User login
MDedge conference coverage features onsite reporting of the latest study results and expert perspectives from leading researchers.
Atopic dermatitis in adults, children linked to neuropsychiatric disorders
according to a study presented at the annual meeting of the Society for Investigative Dermatology, held virtually.
“The risk increase ranges from as low as 5% up to 59%, depending on the outcome, with generally greater effects observed among the adults,” Joy Wan, MD, a postdoctoral dermatology fellow at the University of Pennsylvania, Philadelphia, said in her presentation. The risk was independent of other atopic disease, gender, age, and socioeconomic status.
Dr. Wan and colleagues conducted a cohort study of patients with AD in the United Kingdom using data from the Health Improvement Network (THIN) electronic records database, matching AD patients in THIN with up to five patients without AD, similar in age and also registered to general practices. The researchers validated AD disease status using an algorithm that identified patients with a diagnostic code and two therapy codes related to AD. Outcomes of interest included anxiety, depression, bipolar disorder, obsessive-compulsive disorder, ADHD, schizophrenia, and autism. Patients entered into the cohort when they were diagnosed with AD, registered by a practice, or when data from a practice was reported to THIN. The researchers stopped following patients when they developed a neuropsychiatric outcome of interest, left a practice, died, or when the study ended.
“Previous studies have found associations between atopic dermatitis and anxiety, depression, and attention-deficit/hyperactivity disorder. However, many previous studies had been cross-sectional and they were unable to evaluate the directionality of association between atopic dermatitis and neuropsychiatric outcomes, while other previous studies have relied on the self-report of atopic dermatitis and outcomes as well,” Dr. Wan said. “Thus, longitudinal studies, using validated measures of atopic dermatitis, and those that include the entire age span, are really needed.”
Overall, 434,859 children and adolescents under aged 18 with AD in the THIN database were matched to 1,983,589 controls, and 644,802 adults with AD were matched to almost 2,900,000 adults without AD. In the pediatric group, demographics were mostly balanced between children with and without AD: the average age ranged between about 5 and almost 6 years. In pediatric patients with AD, there was a higher rate of allergic rhinitis (6.2% vs. 4%) and asthma (13.5% vs. 9.3%) than in the control group.
For adults, the average age was about 48 years in both groups. Compared with patients who did not have AD, adults with AD also had higher rates of allergic rhinitis (15.2% vs. 9.6%) and asthma (19.9% vs. 12.6%).
After adjusting for age, gender, socioeconomic status, asthma, and allergic rhinitis, Dr. Wan and colleagues found greater rates of bipolar disorder (hazard ratio, 1.34; 95% confidence interval, 1.09-1.65), obsessive-compulsive disorder (HR, 1.30; 95% CI, 1.21-1.41), anxiety (HR, 1.09; 95% CI, 1.07-1.11), and depression (HR, 1.06; 95% CI, 1.04-1.08) among children and adolescents with AD, compared with controls.
In the adult cohort, a diagnosis of AD was associated with an increased risk of autism (HR, 1.53; 95% CI, 1.30-1.80), obsessive-compulsive disorder (HR, 1.49; 95% CI, 1.40-1.59), ADHD (HR, 1.31; 95% CI, 1.13-1.53), anxiety (HR, 1.17; 95% CI, 1.15-1.18), depression (HR, 1.15; 95% CI, 1.14-1.16), and bipolar disorder (HR, 1.12; 95% CI, 1.04-1.21), after adjusting for age, gender, socioeconomic status, asthma, and allergic rhinitis.
One reason for the increased associations among the adults, even for ADHD and autism, which are more characteristically diagnosed in childhood, Dr. Wan said, is that, since they looked at incident outcomes, “many children may already have had these prevalent comorbidities at the time of the entry in the cohort.”
She noted that the study may have observation bias or unknown confounders, but she hopes these results raise awareness of the association between AD and neuropsychiatric disorders, although more research is needed to determine how AD severity affects neuropsychiatric outcomes. “Additional work is needed to really understand the mechanisms that drive these associations, whether it’s mediated through symptoms of atopic dermatitis such as itch and poor sleep, or potentially the stigma of having a chronic skin disease, or perhaps shared pathophysiology between atopic dermatitis and these neuropsychiatric diseases,” she said.
The study was funded by a grant from Pfizer. Dr. Wan reports receiving research funding from Pfizer paid to the University of Pennsylvania.
according to a study presented at the annual meeting of the Society for Investigative Dermatology, held virtually.
“The risk increase ranges from as low as 5% up to 59%, depending on the outcome, with generally greater effects observed among the adults,” Joy Wan, MD, a postdoctoral dermatology fellow at the University of Pennsylvania, Philadelphia, said in her presentation. The risk was independent of other atopic disease, gender, age, and socioeconomic status.
