-negative locally advanced or metastatic breast cancer who had previously been treated with a taxane.
Being intrinsically orally bioavailable and more soluble than the other taxanes means that tesetaxel has a much longer half-life that allows for a “more convenient treatment experience for patients,” Dr. O’Shaughnessy observed.
Indeed, because tesetaxel only needs to be dosed once every 3 weeks, patients in the trial received tesetaxel at 27 mg/m2 only on the first day of a 21-day treatment cycle. This was combined with a reduced, 825-mg/m2 dose of capecitabine, given orally twice-daily on days 2-14 but once daily on the evening of day 1 and on the morning of day 15.
The combination regimen was compared with the recommended full dose of capecitabine alone, 1,250 mg/m2 given orally twice daily on days 2-14 but once daily on the evening of day 1 and on the morning of day 15.
Efficacy and safety
PFS was 9.8 months with tesetaxel plus capecitabine and 6.9 months with capecitabine alone, representing a 2.9-month improvement with the combination (hazard ratio, 0.716; P = .003).
A similar PFS benefit was seen regardless of multiple predefined subgroups, such as age, baseline performance status, duration of disease-free interval before study entry, and the use of CDK4/6 inhibitors.
The objective response rate was 57% with tesetaxel plus capecitabine and 41% with capecitabine alone (P = .0002). The 24-week disease control rate was 67% and 50%, respectively (P < .0001).
The most frequent treatment-emergent adverse event seen with the tesetaxel-capecitabine combination was neutropenia, occurring in 76.9% of patients, compared with 22.6% of patients in the monotherapy arm. Rates of grade 3-4 neutropenia were much higher in the combination arm (32.6% and 38.3%, respectively) than in the monotherapy arm (7.4% and 0.9%, respectively).
The neutropenia seen was “generally manageable,” Dr. O’Shaughnessy said, primarily with dose reductions and granulocyte colony–stimulating factor as needed.
She pointed out that rates of grade 3 or higher neuropathy and grade 2 alopecia were low, a respective 5.9% and 8%, with the combination.
The dose of capecitabine used in the control arm was noted to be higher than that used in usual practice.
“This was because of the global nature of the study and the regulatory requirements globally,” Dr. O’Shaughnessy said.
“The dose-modification scheme was that patients could have a dose reduction at the first sign of grade 2 toxicity,” she added, giving investigators the flexibility to reduce the dose as soon as possible.
This study was sponsored by Odonate Therapeutics. Dr. O’Shaughnessy disclosed consulting fees from AbbVie, Agendia, AstraZeneca, Bristol-Myers Squibb, Celgene, Eisai, Genentech/Roche, Genomic Health, GRAIL, Heron, Immunomedics, Ipsen, Jounce, Lilly, Novartis, Odonate, Pfizer, Puma, and Seagen. Dr. Burstein and Dr. Cardoso had no relevant disclosures.
SOURCE: O’Shaughnessy J et al. SABCS 2020, Abstract GS4-01.
These results suggest tesetaxel plus capecitabine is “a potential new treatment option” for this patient population, said study investigator Joyce O’Shaughnessy, MD, of Baylor University Medical Center and Texas Oncology, both in Dallas.
“This should launch an oral taxane into the clinical space, which will be a nice addition to the toolbox for treating advanced breast cancer, with real upsides for patients,” said Hal Burstein, MD, PhD, of Dana-Farber Cancer Institute and Harvard Medical School, both in Boston, who was not involved in the trial but commented on the results in an interview.
Another commenter was more critical of CONTESSA’s results, which were presented at the 2020 San Antonio Breast Cancer Symposium.
“Three months’ difference in PFS in this setting is meaningless without overall survival [OS] results,” Fatima Cardoso, MD, of Champalimaud Clinical Center in Lisbon, Portugal, said in a question submitted through the virtual meeting’s chat system.
At this point, the OS data are immature, and mature data won’t be available for another couple of years at least, according to the study’s protocol.
Dr. O’Shaughnessy defended the PFS result as being significant, however, saying it was comparable with outcomes seen previously with docetaxel-capecitabine and paclitaxel-gemcitabine combinations.
Other meeting attendees questioned why the waters had been muddied by testing the effects of tesetaxel in combination with capecitabine, albeit at a reduced dose, versus the approved full dose of capecitabine as monotherapy, particularly as a phase 2 trial had shown that tesetaxel demonstrated “significant activity” as monotherapy.
“The reason for the combination versus a monotherapy is because it was designed as a registration trial,” Dr. O’Shaughnessy explained. The trial was designed to be very similar to early taxane studies where docetaxel was assessed with or without capecitabine, or paclitaxel with or without gemcitabine.
“Probably we’re going to be using a doublet for patients who have virulent disease who really need a response,” Dr. O’Shaughnessy explained. She noted that the objective response rate was much higher with the tesetaxel-capecitabine combination than with capecitabine alone, and that result alone is “probably enough that we would utilize a doublet.”
The key thing is that it now gives patients an all-oral option, Dr. O’Shaughnessy said.
“The data are exciting because it would be terrific to have an orally available taxane chemotherapy,” agreed Dr. Burstein. “It is far more convenient for patients and opens access globally in places that do not have adequate resources for administration of IV therapeutics. Also, the data suggest that tesetaxel has a different side effect profile than IV taxane, with less neuropathy and less alopecia.”
Trial design
CONTESSA is an ongoing randomized, controlled trial that started in 2017 and is projected to end in early 2023. It is investigating the use of tesetaxel plus a reduced dose of capecitabine versus the approved dose of capecitabine alone in 685 women with hormone receptor–positive, HER2-negative locally advanced or metastatic breast cancer who had previously been treated with a taxane.
Being intrinsically orally bioavailable and more soluble than the other taxanes means that tesetaxel has a much longer half-life that allows for a “more convenient treatment experience for patients,” Dr. O’Shaughnessy observed.
Indeed, because tesetaxel only needs to be dosed once every 3 weeks, patients in the trial received tesetaxel at 27 mg/m2 only on the first day of a 21-day treatment cycle. This was combined with a reduced, 825-mg/m2 dose of capecitabine, given orally twice-daily on days 2-14 but once daily on the evening of day 1 and on the morning of day 15.
The combination regimen was compared with the recommended full dose of capecitabine alone, 1,250 mg/m2 given orally twice daily on days 2-14 but once daily on the evening of day 1 and on the morning of day 15.
Efficacy and safety
PFS was 9.8 months with tesetaxel plus capecitabine and 6.9 months with capecitabine alone, representing a 2.9-month improvement with the combination (hazard ratio, 0.716; P = .003).
A similar PFS benefit was seen regardless of multiple predefined subgroups, such as age, baseline performance status, duration of disease-free interval before study entry, and the use of CDK4/6 inhibitors.
The objective response rate was 57% with tesetaxel plus capecitabine and 41% with capecitabine alone (P = .0002). The 24-week disease control rate was 67% and 50%, respectively (P < .0001).
The most frequent treatment-emergent adverse event seen with the tesetaxel-capecitabine combination was neutropenia, occurring in 76.9% of patients, compared with 22.6% of patients in the monotherapy arm. Rates of grade 3-4 neutropenia were much higher in the combination arm (32.6% and 38.3%, respectively) than in the monotherapy arm (7.4% and 0.9%, respectively).
The neutropenia seen was “generally manageable,” Dr. O’Shaughnessy said, primarily with dose reductions and granulocyte colony–stimulating factor as needed.
She pointed out that rates of grade 3 or higher neuropathy and grade 2 alopecia were low, a respective 5.9% and 8%, with the combination.
The dose of capecitabine used in the control arm was noted to be higher than that used in usual practice.
“This was because of the global nature of the study and the regulatory requirements globally,” Dr. O’Shaughnessy said.