Dr. Wan and colleagues conducted a cohort study of patients with AD in the United Kingdom using data from the Health Improvement Network (THIN) electronic records database, matching AD patients in THIN with up to five patients without AD, similar in age and also registered to general practices. The researchers validated AD disease status using an algorithm that identified patients with a diagnostic code and two therapy codes related to AD. Outcomes of interest included anxiety, depression, bipolar disorder, obsessive-compulsive disorder, ADHD, schizophrenia, and autism. Patients entered into the cohort when they were diagnosed with AD, registered by a practice, or when data from a practice was reported to THIN. The researchers stopped following patients when they developed a neuropsychiatric outcome of interest, left a practice, died, or when the study ended.
“Previous studies have found associations between atopic dermatitis and anxiety, depression, and attention-deficit/hyperactivity disorder. However, many previous studies had been cross-sectional and they were unable to evaluate the directionality of association between atopic dermatitis and neuropsychiatric outcomes, while other previous studies have relied on the self-report of atopic dermatitis and outcomes as well,” Dr. Wan said. “Thus, longitudinal studies, using validated measures of atopic dermatitis, and those that include the entire age span, are really needed.”
Overall, 434,859 children and adolescents under aged 18 with AD in the THIN database were matched to 1,983,589 controls, and 644,802 adults with AD were matched to almost 2,900,000 adults without AD. In the pediatric group, demographics were mostly balanced between children with and without AD: the average age ranged between about 5 and almost 6 years. In pediatric patients with AD, there was a higher rate of allergic rhinitis (6.2% vs. 4%) and asthma (13.5% vs. 9.3%) than in the control group.
For adults, the average age was about 48 years in both groups. Compared with patients who did not have AD, adults with AD also had higher rates of allergic rhinitis (15.2% vs. 9.6%) and asthma (19.9% vs. 12.6%).
After adjusting for age, gender, socioeconomic status, asthma, and allergic rhinitis, Dr. Wan and colleagues found greater rates of bipolar disorder (hazard ratio, 1.34; 95% confidence interval, 1.09-1.65), obsessive-compulsive disorder (HR, 1.30; 95% CI, 1.21-1.41), anxiety (HR, 1.09; 95% CI, 1.07-1.11), and depression (HR, 1.06; 95% CI, 1.04-1.08) among children and adolescents with AD, compared with controls.
In the adult cohort, a diagnosis of AD was associated with an increased risk of autism (HR, 1.53; 95% CI, 1.30-1.80), obsessive-compulsive disorder (HR, 1.49; 95% CI, 1.40-1.59), ADHD (HR, 1.31; 95% CI, 1.13-1.53), anxiety (HR, 1.17; 95% CI, 1.15-1.18), depression (HR, 1.15; 95% CI, 1.14-1.16), and bipolar disorder (HR, 1.12; 95% CI, 1.04-1.21), after adjusting for age, gender, socioeconomic status, asthma, and allergic rhinitis.
One reason for the increased associations among the adults, even for ADHD and autism, which are more characteristically diagnosed in childhood, Dr. Wan said, is that, since they looked at incident outcomes, “many children may already have had these prevalent comorbidities at the time of the entry in the cohort.”
She noted that the study may have observation bias or unknown confounders, but she hopes these results raise awareness of the association between AD and neuropsychiatric disorders, although more research is needed to determine how AD severity affects neuropsychiatric outcomes. “Additional work is needed to really understand the mechanisms that drive these associations, whether it’s mediated through symptoms of atopic dermatitis such as itch and poor sleep, or potentially the stigma of having a chronic skin disease, or perhaps shared pathophysiology between atopic dermatitis and these neuropsychiatric diseases,” she said.
The study was funded by a grant from Pfizer. Dr. Wan reports receiving research funding from Pfizer paid to the University of Pennsylvania.
according to a study presented at the annual meeting of the Society for Investigative Dermatology, held virtually.
“The risk increase ranges from as low as 5% up to 59%, depending on the outcome, with generally greater effects observed among the adults,” Joy Wan, MD, a postdoctoral dermatology fellow at the University of Pennsylvania, Philadelphia, said in her presentation. The risk was independent of other atopic disease, gender, age, and socioeconomic status.
Dr. Wan and colleagues conducted a cohort study of patients with AD in the United Kingdom using data from the Health Improvement Network (THIN) electronic records database, matching AD patients in THIN with up to five patients without AD, similar in age and also registered to general practices. The researchers validated AD disease status using an algorithm that identified patients with a diagnostic code and two therapy codes related to AD. Outcomes of interest included anxiety, depression, bipolar disorder, obsessive-compulsive disorder, ADHD, schizophrenia, and autism. Patients entered into the cohort when they were diagnosed with AD, registered by a practice, or when data from a practice was reported to THIN. The researchers stopped following patients when they developed a neuropsychiatric outcome of interest, left a practice, died, or when the study ended.