“The dose-modification scheme was that patients could have a dose reduction at the first sign of grade 2 toxicity,” she added, giving investigators the flexibility to reduce the dose as soon as possible.
This study was sponsored by Odonate Therapeutics. Dr. O’Shaughnessy disclosed consulting fees from AbbVie, Agendia, AstraZeneca, Bristol-Myers Squibb, Celgene, Eisai, Genentech/Roche, Genomic Health, GRAIL, Heron, Immunomedics, Ipsen, Jounce, Lilly, Novartis, Odonate, Pfizer, Puma, and Seagen. Dr. Burstein and Dr. Cardoso had no relevant disclosures.
SOURCE: O’Shaughnessy J et al. SABCS 2020, Abstract GS4-01.
FROM SABCS 2020
Vaccine-preventable infection risk high for pediatric hematopoietic cell transplantation recipients
Vaccine-preventable infections (VPIs) in pediatric hematopoietic cell transplantation (HCT) recipients cause significant morbidity, health care burden, and mortality.
Dana Danino, MD, and colleagues presented their evaluation of the prevalence and epidemiology of pediatric VPI-associated hospitalizations occurring within 5 years post HCT at the annual meeting of the European Society for Paediatric Infectious Diseases, held virtually this year.
“Pediatric HCT recipients are at increased risk of VPIs, and HCT recipients have poor outcomes from VPIs, compared with the general population,” explained Dr. Danino, of the department of pediatrics, and divisions of infectious diseases and host defense at the Ohio State University, Columbus. “However, the contemporary prevalence, risk factors, morbidity and mortality resulting from VPIs in children post HCT are not well known.”
Their epidemiological study, using the Pediatric Health Information System (PHIS) database, identified all children under 18 years that underwent allogeneic or autologous HCT in an 8-year period. A total of 9,591 unique HCT recipients were identified.
The researchers demonstrated that 7.1% of this cohort were hospitalized for a VPI in the first 5 years post HCT. Dr. Danino explained that 67% of VPI hospitalizations occurred during the first year, at a median of 222 days, and 22% of VPIs occurred during the initial HCT admission.
As to the type of infection, Dr. Danino and colleagues found that, the prevalence of VPI hospitalizations were highest for influenza, followed by varicella and invasive pneumococcal infections. They identified no hospitalizations due to measles or rubella during the study period.
The study findings revealed that the influenza infections occurred a median 231 days post HCT; varicella infections occurred a median 190 days; and invasive pneumococcal infections occurred a median 311 days post HCT.
“When we did a multivariate analysis by time post HCT, we found that age at transplantation, primary immune deficiency as an indication for transplantation, and graft versus host disease were independent predictors of VPIs during the initial HCT admission,” said Dr. Danino.
Children with a VPI who spent longer in hospital were more likely to be admitted to an ICU and have higher mortality, compared with children without a VPI diagnosis.
“VPIs led to longer duration of hospitalization, higher rates of ICU admission, and higher mortality, compared to HCT recipients without VPIs,” Dr. Danino explained. It was not possible in this retrospective study to determine whether increased mortality was VPI related.
These results underline the seriousness of infections in vulnerable children after HCT. Dr. Danino concluded by saying that “efforts to optimize vaccination strategies early post HCT are warranted to decrease VPIs.”
Dr. Danino had nothing to disclose.
Vaccine-preventable infections (VPIs) in pediatric hematopoietic cell transplantation (HCT) recipients cause significant morbidity, health care burden, and mortality.
Dana Danino, MD, and colleagues presented their evaluation of the prevalence and epidemiology of pediatric VPI-associated hospitalizations occurring within 5 years post HCT at the annual meeting of the European Society for Paediatric Infectious Diseases, held virtually this year.
“Pediatric HCT recipients are at increased risk of VPIs, and HCT recipients have poor outcomes from VPIs, compared with the general population,” explained Dr. Danino, of the department of pediatrics, and divisions of infectious diseases and host defense at the Ohio State University, Columbus. “However, the contemporary prevalence, risk factors, morbidity and mortality resulting from VPIs in children post HCT are not well known.”
Their epidemiological study, using the Pediatric Health Information System (PHIS) database, identified all children under 18 years that underwent allogeneic or autologous HCT in an 8-year period. A total of 9,591 unique HCT recipients were identified.
The researchers demonstrated that 7.1% of this cohort were hospitalized for a VPI in the first 5 years post HCT. Dr. Danino explained that 67% of VPI hospitalizations occurred during the first year, at a median of 222 days, and 22% of VPIs occurred during the initial HCT admission.
As to the type of infection, Dr. Danino and colleagues found that, the prevalence of VPI hospitalizations were highest for influenza, followed by varicella and invasive pneumococcal infections. They identified no hospitalizations due to measles or rubella during the study period.
The study findings revealed that the influenza infections occurred a median 231 days post HCT; varicella infections occurred a median 190 days; and invasive pneumococcal infections occurred a median 311 days post HCT.
“When we did a multivariate analysis by time post HCT, we found that age at transplantation, primary immune deficiency as an indication for transplantation, and graft versus host disease were independent predictors of VPIs during the initial HCT admission,” said Dr. Danino.
Children with a VPI who spent longer in hospital were more likely to be admitted to an ICU and have higher mortality, compared with children without a VPI diagnosis.
“VPIs led to longer duration of hospitalization, higher rates of ICU admission, and higher mortality, compared to HCT recipients without VPIs,” Dr. Danino explained. It was not possible in this retrospective study to determine whether increased mortality was VPI related.
These results underline the seriousness of infections in vulnerable children after HCT. Dr. Danino concluded by saying that “efforts to optimize vaccination strategies early post HCT are warranted to decrease VPIs.”
Dr. Danino had nothing to disclose.
Vaccine-preventable infections (VPIs) in pediatric hematopoietic cell transplantation (HCT) recipients cause significant morbidity, health care burden, and mortality.
Dana Danino, MD, and colleagues presented their evaluation of the prevalence and epidemiology of pediatric VPI-associated hospitalizations occurring within 5 years post HCT at the annual meeting of the European Society for Paediatric Infectious Diseases, held virtually this year.
“Pediatric HCT recipients are at increased risk of VPIs, and HCT recipients have poor outcomes from VPIs, compared with the general population,” explained Dr. Danino, of the department of pediatrics, and divisions of infectious diseases and host defense at the Ohio State University, Columbus. “However, the contemporary prevalence, risk factors, morbidity and mortality resulting from VPIs in children post HCT are not well known.”
Their epidemiological study, using the Pediatric Health Information System (PHIS) database, identified all children under 18 years that underwent allogeneic or autologous HCT in an 8-year period. A total of 9,591 unique HCT recipients were identified.
The researchers demonstrated that 7.1% of this cohort were hospitalized for a VPI in the first 5 years post HCT. Dr. Danino explained that 67% of VPI hospitalizations occurred during the first year, at a median of 222 days, and 22% of VPIs occurred during the initial HCT admission.
As to the type of infection, Dr. Danino and colleagues found that, the prevalence of VPI hospitalizations were highest for influenza, followed by varicella and invasive pneumococcal infections. They identified no hospitalizations due to measles or rubella during the study period.
The study findings revealed that the influenza infections occurred a median 231 days post HCT; varicella infections occurred a median 190 days; and invasive pneumococcal infections occurred a median 311 days post HCT.
“When we did a multivariate analysis by time post HCT, we found that age at transplantation, primary immune deficiency as an indication for transplantation, and graft versus host disease were independent predictors of VPIs during the initial HCT admission,” said Dr. Danino.
Children with a VPI who spent longer in hospital were more likely to be admitted to an ICU and have higher mortality, compared with children without a VPI diagnosis.
“VPIs led to longer duration of hospitalization, higher rates of ICU admission, and higher mortality, compared to HCT recipients without VPIs,” Dr. Danino explained. It was not possible in this retrospective study to determine whether increased mortality was VPI related.