“Previous studies have found associations between atopic dermatitis and anxiety, depression, and attention-deficit/hyperactivity disorder. However, many previous studies had been cross-sectional and they were unable to evaluate the directionality of association between atopic dermatitis and neuropsychiatric outcomes, while other previous studies have relied on the self-report of atopic dermatitis and outcomes as well,” Dr. Wan said. “Thus, longitudinal studies, using validated measures of atopic dermatitis, and those that include the entire age span, are really needed.”
Overall, 434,859 children and adolescents under aged 18 with AD in the THIN database were matched to 1,983,589 controls, and 644,802 adults with AD were matched to almost 2,900,000 adults without AD. In the pediatric group, demographics were mostly balanced between children with and without AD: the average age ranged between about 5 and almost 6 years. In pediatric patients with AD, there was a higher rate of allergic rhinitis (6.2% vs. 4%) and asthma (13.5% vs. 9.3%) than in the control group.
For adults, the average age was about 48 years in both groups. Compared with patients who did not have AD, adults with AD also had higher rates of allergic rhinitis (15.2% vs. 9.6%) and asthma (19.9% vs. 12.6%).
After adjusting for age, gender, socioeconomic status, asthma, and allergic rhinitis, Dr. Wan and colleagues found greater rates of bipolar disorder (hazard ratio, 1.34; 95% confidence interval, 1.09-1.65), obsessive-compulsive disorder (HR, 1.30; 95% CI, 1.21-1.41), anxiety (HR, 1.09; 95% CI, 1.07-1.11), and depression (HR, 1.06; 95% CI, 1.04-1.08) among children and adolescents with AD, compared with controls.
In the adult cohort, a diagnosis of AD was associated with an increased risk of autism (HR, 1.53; 95% CI, 1.30-1.80), obsessive-compulsive disorder (HR, 1.49; 95% CI, 1.40-1.59), ADHD (HR, 1.31; 95% CI, 1.13-1.53), anxiety (HR, 1.17; 95% CI, 1.15-1.18), depression (HR, 1.15; 95% CI, 1.14-1.16), and bipolar disorder (HR, 1.12; 95% CI, 1.04-1.21), after adjusting for age, gender, socioeconomic status, asthma, and allergic rhinitis.
One reason for the increased associations among the adults, even for ADHD and autism, which are more characteristically diagnosed in childhood, Dr. Wan said, is that, since they looked at incident outcomes, “many children may already have had these prevalent comorbidities at the time of the entry in the cohort.”
She noted that the study may have observation bias or unknown confounders, but she hopes these results raise awareness of the association between AD and neuropsychiatric disorders, although more research is needed to determine how AD severity affects neuropsychiatric outcomes. “Additional work is needed to really understand the mechanisms that drive these associations, whether it’s mediated through symptoms of atopic dermatitis such as itch and poor sleep, or potentially the stigma of having a chronic skin disease, or perhaps shared pathophysiology between atopic dermatitis and these neuropsychiatric diseases,” she said.
The study was funded by a grant from Pfizer. Dr. Wan reports receiving research funding from Pfizer paid to the University of Pennsylvania.
FROM SID 2020
Constraint-induced movement therapy may boost neuroplasticity in MS
, compared with alternative interventions with medicines. “The findings suggest for the first time that physical behavioral change therapy can significantly stimulate cortical neuroplasticity in a degenerative central nervous system disorder,” said the authors of research presented at the virtual meeting of the Consortium of Multiple Sclerosis Centers (CMSC).
CIMT, an intervention involving 3.5 hours/day of therapist-supervised treatment over 10 consecutive weekdays, has been shown to significantly improve paretic limb use for patients with progressive MS, and the effects are long lasting.
For patients with asymmetric upper limb nonuse, the treatment “is highly successful for promoting increased use by the more-affected arm for everyday activities,” said lead author Victor W. Mark, MD, an associate professor and medical director of the Constraint-Induced Movement Therapy Research Programs at the University of Alabama at Birmingham. “The improvements after CIMT can be found to remain as much as 1 year after the completion of the treatment, and even later. That by itself is novel for MS,” he said.
The team’s previous research in Neurorehabilitation and Neural Repair showed that the CIMT intervention is associated with statistically significant changes in white matter integrity in the brain. In this new study, Dr. Mark and colleagues sought to determine whether the effects would also translate to improvements in cortical gray matter.
Promoting neuroplasticity, improving motor function
For their study, they enrolled 20 adults with chronic MS who were matched with respect to unilateral arm disability. The participants were randomly assigned to receive 35 hours of either CIMT or a holistic complementary alternative medicine program, which included yoga, aquatic therapy, massage, and/or relaxation techniques, over the course of 2 weeks.