These results underline the seriousness of infections in vulnerable children after HCT. Dr. Danino concluded by saying that “efforts to optimize vaccination strategies early post HCT are warranted to decrease VPIs.”
Dr. Danino had nothing to disclose.
FROM ESPID 2020
On the horizon: Asciminib, a new drug for treating r/r CML
The investigational drug asciminib (being developed by Novartis) may become the new kid on the block for the treatment of chronic phase chronic myeloid leukemia (CMP-CP) for patients who have relapsed on or are refractory to at least two prior tyrosine kinase inhibitors (TKIs).
New results from the ASCEMBL study (NCT03106779) show that patients who received asciminib, which works differently from currently approved therapies for CML-CP, achieved better responses, compared with bosutinib (Bosulif) as third-line therapy.
“The ASCEMBL study opens a new chapter for CML, proving comparatively superior efficacy and excellent safety for a new class of ABL inhibitors,” coinvestigator Michael J. Mauro, MD, from Memorial Sloan Kettering Cancer Center, New York, said in an interview.
The trial was presented as a late-breaking abstract at the annual meeting of the American Society of Hematology.
Asciminib is a first-of-a-kind STAMP (Specifically Targeting the ABL Myristoyl Pocket) inhibitor that works differently from currently approved TKIs, which are adenosine triphosphate (ATP)-–competitive ABL inhibitors.
Five TKIs have been approved by the Food and Drug Administration to treat CML: imatinib (Gleevec; generics), nilotinib (Tasigna), dasatinib (Sprycel), bosutinib, and ponatinib (Iclusig).
All of them inhibit BCR/ABL tyrosine kinase by binding to the ATP-binding pocket.
Most patients with TKI resistant disease develop mutations in the ATP-binding pocket, explained Michael Jay Styler, MD, associate professor at Fox Chase–Temple University Hospital bone marrow transplant program, Fox Chase Cancer Center, Philadelphia.
By inactivating the protein through binding outside the ATP site, asciminib is a novel BCR-ABL inhibitor and may be a superior alternative to further traditional TKIs. “This agent promises to be an important addition to our treatment armamentarium for CML,” Dr. Styler said in an interview.
Another expert agreed. “Although we have many excellent therapies for CML, having a new medication that targets BCR-ABL in a novel way is still welcome to help us better care for CML patients,” Gabriela S. Hobbs, MD, said in an interview. Dr. Hobbs is the clinical director of leukemia services at Boston’s Mass General Cancer Center.
Patients in this study had previously been receiving at least two different types of TKIs. “The responses looked very encouraging for this group of heavily pretreated patients. Although CML patients do very well on current therapies, those that don’t get a response with TKI remain a difficult clinical challenge,” Dr. Hobbs said.
“This is the first study comparing asciminib to a TKI directly (in this case bosutinib) and it showed safety as well as preliminary evidence of efficacy. I look forward to seeing additional studies with this promising drug and to have a new drug to add to the CML arsenal,” she added.
Identifying patients who will benefit from asciminib
Patients with CML are currently sequenced through more than one second-generation TKI, Dr. Mauro commented. “If imatinib and a second-generation TKI have not served a patient well, only bosutinib has been studied in the third line and comparatively in the ASCEMBL study.” Asciminib was shown to be superior and could offer a clear alternative to ponatinib, which would be the other choice and is typically given even later after sequencing all other available options.
Dr. Hobbs agreed. “This is a challenging group of patients to manage as their options are limited. Ponatinib is often the drug of choice in these scenarios, as well as bone marrow transplant.”
They also agreed that it may be effective (alone or in combination) in treating patients with T315I-mutation CML, which is a particularly challenging disease.
Senior study author Andreas Hochhaus, MD, of the Klinik für Innere Medizin II in Jena, Germany, who presented the data at the meeting, noted new trials to test the efficacy of asciminib alone or in combination in earlier lines of therapy are ongoing and include the investigator-initiated FASCINATION study (first-line asciminib in combination) in Germany (NCT03906292).
ASCEMBL study details
ASCEMBL is a phase 3 study in which patients with CML who had received at least two previous TKIs were randomized to asciminib (n = 157) 40 mg twice daily or bosutinib (n = 76) 500 mg once daily. In a protocol amendment, patients with documented failure on bosutinib were allowed to switch to asciminib.
The main reason for discontinuing the last TKI therapy was lack of efficacy in approximately two-thirds of patients. More patients in the asciminib than the bosutinib group received two prior lines of therapy (52% vs. 40%); the others had received three or more prior lines of therapy.
Median follow-up for the data cutoff was 14.9 months.
Dr. Hochhaus reported that treatment discontinuation was lower in patients receiving asciminib than bosutinib (38% vs. 70%) and was mostly due to lack of efficacy (21% vs. 32%) or adverse events (5% vs. 21%).
The study met its primary endpoint: major molecular response (MMR) was approximately twice as high with asciminib than bosutinib at 24 weeks (25.5% vs. 13.2%; P = .029). Treatment effect for MMR was 12.2%. Median duration of exposure to asciminib was 43.4 weeks for asciminib and 29.2 weeks for bosutinib.
“Consistent treatment effect was seen across all subgroups of patients, and MMR rates were consistently high for patients on asciminib across all prior lines of therapy,” Dr. Hochhaus reported.
The probability of achieving MMR at 24 weeks was higher for patients receiving asciminib (25% vs. 11.9%) and started at week 12, he noted. Complete cytogenetic response was also higher for patients receiving asciminib (40.8% vs. 24.2%).
The occurrence of grade 3 or higher adverse events was lower with asciminib than bosutinib (51% vs. 61%). Thrombocytopenia and neutropenia were more common with asciminib and gastrointestinal events were more common with bosutinib. Arterial occlusion events were reported in five patients receiving asciminib and one patient receiving bosutinib. Most of these patients had prior exposure to imatinib, nilotinib, and/or dasatinib.
Dr. Mauro, a coinvestigator of the phase 3 study, also treated patients with the drug in the phase 1 study. “I feel asciminib has proven to be very well tolerated, with rare to absent cases of intolerance,” he said. Cardiovascular and cardiopulmonary adverse events are exceedingly rare as well.
Longer follow-up of the ASCEMBL study and continued follow-up of the myriad of groups from the phase 1 trial (T315I-positive patients treated with higher-dose asciminib, combination therapy with imatinib/nilotinib/dasatinib plus asciminib, and others) will be essential to settle any questions regarding selective adverse events of interest such as vascular occlusion, Dr. Mauro noted.
Dr. Hochhaus has reported receiving research funding from Novartis, Incyte, Pfizer, and Bristol-Myers Squibb. Dr. Hobbs has reported serving on advisory boards for Novartis. Dr. Mauro has reported financial relationships with Bristol-Myers Squibb, Novartis, Takeda, Pfizer, and Sun Pharma/SPARC.
A version of this article first appeared on Medscape.com.
The investigational drug asciminib (being developed by Novartis) may become the new kid on the block for the treatment of chronic phase chronic myeloid leukemia (CMP-CP) for patients who have relapsed on or are refractory to at least two prior tyrosine kinase inhibitors (TKIs).
New results from the ASCEMBL study (NCT03106779) show that patients who received asciminib, which works differently from currently approved therapies for CML-CP, achieved better responses, compared with bosutinib (Bosulif) as third-line therapy.
“The ASCEMBL study opens a new chapter for CML, proving comparatively superior efficacy and excellent safety for a new class of ABL inhibitors,” coinvestigator Michael J. Mauro, MD, from Memorial Sloan Kettering Cancer Center, New York, said in an interview.
The trial was presented as a late-breaking abstract at the annual meeting of the American Society of Hematology.