Both groups expressed the same degree of expectancy of benefits from the intervention. Those who received CIMT showed a significantly larger effect size on the Motor Activity Log, a measure that has been validated against real-world upper-limb accelerometry, compared with the control group (d = 3.2, vs. d = 0.7).
Imaging with tensor-based morphometry showed an increase in the thickness of the primary motor cortex in patients who underwent CIMT but not those who received the alternative medicine treatment. Furthermore, a change in the primary motor cortex was observed in the CIMT group on voxel-based morphometry, suggesting an increase in cortical density or volume, or both. Similar changes were not seen in the alternative medicine group.
“We evaluated the density of the brain cortical gray area before and after treatment, and we found increased gray matter in the area of the brain that is concentrated with voluntary limb movement (the motor cortex),” Dr. Mark said. “As in (previous) studies, we did not find such changes, or any changes, after the other form of treatment,” he said.
The results are important, Dr. Mark noted, “because CIMT seems to specifically promote neuroplasticity changes that appear to be healthy, for what is otherwise a chronically progressive degenerative neurological disorder.”
In addition to the improvements in MS, CIMT has led to improvement in motor function for patients who have experienced other central nervous system injuries, including stroke, traumatic brain injury, cerebral palsy, and, in musicians, focal hand dystonia.
The new findings offer intriguing insights into the effects in progressive MS, commented rehabilitation specialist Patricia Bobryk, MHS, a physical therapist with the UCHealth Yampa Valley Medical Center, in Colorado Springs.
“There is more evidence for CIMT in the area of stroke, which is more acute onset and with more potential recovery, especially early on, so this is exciting initial work in terms of MS,” she said.
“If we’re trying to find new avenues in the brain for better pathways, rather than using something that’s damaged in MS, it makes perfect sense that CIMT really forces and drives those connections, because you’re doing a repetitive, high-intensity patterning throughout the day, so you set up that environment for things to progress, especially in motor functioning,” she said.
Repetition, ‘prevention of compensation’
CIMT was developed at the University of Alabama, Birmingham, 30 years ago and involves four components. The first, described as “massed practice,” involves intensive, repetitive arm movements of the affected arm. The second component involves “shaping,” in which the patient is encouraged to perform his or her best attempts at the movements.
For the third component, described as “prevention of compensation,” the patient’s more-functional arm is inhibited from being used in everyday activities by wearing a padded mitt.
“This permits the patient to brace him- or herself whenever needed, but the better hand nonetheless lacks the dexterity to take over the activities that should be performed by the worse arm,” Dr. Mark explained.
“The patient wears the padded mitt after hours, too, except when using water or when sleeping,” he said.
The fourth component is a set of behavioral enforcement techniques involving goal-setting; daily interviews and discussion of progress and challenges; nightly homework; diary keeping; and telephone follow-up.
Dr. Mark noted that the intervention could have benefits that are secondary to motor and movement function. “We consider that the improvement of limb activity in a motor-challenged person with MS could afford a way to offset the deleterious effects of inactivity that can occur, such as weight gain, diabetes, osteoporosis, cardiac disease, and other conditions associated with prolonged inactivity,” he said.
Although it was developed at the University of Alabama, CIMT is currently more widely practiced in Europe than the United States, likely because of differences in care support, which in Europe is provided through socialized medicine, Dr. Mark pointed out.
Although the detailed methods for conducting CIMT are published in peer-reviewed journals, Dr. Mark recommends hands-on and interactive teaching. Such training is offered to clinicians and affiliated physical therapists and occupational therapists through Mark’s program at the University of Alabama in a semiannual, week-long training course, which includes hands-on treatment practice with actual patients.
Proof of principle
In further commenting on the study, Kathy M. Zackowski, PhD, of the National MS Society, said the findings provide an intriguing proof of concept that should be tested in a larger cohort. “The question of how much a behavioral (therapy) can impact true brain structural change or change in the pathologic mechanism is intriguing and of high importance,” she said.
“It is important to take this information as ‘proof of principle’ of the importance of CIMT for improving upper limb activity,” according to Dr. Zackowski, senior director, patient management, care and rehabilitation research at the society.
“Importantly, this team needs to move forward testing their hypothesis in a larger randomized, clinical trial with a full control group in order to show causal evidence that one intervention caused the structural brain changes seen,” she said in an interview.
Dr. Zackowski added that a caveat of CIMT is that the approach assumes one limb is more impaired than the other, which is always the case in stroke but is true only in some cases of MS. “Therefore, this method may not be effective for everyone with MS, but offers another option for tailoring an intervention to a person’s abilities and interests,” she said.
“Another important detail is that CIMT is also being explored for lower extremity use,” she added. “This is exciting, as lower extremity dysfunction is a very common problem in MS, and may be useful in treating walking disability.”
The authors, Ms. Bobryk, and Dr. Zackowski have disclosed no relevant financial relationships.
A version of this article originally appeared on Medscape.com.
, compared with alternative interventions with medicines. “The findings suggest for the first time that physical behavioral change therapy can significantly stimulate cortical neuroplasticity in a degenerative central nervous system disorder,” said the authors of research presented at the virtual meeting of the Consortium of Multiple Sclerosis Centers (CMSC).
CIMT, an intervention involving 3.5 hours/day of therapist-supervised treatment over 10 consecutive weekdays, has been shown to significantly improve paretic limb use for patients with progressive MS, and the effects are long lasting.
For patients with asymmetric upper limb nonuse, the treatment “is highly successful for promoting increased use by the more-affected arm for everyday activities,” said lead author Victor W. Mark, MD, an associate professor and medical director of the Constraint-Induced Movement Therapy Research Programs at the University of Alabama at Birmingham. “The improvements after CIMT can be found to remain as much as 1 year after the completion of the treatment, and even later. That by itself is novel for MS,” he said.
The team’s previous research in Neurorehabilitation and Neural Repair showed that the CIMT intervention is associated with statistically significant changes in white matter integrity in the brain. In this new study, Dr. Mark and colleagues sought to determine whether the effects would also translate to improvements in cortical gray matter.
Promoting neuroplasticity, improving motor function
For their study, they enrolled 20 adults with chronic MS who were matched with respect to unilateral arm disability. The participants were randomly assigned to receive 35 hours of either CIMT or a holistic complementary alternative medicine program, which included yoga, aquatic therapy, massage, and/or relaxation techniques, over the course of 2 weeks.
Both groups expressed the same degree of expectancy of benefits from the intervention. Those who received CIMT showed a significantly larger effect size on the Motor Activity Log, a measure that has been validated against real-world upper-limb accelerometry, compared with the control group (d = 3.2, vs. d = 0.7).
Imaging with tensor-based morphometry showed an increase in the thickness of the primary motor cortex in patients who underwent CIMT but not those who received the alternative medicine treatment. Furthermore, a change in the primary motor cortex was observed in the CIMT group on voxel-based morphometry, suggesting an increase in cortical density or volume, or both. Similar changes were not seen in the alternative medicine group.
“We evaluated the density of the brain cortical gray area before and after treatment, and we found increased gray matter in the area of the brain that is concentrated with voluntary limb movement (the motor cortex),” Dr. Mark said. “As in (previous) studies, we did not find such changes, or any changes, after the other form of treatment,” he said.
The results are important, Dr. Mark noted, “because CIMT seems to specifically promote neuroplasticity changes that appear to be healthy, for what is otherwise a chronically progressive degenerative neurological disorder.”
In addition to the improvements in MS, CIMT has led to improvement in motor function for patients who have experienced other central nervous system injuries, including stroke, traumatic brain injury, cerebral palsy, and, in musicians, focal hand dystonia.
The new findings offer intriguing insights into the effects in progressive MS, commented rehabilitation specialist Patricia Bobryk, MHS, a physical therapist with the UCHealth Yampa Valley Medical Center, in Colorado Springs.
“There is more evidence for CIMT in the area of stroke, which is more acute onset and with more potential recovery, especially early on, so this is exciting initial work in terms of MS,” she said.
“If we’re trying to find new avenues in the brain for better pathways, rather than using something that’s damaged in MS, it makes perfect sense that CIMT really forces and drives those connections, because you’re doing a repetitive, high-intensity patterning throughout the day, so you set up that environment for things to progress, especially in motor functioning,” she said.
Repetition, ‘prevention of compensation’
CIMT was developed at the University of Alabama, Birmingham, 30 years ago and involves four components. The first, described as “massed practice,” involves intensive, repetitive arm movements of the affected arm. The second component involves “shaping,” in which the patient is encouraged to perform his or her best attempts at the movements.
For the third component, described as “prevention of compensation,” the patient’s more-functional arm is inhibited from being used in everyday activities by wearing a padded mitt.
“This permits the patient to brace him- or herself whenever needed, but the better hand nonetheless lacks the dexterity to take over the activities that should be performed by the worse arm,” Dr. Mark explained.
“The patient wears the padded mitt after hours, too, except when using water or when sleeping,” he said.
The fourth component is a set of behavioral enforcement techniques involving goal-setting; daily interviews and discussion of progress and challenges; nightly homework; diary keeping; and telephone follow-up.
Dr. Mark noted that the intervention could have benefits that are secondary to motor and movement function. “We consider that the improvement of limb activity in a motor-challenged person with MS could afford a way to offset the deleterious effects of inactivity that can occur, such as weight gain, diabetes, osteoporosis, cardiac disease, and other conditions associated with prolonged inactivity,” he said.
Although it was developed at the University of Alabama, CIMT is currently more widely practiced in Europe than the United States, likely because of differences in care support, which in Europe is provided through socialized medicine, Dr. Mark pointed out.