Asciminib is a first-of-a-kind STAMP (Specifically Targeting the ABL Myristoyl Pocket) inhibitor that works differently from currently approved TKIs, which are adenosine triphosphate (ATP)-–competitive ABL inhibitors.
Five TKIs have been approved by the Food and Drug Administration to treat CML: imatinib (Gleevec; generics), nilotinib (Tasigna), dasatinib (Sprycel), bosutinib, and ponatinib (Iclusig).
All of them inhibit BCR/ABL tyrosine kinase by binding to the ATP-binding pocket.
Most patients with TKI resistant disease develop mutations in the ATP-binding pocket, explained Michael Jay Styler, MD, associate professor at Fox Chase–Temple University Hospital bone marrow transplant program, Fox Chase Cancer Center, Philadelphia.
By inactivating the protein through binding outside the ATP site, asciminib is a novel BCR-ABL inhibitor and may be a superior alternative to further traditional TKIs. “This agent promises to be an important addition to our treatment armamentarium for CML,” Dr. Styler said in an interview.
Another expert agreed. “Although we have many excellent therapies for CML, having a new medication that targets BCR-ABL in a novel way is still welcome to help us better care for CML patients,” Gabriela S. Hobbs, MD, said in an interview. Dr. Hobbs is the clinical director of leukemia services at Boston’s Mass General Cancer Center.
Patients in this study had previously been receiving at least two different types of TKIs. “The responses looked very encouraging for this group of heavily pretreated patients. Although CML patients do very well on current therapies, those that don’t get a response with TKI remain a difficult clinical challenge,” Dr. Hobbs said.
“This is the first study comparing asciminib to a TKI directly (in this case bosutinib) and it showed safety as well as preliminary evidence of efficacy. I look forward to seeing additional studies with this promising drug and to have a new drug to add to the CML arsenal,” she added.
Identifying patients who will benefit from asciminib
Patients with CML are currently sequenced through more than one second-generation TKI, Dr. Mauro commented. “If imatinib and a second-generation TKI have not served a patient well, only bosutinib has been studied in the third line and comparatively in the ASCEMBL study.” Asciminib was shown to be superior and could offer a clear alternative to ponatinib, which would be the other choice and is typically given even later after sequencing all other available options.
Dr. Hobbs agreed. “This is a challenging group of patients to manage as their options are limited. Ponatinib is often the drug of choice in these scenarios, as well as bone marrow transplant.”
They also agreed that it may be effective (alone or in combination) in treating patients with T315I-mutation CML, which is a particularly challenging disease.
Senior study author Andreas Hochhaus, MD, of the Klinik für Innere Medizin II in Jena, Germany, who presented the data at the meeting, noted new trials to test the efficacy of asciminib alone or in combination in earlier lines of therapy are ongoing and include the investigator-initiated FASCINATION study (first-line asciminib in combination) in Germany (NCT03906292).
ASCEMBL study details
ASCEMBL is a phase 3 study in which patients with CML who had received at least two previous TKIs were randomized to asciminib (n = 157) 40 mg twice daily or bosutinib (n = 76) 500 mg once daily. In a protocol amendment, patients with documented failure on bosutinib were allowed to switch to asciminib.
The main reason for discontinuing the last TKI therapy was lack of efficacy in approximately two-thirds of patients. More patients in the asciminib than the bosutinib group received two prior lines of therapy (52% vs. 40%); the others had received three or more prior lines of therapy.
Median follow-up for the data cutoff was 14.9 months.
Dr. Hochhaus reported that treatment discontinuation was lower in patients receiving asciminib than bosutinib (38% vs. 70%) and was mostly due to lack of efficacy (21% vs. 32%) or adverse events (5% vs. 21%).
The study met its primary endpoint: major molecular response (MMR) was approximately twice as high with asciminib than bosutinib at 24 weeks (25.5% vs. 13.2%; P = .029). Treatment effect for MMR was 12.2%. Median duration of exposure to asciminib was 43.4 weeks for asciminib and 29.2 weeks for bosutinib.
“Consistent treatment effect was seen across all subgroups of patients, and MMR rates were consistently high for patients on asciminib across all prior lines of therapy,” Dr. Hochhaus reported.
The probability of achieving MMR at 24 weeks was higher for patients receiving asciminib (25% vs. 11.9%) and started at week 12, he noted. Complete cytogenetic response was also higher for patients receiving asciminib (40.8% vs. 24.2%).
The occurrence of grade 3 or higher adverse events was lower with asciminib than bosutinib (51% vs. 61%). Thrombocytopenia and neutropenia were more common with asciminib and gastrointestinal events were more common with bosutinib. Arterial occlusion events were reported in five patients receiving asciminib and one patient receiving bosutinib. Most of these patients had prior exposure to imatinib, nilotinib, and/or dasatinib.
Dr. Mauro, a coinvestigator of the phase 3 study, also treated patients with the drug in the phase 1 study. “I feel asciminib has proven to be very well tolerated, with rare to absent cases of intolerance,” he said. Cardiovascular and cardiopulmonary adverse events are exceedingly rare as well.
Longer follow-up of the ASCEMBL study and continued follow-up of the myriad of groups from the phase 1 trial (T315I-positive patients treated with higher-dose asciminib, combination therapy with imatinib/nilotinib/dasatinib plus asciminib, and others) will be essential to settle any questions regarding selective adverse events of interest such as vascular occlusion, Dr. Mauro noted.
Dr. Hochhaus has reported receiving research funding from Novartis, Incyte, Pfizer, and Bristol-Myers Squibb. Dr. Hobbs has reported serving on advisory boards for Novartis. Dr. Mauro has reported financial relationships with Bristol-Myers Squibb, Novartis, Takeda, Pfizer, and Sun Pharma/SPARC.
A version of this article first appeared on Medscape.com.
The investigational drug asciminib (being developed by Novartis) may become the new kid on the block for the treatment of chronic phase chronic myeloid leukemia (CMP-CP) for patients who have relapsed on or are refractory to at least two prior tyrosine kinase inhibitors (TKIs).
New results from the ASCEMBL study (NCT03106779) show that patients who received asciminib, which works differently from currently approved therapies for CML-CP, achieved better responses, compared with bosutinib (Bosulif) as third-line therapy.
“The ASCEMBL study opens a new chapter for CML, proving comparatively superior efficacy and excellent safety for a new class of ABL inhibitors,” coinvestigator Michael J. Mauro, MD, from Memorial Sloan Kettering Cancer Center, New York, said in an interview.
The trial was presented as a late-breaking abstract at the annual meeting of the American Society of Hematology.
Asciminib is a first-of-a-kind STAMP (Specifically Targeting the ABL Myristoyl Pocket) inhibitor that works differently from currently approved TKIs, which are adenosine triphosphate (ATP)-–competitive ABL inhibitors.
Five TKIs have been approved by the Food and Drug Administration to treat CML: imatinib (Gleevec; generics), nilotinib (Tasigna), dasatinib (Sprycel), bosutinib, and ponatinib (Iclusig).
All of them inhibit BCR/ABL tyrosine kinase by binding to the ATP-binding pocket.
Most patients with TKI resistant disease develop mutations in the ATP-binding pocket, explained Michael Jay Styler, MD, associate professor at Fox Chase–Temple University Hospital bone marrow transplant program, Fox Chase Cancer Center, Philadelphia.
By inactivating the protein through binding outside the ATP site, asciminib is a novel BCR-ABL inhibitor and may be a superior alternative to further traditional TKIs. “This agent promises to be an important addition to our treatment armamentarium for CML,” Dr. Styler said in an interview.
Another expert agreed. “Although we have many excellent therapies for CML, having a new medication that targets BCR-ABL in a novel way is still welcome to help us better care for CML patients,” Gabriela S. Hobbs, MD, said in an interview. Dr. Hobbs is the clinical director of leukemia services at Boston’s Mass General Cancer Center.