Although the detailed methods for conducting CIMT are published in peer-reviewed journals, Dr. Mark recommends hands-on and interactive teaching. Such training is offered to clinicians and affiliated physical therapists and occupational therapists through Mark’s program at the University of Alabama in a semiannual, week-long training course, which includes hands-on treatment practice with actual patients.
Proof of principle
In further commenting on the study, Kathy M. Zackowski, PhD, of the National MS Society, said the findings provide an intriguing proof of concept that should be tested in a larger cohort. “The question of how much a behavioral (therapy) can impact true brain structural change or change in the pathologic mechanism is intriguing and of high importance,” she said.
“It is important to take this information as ‘proof of principle’ of the importance of CIMT for improving upper limb activity,” according to Dr. Zackowski, senior director, patient management, care and rehabilitation research at the society.
“Importantly, this team needs to move forward testing their hypothesis in a larger randomized, clinical trial with a full control group in order to show causal evidence that one intervention caused the structural brain changes seen,” she said in an interview.
Dr. Zackowski added that a caveat of CIMT is that the approach assumes one limb is more impaired than the other, which is always the case in stroke but is true only in some cases of MS. “Therefore, this method may not be effective for everyone with MS, but offers another option for tailoring an intervention to a person’s abilities and interests,” she said.
“Another important detail is that CIMT is also being explored for lower extremity use,” she added. “This is exciting, as lower extremity dysfunction is a very common problem in MS, and may be useful in treating walking disability.”
The authors, Ms. Bobryk, and Dr. Zackowski have disclosed no relevant financial relationships.
A version of this article originally appeared on Medscape.com.
, compared with alternative interventions with medicines. “The findings suggest for the first time that physical behavioral change therapy can significantly stimulate cortical neuroplasticity in a degenerative central nervous system disorder,” said the authors of research presented at the virtual meeting of the Consortium of Multiple Sclerosis Centers (CMSC).
CIMT, an intervention involving 3.5 hours/day of therapist-supervised treatment over 10 consecutive weekdays, has been shown to significantly improve paretic limb use for patients with progressive MS, and the effects are long lasting.
For patients with asymmetric upper limb nonuse, the treatment “is highly successful for promoting increased use by the more-affected arm for everyday activities,” said lead author Victor W. Mark, MD, an associate professor and medical director of the Constraint-Induced Movement Therapy Research Programs at the University of Alabama at Birmingham. “The improvements after CIMT can be found to remain as much as 1 year after the completion of the treatment, and even later. That by itself is novel for MS,” he said.
The team’s previous research in Neurorehabilitation and Neural Repair showed that the CIMT intervention is associated with statistically significant changes in white matter integrity in the brain. In this new study, Dr. Mark and colleagues sought to determine whether the effects would also translate to improvements in cortical gray matter.
Promoting neuroplasticity, improving motor function
For their study, they enrolled 20 adults with chronic MS who were matched with respect to unilateral arm disability. The participants were randomly assigned to receive 35 hours of either CIMT or a holistic complementary alternative medicine program, which included yoga, aquatic therapy, massage, and/or relaxation techniques, over the course of 2 weeks.
Both groups expressed the same degree of expectancy of benefits from the intervention. Those who received CIMT showed a significantly larger effect size on the Motor Activity Log, a measure that has been validated against real-world upper-limb accelerometry, compared with the control group (d = 3.2, vs. d = 0.7).
Imaging with tensor-based morphometry showed an increase in the thickness of the primary motor cortex in patients who underwent CIMT but not those who received the alternative medicine treatment. Furthermore, a change in the primary motor cortex was observed in the CIMT group on voxel-based morphometry, suggesting an increase in cortical density or volume, or both. Similar changes were not seen in the alternative medicine group.
“We evaluated the density of the brain cortical gray area before and after treatment, and we found increased gray matter in the area of the brain that is concentrated with voluntary limb movement (the motor cortex),” Dr. Mark said. “As in (previous) studies, we did not find such changes, or any changes, after the other form of treatment,” he said.
The results are important, Dr. Mark noted, “because CIMT seems to specifically promote neuroplasticity changes that appear to be healthy, for what is otherwise a chronically progressive degenerative neurological disorder.”
In addition to the improvements in MS, CIMT has led to improvement in motor function for patients who have experienced other central nervous system injuries, including stroke, traumatic brain injury, cerebral palsy, and, in musicians, focal hand dystonia.
The new findings offer intriguing insights into the effects in progressive MS, commented rehabilitation specialist Patricia Bobryk, MHS, a physical therapist with the UCHealth Yampa Valley Medical Center, in Colorado Springs.
“There is more evidence for CIMT in the area of stroke, which is more acute onset and with more potential recovery, especially early on, so this is exciting initial work in terms of MS,” she said.