Patients in this study had previously been receiving at least two different types of TKIs. “The responses looked very encouraging for this group of heavily pretreated patients. Although CML patients do very well on current therapies, those that don’t get a response with TKI remain a difficult clinical challenge,” Dr. Hobbs said.
“This is the first study comparing asciminib to a TKI directly (in this case bosutinib) and it showed safety as well as preliminary evidence of efficacy. I look forward to seeing additional studies with this promising drug and to have a new drug to add to the CML arsenal,” she added.
Identifying patients who will benefit from asciminib
Patients with CML are currently sequenced through more than one second-generation TKI, Dr. Mauro commented. “If imatinib and a second-generation TKI have not served a patient well, only bosutinib has been studied in the third line and comparatively in the ASCEMBL study.” Asciminib was shown to be superior and could offer a clear alternative to ponatinib, which would be the other choice and is typically given even later after sequencing all other available options.
Dr. Hobbs agreed. “This is a challenging group of patients to manage as their options are limited. Ponatinib is often the drug of choice in these scenarios, as well as bone marrow transplant.”
They also agreed that it may be effective (alone or in combination) in treating patients with T315I-mutation CML, which is a particularly challenging disease.
Senior study author Andreas Hochhaus, MD, of the Klinik für Innere Medizin II in Jena, Germany, who presented the data at the meeting, noted new trials to test the efficacy of asciminib alone or in combination in earlier lines of therapy are ongoing and include the investigator-initiated FASCINATION study (first-line asciminib in combination) in Germany (NCT03906292).
ASCEMBL study details
ASCEMBL is a phase 3 study in which patients with CML who had received at least two previous TKIs were randomized to asciminib (n = 157) 40 mg twice daily or bosutinib (n = 76) 500 mg once daily. In a protocol amendment, patients with documented failure on bosutinib were allowed to switch to asciminib.
The main reason for discontinuing the last TKI therapy was lack of efficacy in approximately two-thirds of patients. More patients in the asciminib than the bosutinib group received two prior lines of therapy (52% vs. 40%); the others had received three or more prior lines of therapy.
Median follow-up for the data cutoff was 14.9 months.
Dr. Hochhaus reported that treatment discontinuation was lower in patients receiving asciminib than bosutinib (38% vs. 70%) and was mostly due to lack of efficacy (21% vs. 32%) or adverse events (5% vs. 21%).
The study met its primary endpoint: major molecular response (MMR) was approximately twice as high with asciminib than bosutinib at 24 weeks (25.5% vs. 13.2%; P = .029). Treatment effect for MMR was 12.2%. Median duration of exposure to asciminib was 43.4 weeks for asciminib and 29.2 weeks for bosutinib.
“Consistent treatment effect was seen across all subgroups of patients, and MMR rates were consistently high for patients on asciminib across all prior lines of therapy,” Dr. Hochhaus reported.
The probability of achieving MMR at 24 weeks was higher for patients receiving asciminib (25% vs. 11.9%) and started at week 12, he noted. Complete cytogenetic response was also higher for patients receiving asciminib (40.8% vs. 24.2%).
The occurrence of grade 3 or higher adverse events was lower with asciminib than bosutinib (51% vs. 61%). Thrombocytopenia and neutropenia were more common with asciminib and gastrointestinal events were more common with bosutinib. Arterial occlusion events were reported in five patients receiving asciminib and one patient receiving bosutinib. Most of these patients had prior exposure to imatinib, nilotinib, and/or dasatinib.
Dr. Mauro, a coinvestigator of the phase 3 study, also treated patients with the drug in the phase 1 study. “I feel asciminib has proven to be very well tolerated, with rare to absent cases of intolerance,” he said. Cardiovascular and cardiopulmonary adverse events are exceedingly rare as well.
Longer follow-up of the ASCEMBL study and continued follow-up of the myriad of groups from the phase 1 trial (T315I-positive patients treated with higher-dose asciminib, combination therapy with imatinib/nilotinib/dasatinib plus asciminib, and others) will be essential to settle any questions regarding selective adverse events of interest such as vascular occlusion, Dr. Mauro noted.
Dr. Hochhaus has reported receiving research funding from Novartis, Incyte, Pfizer, and Bristol-Myers Squibb. Dr. Hobbs has reported serving on advisory boards for Novartis. Dr. Mauro has reported financial relationships with Bristol-Myers Squibb, Novartis, Takeda, Pfizer, and Sun Pharma/SPARC.
A version of this article first appeared on Medscape.com.
Preadolescent acne: Management from birth requires increasing vigilance
No treatment may be necessary for acne in the first few months of life, but the condition can leave scars in children as young as ages 3-6 months, said Andrea L. Zaenglein, MD, professor of dermatology and pediatric dermatology, Penn State University, Hershey, Penn., said in a presentation at MedscapeLive’s virtual Women’s & Pediatric Dermatology Seminar.
Neonatal acne occurs in more than 20% of newborns aged 2 weeks to 3 months. “Typically we don’t need to treat it. But if you do, you could use a topical antifungal like clotrimazole cream twice a day,” but in most babies, “this will just improve over time and resolve without any scarring or sequelae,” she said.
Infantile acne begins about 3-6 months of age typically, or a little bit older, and lasts up to 2 years of age, Dr. Zaenglein said. “You will see comedones in infantile acne, so this is actually a true form of acne. It’s due to increased adrenal production of androgens.”
She added: “The scarring can be permanent. It’s important that you recognize infantile acne and treat it, even though it seems pretty mild.”
For infantile acne, she recommends performing a full-skin exam to rule out hyperandrogenic disorders such as Cushing syndrome, congenital adrenal hyperplasia, premature adrenarche, a gonadal/adrenal tumor and precocious puberty.
Treatments are similar to those in teenagers, she said, “but make sure you use baby-friendly formulations,” with lower concentrations of active ingredients – and avoid tetracyclines and benzoyl peroxide (BPO) washes. BPO can be used in leave-on formulations/creams at lower strengths (2.5%-5%).
One possible combination option is tretinoin 0.025% cream or adapalene 0.1% gel plus BPO 2.5% cream or clindamycin/BPO gel. Another combination is adapalene/BPO 2.5% gel.
Erythromycin can be appropriate at 30-50 mg/kg per day divided in two or three doses a day, but beware of possible gastrointestinal upset. Azithromycin at 5 mg/kg per day is another option.
“Rarely do we have to go to isotretinoin,” Dr. Zaenglein said. “I think in all my years, I’ve only treated one baby with isotretinoin for infantile acne. But severe forms can occur.”
Midchildhood and preadolescent acne conditions occur in children starting at ages 1 up to 10 years, Dr. Zaenglein said. In this population, she also recommends ruling out hyperandrogenism by looking for secondary sexual characteristics with full-body skin exams. “The workup can be broad and includes looking at adrenal androgens and total and free testosterone, as well as looking at growth charts and bone age. Typically, you’ll refer these kids to pediatric endocrinology.”
Keep in mind, she said, that early adrenarche starts at ages 6-7 years in girls and 7-8 years in boys. “That’s when we expect to start seeing that very early acne. You can see it even earlier in patients with elevated BMI, and it’s more common in Hispanic and Black children as well.”
She added that it’s important to remember that early adrenarche is a risk factor for polycystic ovarian syndrome (PCOS). “So ask patients about their family history and look for other signs of PCOS as they move further into adolescence.”
Milder cases of acne in this age group can be treated with “salicylic acid wipes and things that are kind of a rite of passage. But if they have any more severe acne, you’re going to want to treat it more or less like you do adolescent acne.”
MedscapeLive and this news organization are owned by the same parent company. Dr. Zaenglein disclosed receiving consulting fees from Cassiopea, Dermata, and Regeneron and fees for contracted research support from Incyte.
No treatment may be necessary for acne in the first few months of life, but the condition can leave scars in children as young as ages 3-6 months, said Andrea L. Zaenglein, MD, professor of dermatology and pediatric dermatology, Penn State University, Hershey, Penn., said in a presentation at MedscapeLive’s virtual Women’s & Pediatric Dermatology Seminar.
Neonatal acne occurs in more than 20% of newborns aged 2 weeks to 3 months. “Typically we don’t need to treat it. But if you do, you could use a topical antifungal like clotrimazole cream twice a day,” but in most babies, “this will just improve over time and resolve without any scarring or sequelae,” she said.
Infantile acne begins about 3-6 months of age typically, or a little bit older, and lasts up to 2 years of age, Dr. Zaenglein said. “You will see comedones in infantile acne, so this is actually a true form of acne. It’s due to increased adrenal production of androgens.”
She added: “The scarring can be permanent. It’s important that you recognize infantile acne and treat it, even though it seems pretty mild.”
For infantile acne, she recommends performing a full-skin exam to rule out hyperandrogenic disorders such as Cushing syndrome, congenital adrenal hyperplasia, premature adrenarche, a gonadal/adrenal tumor and precocious puberty.
Treatments are similar to those in teenagers, she said, “but make sure you use baby-friendly formulations,” with lower concentrations of active ingredients – and avoid tetracyclines and benzoyl peroxide (BPO) washes. BPO can be used in leave-on formulations/creams at lower strengths (2.5%-5%).
One possible combination option is tretinoin 0.025% cream or adapalene 0.1% gel plus BPO 2.5% cream or clindamycin/BPO gel. Another combination is adapalene/BPO 2.5% gel.
Erythromycin can be appropriate at 30-50 mg/kg per day divided in two or three doses a day, but beware of possible gastrointestinal upset. Azithromycin at 5 mg/kg per day is another option.
“Rarely do we have to go to isotretinoin,” Dr. Zaenglein said. “I think in all my years, I’ve only treated one baby with isotretinoin for infantile acne. But severe forms can occur.”
Midchildhood and preadolescent acne conditions occur in children starting at ages 1 up to 10 years, Dr. Zaenglein said. In this population, she also recommends ruling out hyperandrogenism by looking for secondary sexual characteristics with full-body skin exams. “The workup can be broad and includes looking at adrenal androgens and total and free testosterone, as well as looking at growth charts and bone age. Typically, you’ll refer these kids to pediatric endocrinology.”
Keep in mind, she said, that early adrenarche starts at ages 6-7 years in girls and 7-8 years in boys. “That’s when we expect to start seeing that very early acne. You can see it even earlier in patients with elevated BMI, and it’s more common in Hispanic and Black children as well.”
She added that it’s important to remember that early adrenarche is a risk factor for polycystic ovarian syndrome (PCOS). “So ask patients about their family history and look for other signs of PCOS as they move further into adolescence.”
Milder cases of acne in this age group can be treated with “salicylic acid wipes and things that are kind of a rite of passage. But if they have any more severe acne, you’re going to want to treat it more or less like you do adolescent acne.”
MedscapeLive and this news organization are owned by the same parent company. Dr. Zaenglein disclosed receiving consulting fees from Cassiopea, Dermata, and Regeneron and fees for contracted research support from Incyte.
No treatment may be necessary for acne in the first few months of life, but the condition can leave scars in children as young as ages 3-6 months, said Andrea L. Zaenglein, MD, professor of dermatology and pediatric dermatology, Penn State University, Hershey, Penn., said in a presentation at MedscapeLive’s virtual Women’s & Pediatric Dermatology Seminar.
Neonatal acne occurs in more than 20% of newborns aged 2 weeks to 3 months. “Typically we don’t need to treat it. But if you do, you could use a topical antifungal like clotrimazole cream twice a day,” but in most babies, “this will just improve over time and resolve without any scarring or sequelae,” she said.
Infantile acne begins about 3-6 months of age typically, or a little bit older, and lasts up to 2 years of age, Dr. Zaenglein said. “You will see comedones in infantile acne, so this is actually a true form of acne. It’s due to increased adrenal production of androgens.”
She added: “The scarring can be permanent. It’s important that you recognize infantile acne and treat it, even though it seems pretty mild.”
For infantile acne, she recommends performing a full-skin exam to rule out hyperandrogenic disorders such as Cushing syndrome, congenital adrenal hyperplasia, premature adrenarche, a gonadal/adrenal tumor and precocious puberty.
Treatments are similar to those in teenagers, she said, “but make sure you use baby-friendly formulations,” with lower concentrations of active ingredients – and avoid tetracyclines and benzoyl peroxide (BPO) washes. BPO can be used in leave-on formulations/creams at lower strengths (2.5%-5%).
One possible combination option is tretinoin 0.025% cream or adapalene 0.1% gel plus BPO 2.5% cream or clindamycin/BPO gel. Another combination is adapalene/BPO 2.5% gel.
Erythromycin can be appropriate at 30-50 mg/kg per day divided in two or three doses a day, but beware of possible gastrointestinal upset. Azithromycin at 5 mg/kg per day is another option.
“Rarely do we have to go to isotretinoin,” Dr. Zaenglein said. “I think in all my years, I’ve only treated one baby with isotretinoin for infantile acne. But severe forms can occur.”
Midchildhood and preadolescent acne conditions occur in children starting at ages 1 up to 10 years, Dr. Zaenglein said. In this population, she also recommends ruling out hyperandrogenism by looking for secondary sexual characteristics with full-body skin exams. “The workup can be broad and includes looking at adrenal androgens and total and free testosterone, as well as looking at growth charts and bone age. Typically, you’ll refer these kids to pediatric endocrinology.”
Keep in mind, she said, that early adrenarche starts at ages 6-7 years in girls and 7-8 years in boys. “That’s when we expect to start seeing that very early acne. You can see it even earlier in patients with elevated BMI, and it’s more common in Hispanic and Black children as well.”
She added that it’s important to remember that early adrenarche is a risk factor for polycystic ovarian syndrome (PCOS). “So ask patients about their family history and look for other signs of PCOS as they move further into adolescence.”
Milder cases of acne in this age group can be treated with “salicylic acid wipes and things that are kind of a rite of passage. But if they have any more severe acne, you’re going to want to treat it more or less like you do adolescent acne.”
MedscapeLive and this news organization are owned by the same parent company. Dr. Zaenglein disclosed receiving consulting fees from Cassiopea, Dermata, and Regeneron and fees for contracted research support from Incyte.
FROM MEDSCAPELIVE WOMEN’S & PEDIATRIC DERMATOLOGY SEMINAR
Pembro benefits in mTNBC regardless of chemo type
Adding pembrolizumab to chemotherapy substantially increases progression-free survival (PFS) in treatment-naive advanced or metastatic triple-negative breast cancer (TNBC) regardless of chemotherapy type, suggests an analysis of the clinical trial KEYNOTE-355.
There was also a trend for improved outcomes with increasing programmed death–ligand 1 (PD-L1) expression in the tumor, as measured by combined positive score (CPS).
“These data further support a role for the addition of pembro to standard chemo for the first-line treatment of metastatic TNBC,” said study presenter Hope S. Rugo, MD, from the Helen Diller Family Comprehensive Cancer Center, University of California, San Francisco.
The research was presented at the 2020 San Antonio Breast Cancer Symposium on Dec. 10.
Last month, pembrolizumab was granted accelerated approval by the Food and Drug Administration in combination with chemotherapy for the treatment of patients with locally recurrent unresectable or metastatic TNBC whose tumors express PD-L1 (CPS ≥10).
The approval was based on data from KEYNOTE-355, which involved almost 850 women with previously untreated locally recurrent inoperable or metastatic TNBC randomized 2:1 to pembrolizumab plus investigator’s choice of chemotherapy who were followed for 2 years.