“If we’re trying to find new avenues in the brain for better pathways, rather than using something that’s damaged in MS, it makes perfect sense that CIMT really forces and drives those connections, because you’re doing a repetitive, high-intensity patterning throughout the day, so you set up that environment for things to progress, especially in motor functioning,” she said.
Repetition, ‘prevention of compensation’
CIMT was developed at the University of Alabama, Birmingham, 30 years ago and involves four components. The first, described as “massed practice,” involves intensive, repetitive arm movements of the affected arm. The second component involves “shaping,” in which the patient is encouraged to perform his or her best attempts at the movements.
For the third component, described as “prevention of compensation,” the patient’s more-functional arm is inhibited from being used in everyday activities by wearing a padded mitt.
“This permits the patient to brace him- or herself whenever needed, but the better hand nonetheless lacks the dexterity to take over the activities that should be performed by the worse arm,” Dr. Mark explained.
“The patient wears the padded mitt after hours, too, except when using water or when sleeping,” he said.
The fourth component is a set of behavioral enforcement techniques involving goal-setting; daily interviews and discussion of progress and challenges; nightly homework; diary keeping; and telephone follow-up.
Dr. Mark noted that the intervention could have benefits that are secondary to motor and movement function. “We consider that the improvement of limb activity in a motor-challenged person with MS could afford a way to offset the deleterious effects of inactivity that can occur, such as weight gain, diabetes, osteoporosis, cardiac disease, and other conditions associated with prolonged inactivity,” he said.
Although it was developed at the University of Alabama, CIMT is currently more widely practiced in Europe than the United States, likely because of differences in care support, which in Europe is provided through socialized medicine, Dr. Mark pointed out.
Although the detailed methods for conducting CIMT are published in peer-reviewed journals, Dr. Mark recommends hands-on and interactive teaching. Such training is offered to clinicians and affiliated physical therapists and occupational therapists through Mark’s program at the University of Alabama in a semiannual, week-long training course, which includes hands-on treatment practice with actual patients.
Proof of principle
In further commenting on the study, Kathy M. Zackowski, PhD, of the National MS Society, said the findings provide an intriguing proof of concept that should be tested in a larger cohort. “The question of how much a behavioral (therapy) can impact true brain structural change or change in the pathologic mechanism is intriguing and of high importance,” she said.
“It is important to take this information as ‘proof of principle’ of the importance of CIMT for improving upper limb activity,” according to Dr. Zackowski, senior director, patient management, care and rehabilitation research at the society.
“Importantly, this team needs to move forward testing their hypothesis in a larger randomized, clinical trial with a full control group in order to show causal evidence that one intervention caused the structural brain changes seen,” she said in an interview.
Dr. Zackowski added that a caveat of CIMT is that the approach assumes one limb is more impaired than the other, which is always the case in stroke but is true only in some cases of MS. “Therefore, this method may not be effective for everyone with MS, but offers another option for tailoring an intervention to a person’s abilities and interests,” she said.
“Another important detail is that CIMT is also being explored for lower extremity use,” she added. “This is exciting, as lower extremity dysfunction is a very common problem in MS, and may be useful in treating walking disability.”
The authors, Ms. Bobryk, and Dr. Zackowski have disclosed no relevant financial relationships.
A version of this article originally appeared on Medscape.com.
FROM CMSC 2020
Secondary surgery extends OS in recurrent ovarian cancer
The trial, AGO DESKTOP III/ENGOT ov20, is the first prospective, randomized study showing an overall survival benefit for debulking surgery in patients with recurrent ovarian cancer.
Among 406 patients in first relapse, the median overall survival was 53.7 months for those randomized to cytoreductive surgery plus chemotherapy and 46 months for patients randomized to chemotherapy alone (P = .02).
“The overall survival benefit was highest and exclusively seen in the cohort with complete resection, indicating the importance of a thorough selection process of both the right patient and the right center,” said investigator Andreas du Bois, MD, of the Kliniken Essen-Mitte (Germany).
The median survival gain for patients with platinum-free intervals of more than 6 months who undergo complete resection is nearly 16 months “and is worth going for,” he added.
Dr. du Bois presented these results as part of the American Society of Clinical Oncology virtual scientific program (Abstract 6000).
In another trial, SOC-1, that was also presented in the virtual program, investigators reported a progression-free survival advantage of 5.5 months for patients with recurrent ovarian cancer who underwent debulking surgery, compared with those who did not (Abstract 6001).
Different trials, different results
The invited discussant for Dr. du Bois’s presentation was Robert L. Coleman, MD, chief scientific officer of the U.S. Oncology Network in The Woodlands, Tex., who was the principal investigator of the GOG-0213 trial (N Engl J Med. 2019;381:1929-39).