For the current analysis, patients were stratified by PD-L1 CPS in the tumor, including over 320 patients with CPS ≥10, and by accompanying chemotherapy regimen.
In the overall intention-to-treat (ITT) population (n = 847), median PFS was longer with pembrolizumab plus chemotherapy versus placebo plus chemotherapy, at 9.7 months versus 5.6 months (hazard ratio, 0.82).
PFS improved step-wise with increased PD-L1 expression. In patients with PD-L1 CPS ≥1, the HR was 0.74, and in those with PD-L1 CPS ≥10, it was 0.65.
A similar incremental improvement by PD-L1 expression was seen in the overall response rate, with the rate topping out at 53.2% in the pembrolizumab plus chemotherapy arm, among the PD-L1 CPS ≥10 group.
Duration of response told a similar story, with the pembro-chemo combination providing superior results and the treatment effect increasing with PD-L1 enrichment.
Study discussant Sylvia Adams, MD, New York University Perlmutter Cancer Center, New York, said the “consistency of treatment effect” with different chemotherapy backbones seen in the study is “very important, as it is currently unknown what the optimal backbone is.”
She also noted that the chemotherapy analysis presented by Dr. Rugo was “exploratory” and “not powered to show the winner of the chemotherapy backbone.”
Nevertheless, in the postpresentation debate, Ian Krop, MD, PhD, Dana-Farber Cancer Institute, Boston, said that there are “several questions over the chemotherapy partner,” including whether there were differences in the populations who received each type of regimen.
Dr. Rugo replied that “because the trial wasn’t powered to look at the separate chemotherapy groups with any statistical significance ... it’s really impossible to draw any specific conclusions because it’s the overall population that’s evaluated.”
Asked about when overall survival results will be presented, Dr. Rugo said that “everybody is very interested” in that, “and we expect these results to be available next year.”
Study details
For KEYNOTE-355, researchers recruited women with previously untreated metastatic TNBC who had completed treatment with curative intent ≥6 months prior to their first disease recurrence.
They were randomized 2:1 to pembrolizumab or placebo plus investigator’s choice of chemotherapy from nab-paclitaxel, paclitaxel, or gemcitabine/carboplatin for up to 35 administrations of pembrolizumab or placebo or until progression, intolerable toxicity, or cessation of treatment.
Crossover was not allowed. Patients were stratified by type of chemotherapy, PD-L1 expression in the tumor, and prior treatment in the neoadjuvant or adjuvant setting with the same class of chemotherapy.
Response was assessed with imaging every 8 weeks until week 24, then every 9 weeks during the first year of follow-up, and then every 12 weeks.
Of 847 randomized patients, 566 received pembrolizumab plus chemotherapy and 281 were assigned to the placebo group. The median age was 53 years in both groups.
The majority (75.1%) of patients in both groups were PD-L1 positive with a centrally assessed CPS ≥1, while 38.9% of patients in the pembrolizumab arm and 36.7% of those given placebo had a CPS ≥10.
After a median follow-up of 25.9 months, 16 patients given pembrolizumab had completed the study and 33 were still ongoing.
This compares with five patients having completed the placebo arm, and 12 still ongoing, after a median follow-up of 26.3 months.
The overall response rate was higher with pembrolizumab plus chemotherapy in the ITT population, at 41.0% versus 35.9%, rising to 45.2% versus 37.9% in patients with PD-L1 CPS ≥1 and 53.2% versus 39.8% in the PD-L1 CPS ≥10 group.
Again, when the groups were stratified by on-study chemotherapy, the overall response rate was higher with pembrolizumab versus placebo regardless of the chemotherapy partner.
Finally, the duration of response with pembrolizumab plus chemotherapy was longer than that seen with placebo, at a median of 10.1 months versus 6.4 months in the ITT population.
In the PD-L1 CPS ≥1 group, the duration of response was 10.1 months versus 6.5 months, rising to 19.3 months versus 7.3 months in the PD-L1 CPS ≥10 group.
Dr. Adams nevertheless said that PD-L1 remains an “imperfect” biomarker in metastatic TNBC, although it is “the best to date.” Furthermore, the IMpassion130 trial, featuring atezolizumab, showed that there is “very poor” analytic and clinical concordance between assays, which “complicates clinical decision-making.”
This study was sponsored by Merck. Dr. Rugo, Dr. Adams, and Dr. Krop have disclosed financial ties to multiple pharmaceutical companies, including Merck.
A version of this article first appeared on Medscape.com.
Adding pembrolizumab to chemotherapy substantially increases progression-free survival (PFS) in treatment-naive advanced or metastatic triple-negative breast cancer (TNBC) regardless of chemotherapy type, suggests an analysis of the clinical trial KEYNOTE-355.
There was also a trend for improved outcomes with increasing programmed death–ligand 1 (PD-L1) expression in the tumor, as measured by combined positive score (CPS).
“These data further support a role for the addition of pembro to standard chemo for the first-line treatment of metastatic TNBC,” said study presenter Hope S. Rugo, MD, from the Helen Diller Family Comprehensive Cancer Center, University of California, San Francisco.
The research was presented at the 2020 San Antonio Breast Cancer Symposium on Dec. 10.
Last month, pembrolizumab was granted accelerated approval by the Food and Drug Administration in combination with chemotherapy for the treatment of patients with locally recurrent unresectable or metastatic TNBC whose tumors express PD-L1 (CPS ≥10).
The approval was based on data from KEYNOTE-355, which involved almost 850 women with previously untreated locally recurrent inoperable or metastatic TNBC randomized 2:1 to pembrolizumab plus investigator’s choice of chemotherapy who were followed for 2 years.
For the current analysis, patients were stratified by PD-L1 CPS in the tumor, including over 320 patients with CPS ≥10, and by accompanying chemotherapy regimen.
In the overall intention-to-treat (ITT) population (n = 847), median PFS was longer with pembrolizumab plus chemotherapy versus placebo plus chemotherapy, at 9.7 months versus 5.6 months (hazard ratio, 0.82).
PFS improved step-wise with increased PD-L1 expression. In patients with PD-L1 CPS ≥1, the HR was 0.74, and in those with PD-L1 CPS ≥10, it was 0.65.
A similar incremental improvement by PD-L1 expression was seen in the overall response rate, with the rate topping out at 53.2% in the pembrolizumab plus chemotherapy arm, among the PD-L1 CPS ≥10 group.
Duration of response told a similar story, with the pembro-chemo combination providing superior results and the treatment effect increasing with PD-L1 enrichment.
Study discussant Sylvia Adams, MD, New York University Perlmutter Cancer Center, New York, said the “consistency of treatment effect” with different chemotherapy backbones seen in the study is “very important, as it is currently unknown what the optimal backbone is.”
She also noted that the chemotherapy analysis presented by Dr. Rugo was “exploratory” and “not powered to show the winner of the chemotherapy backbone.”
Nevertheless, in the postpresentation debate, Ian Krop, MD, PhD, Dana-Farber Cancer Institute, Boston, said that there are “several questions over the chemotherapy partner,” including whether there were differences in the populations who received each type of regimen.
Dr. Rugo replied that “because the trial wasn’t powered to look at the separate chemotherapy groups with any statistical significance ... it’s really impossible to draw any specific conclusions because it’s the overall population that’s evaluated.”
Asked about when overall survival results will be presented, Dr. Rugo said that “everybody is very interested” in that, “and we expect these results to be available next year.”
Study details
For KEYNOTE-355, researchers recruited women with previously untreated metastatic TNBC who had completed treatment with curative intent ≥6 months prior to their first disease recurrence.
They were randomized 2:1 to pembrolizumab or placebo plus investigator’s choice of chemotherapy from nab-paclitaxel, paclitaxel, or gemcitabine/carboplatin for up to 35 administrations of pembrolizumab or placebo or until progression, intolerable toxicity, or cessation of treatment.
Crossover was not allowed. Patients were stratified by type of chemotherapy, PD-L1 expression in the tumor, and prior treatment in the neoadjuvant or adjuvant setting with the same class of chemotherapy.
Response was assessed with imaging every 8 weeks until week 24, then every 9 weeks during the first year of follow-up, and then every 12 weeks.
Of 847 randomized patients, 566 received pembrolizumab plus chemotherapy and 281 were assigned to the placebo group. The median age was 53 years in both groups.
The majority (75.1%) of patients in both groups were PD-L1 positive with a centrally assessed CPS ≥1, while 38.9% of patients in the pembrolizumab arm and 36.7% of those given placebo had a CPS ≥10.
After a median follow-up of 25.9 months, 16 patients given pembrolizumab had completed the study and 33 were still ongoing.
This compares with five patients having completed the placebo arm, and 12 still ongoing, after a median follow-up of 26.3 months.
The overall response rate was higher with pembrolizumab plus chemotherapy in the ITT population, at 41.0% versus 35.9%, rising to 45.2% versus 37.9% in patients with PD-L1 CPS ≥1 and 53.2% versus 39.8% in the PD-L1 CPS ≥10 group.
Again, when the groups were stratified by on-study chemotherapy, the overall response rate was higher with pembrolizumab versus placebo regardless of the chemotherapy partner.
Finally, the duration of response with pembrolizumab plus chemotherapy was longer than that seen with placebo, at a median of 10.1 months versus 6.4 months in the ITT population.
In the PD-L1 CPS ≥1 group, the duration of response was 10.1 months versus 6.5 months, rising to 19.3 months versus 7.3 months in the PD-L1 CPS ≥10 group.
Dr. Adams nevertheless said that PD-L1 remains an “imperfect” biomarker in metastatic TNBC, although it is “the best to date.” Furthermore, the IMpassion130 trial, featuring atezolizumab, showed that there is “very poor” analytic and clinical concordance between assays, which “complicates clinical decision-making.”
This study was sponsored by Merck. Dr. Rugo, Dr. Adams, and Dr. Krop have disclosed financial ties to multiple pharmaceutical companies, including Merck.
A version of this article first appeared on Medscape.com.
Adding pembrolizumab to chemotherapy substantially increases progression-free survival (PFS) in treatment-naive advanced or metastatic triple-negative breast cancer (TNBC) regardless of chemotherapy type, suggests an analysis of the clinical trial KEYNOTE-355.
There was also a trend for improved outcomes with increasing programmed death–ligand 1 (PD-L1) expression in the tumor, as measured by combined positive score (CPS).
“These data further support a role for the addition of pembro to standard chemo for the first-line treatment of metastatic TNBC,” said study presenter Hope S. Rugo, MD, from the Helen Diller Family Comprehensive Cancer Center, University of California, San Francisco.
The research was presented at the 2020 San Antonio Breast Cancer Symposium on Dec. 10.
Last month, pembrolizumab was granted accelerated approval by the Food and Drug Administration in combination with chemotherapy for the treatment of patients with locally recurrent unresectable or metastatic TNBC whose tumors express PD-L1 (CPS ≥10).
The approval was based on data from KEYNOTE-355, which involved almost 850 women with previously untreated locally recurrent inoperable or metastatic TNBC randomized 2:1 to pembrolizumab plus investigator’s choice of chemotherapy who were followed for 2 years.
For the current analysis, patients were stratified by PD-L1 CPS in the tumor, including over 320 patients with CPS ≥10, and by accompanying chemotherapy regimen.
In the overall intention-to-treat (ITT) population (n = 847), median PFS was longer with pembrolizumab plus chemotherapy versus placebo plus chemotherapy, at 9.7 months versus 5.6 months (hazard ratio, 0.82).
PFS improved step-wise with increased PD-L1 expression. In patients with PD-L1 CPS ≥1, the HR was 0.74, and in those with PD-L1 CPS ≥10, it was 0.65.
A similar incremental improvement by PD-L1 expression was seen in the overall response rate, with the rate topping out at 53.2% in the pembrolizumab plus chemotherapy arm, among the PD-L1 CPS ≥10 group.
Duration of response told a similar story, with the pembro-chemo combination providing superior results and the treatment effect increasing with PD-L1 enrichment.
Study discussant Sylvia Adams, MD, New York University Perlmutter Cancer Center, New York, said the “consistency of treatment effect” with different chemotherapy backbones seen in the study is “very important, as it is currently unknown what the optimal backbone is.”
She also noted that the chemotherapy analysis presented by Dr. Rugo was “exploratory” and “not powered to show the winner of the chemotherapy backbone.”
Nevertheless, in the postpresentation debate, Ian Krop, MD, PhD, Dana-Farber Cancer Institute, Boston, said that there are “several questions over the chemotherapy partner,” including whether there were differences in the populations who received each type of regimen.
Dr. Rugo replied that “because the trial wasn’t powered to look at the separate chemotherapy groups with any statistical significance ... it’s really impossible to draw any specific conclusions because it’s the overall population that’s evaluated.”
Asked about when overall survival results will be presented, Dr. Rugo said that “everybody is very interested” in that, “and we expect these results to be available next year.”
Study details
For KEYNOTE-355, researchers recruited women with previously untreated metastatic TNBC who had completed treatment with curative intent ≥6 months prior to their first disease recurrence.
They were randomized 2:1 to pembrolizumab or placebo plus investigator’s choice of chemotherapy from nab-paclitaxel, paclitaxel, or gemcitabine/carboplatin for up to 35 administrations of pembrolizumab or placebo or until progression, intolerable toxicity, or cessation of treatment.
Crossover was not allowed. Patients were stratified by type of chemotherapy, PD-L1 expression in the tumor, and prior treatment in the neoadjuvant or adjuvant setting with the same class of chemotherapy.
Response was assessed with imaging every 8 weeks until week 24, then every 9 weeks during the first year of follow-up, and then every 12 weeks.
Of 847 randomized patients, 566 received pembrolizumab plus chemotherapy and 281 were assigned to the placebo group. The median age was 53 years in both groups.
The majority (75.1%) of patients in both groups were PD-L1 positive with a centrally assessed CPS ≥1, while 38.9% of patients in the pembrolizumab arm and 36.7% of those given placebo had a CPS ≥10.
After a median follow-up of 25.9 months, 16 patients given pembrolizumab had completed the study and 33 were still ongoing.
This compares with five patients having completed the placebo arm, and 12 still ongoing, after a median follow-up of 26.3 months.
The overall response rate was higher with pembrolizumab plus chemotherapy in the ITT population, at 41.0% versus 35.9%, rising to 45.2% versus 37.9% in patients with PD-L1 CPS ≥1 and 53.2% versus 39.8% in the PD-L1 CPS ≥10 group.
Again, when the groups were stratified by on-study chemotherapy, the overall response rate was higher with pembrolizumab versus placebo regardless of the chemotherapy partner.
Finally, the duration of response with pembrolizumab plus chemotherapy was longer than that seen with placebo, at a median of 10.1 months versus 6.4 months in the ITT population.
In the PD-L1 CPS ≥1 group, the duration of response was 10.1 months versus 6.5 months, rising to 19.3 months versus 7.3 months in the PD-L1 CPS ≥10 group.
Dr. Adams nevertheless said that PD-L1 remains an “imperfect” biomarker in metastatic TNBC, although it is “the best to date.” Furthermore, the IMpassion130 trial, featuring atezolizumab, showed that there is “very poor” analytic and clinical concordance between assays, which “complicates clinical decision-making.”
This study was sponsored by Merck. Dr. Rugo, Dr. Adams, and Dr. Krop have disclosed financial ties to multiple pharmaceutical companies, including Merck.
A version of this article first appeared on Medscape.com.