That trial did not show an overall survival advantage to secondary surgical cytoreduction followed by chemotherapy, compared with chemotherapy alone, among 485 women with platinum-sensitive recurrent ovarian cancer.
Referring to both AGO DESKTOP III and SOC-1, Dr. Coleman noted that, “while only DESKTOP III met its primary endpoint of improving overall survival, both demonstrated a benefit on PFS [progression-free survival].” Both trials also support a triage algorithm for selecting the approximately 75% of patients who are likely to benefit from secondary cytoreductive surgery.
“However, the price paid for being wrong is substantial, with no benefit seen in progression-free survival and possibly a detriment in overall survival. Because of these observations, both [presenters of SOC-1 and AGO DESKTOP III data] recommended that procedures be limited to select women having surgery performed at sites of excellence,” Dr. Coleman said.
Potential explanations for the differential findings of a secondary surgery benefit in DESKTOP III and SOC-1 versus GOG-0213 include the use of a selection algorithm in the former versus investigator selection based on clinical parameters and imaging in the latter.
In addition, “while platinum-based therapy was the rule in all trials, the use of concomitant and maintenance bevacizumab, a regimen found to improve overall survival in GOG-0213, was used in substantially higher numbers of patients in that trial relative to the two current trials,” Dr. Coleman said.
The GOG-0213 trial also demonstrated an advantage for adjuvant therapy with platinum-based chemotherapy and bevacizumab, which was given to 84% of patients in GOG-0213. That trial had a median overall survival for patients who did not undergo surgery of 65.7 months, compared with 46 months in AGO DESKTOP III and 53.9 months in SOC-1, Dr. Coleman said.
Third time’s a charm
As its name implies, the AGO DESKTOP III trial is the third in a series. AGO DESKTOP I developed the hypothesis that a positive AGO score – consisting of an Eastern Cooperative Oncology Group performance status score of 0, complete resection during first-line therapy, and ascites less than 500 mL – could be predictive of favorable outcomes with debulking surgery (Ann Surg Oncol. 2006 Dec;13[12]:1702-10).
AGO DESKTOP II was a prospective, multicenter trial testing the score in patients with platinum-free intervals of more than 6 months (Int J Gynecol Cancer. 2011 Feb;21[2]:289-95). In this trial, 51% of patients had a positive AGO score, and the score was shown to predict, with 95% probability, complete resectability in two-thirds of these patients, Dr. Du Bois said.
In AGO DESKTOP III, 407 patients were prospectively randomized to second-line chemotherapy alone (n = 201) or to cytoreductive surgery (n = 206) followed by the same chemotherapy, with platinum-containing regimens highly recommended.
Patient characteristics were well balanced between the arms. Nearly all patients (99%) in each arm had prior platinum exposure, and 75% had a platinum-free interval of more than 12 months (a median of 21.1 months in the surgery arm versus 18.7 months in the no-surgery arm).
Complete resections extend OS
There were 8 patients (4%) in the chemotherapy-only arm and 14 (6.8%) in the surgery arm who were noncompliant with randomization. The complete resection rate was 74.2%.
Following randomization, 88.8% of patients in the surgery arm and 90% in the no-surgery arm received platinum-containing chemotherapy; 22.8% and 23.4%, respectively, received bevacizumab; and 3.9% and 6.0% received a poly (ADP-ribose) polymerase inhibitor.
The median overall survival in the intention-to-treat population was 53.7 months in the surgery arm and 46 months in the no-surgery arm, an absolute difference of 7.7 months (hazard ratio, 0.75; P = .02).
The median progression-free survival, assessed in the intention-to-treat population after database closure in January 2020, was 18.4 months with surgery and 14 months without (HR, 0.66; P < .001).
A post hoc analysis showed the importance of complete versus partial resection. The median overall survival was 61.9 months in patients with complete resections and 28.8 months for patients with residual tumor after cytoreductive surgery, an absolute difference of nearly 3 years (HR, 0.40; P < .001).
Comparing only those patients with complete resections with patients who did not undergo surgery, the respective median overall survival was 61.9 months and 46 months (HR, 0.57; P < .001).
AGO DESKTOP III was sponsored by the AGO study group in collaboration with other oncology groups, Medac, and GlaxoSmithKline. Dr. du Bois and Dr. Coleman disclosed relationships with many companies.
SOURCE: du Bois A et al. ASCO 2020, Abstract 6000.
The trial, AGO DESKTOP III/ENGOT ov20, is the first prospective, randomized study showing an overall survival benefit for debulking surgery in patients with recurrent ovarian cancer.
Among 406 patients in first relapse, the median overall survival was 53.7 months for those randomized to cytoreductive surgery plus chemotherapy and 46 months for patients randomized to chemotherapy alone (P = .02).
“The overall survival benefit was highest and exclusively seen in the cohort with complete resection, indicating the importance of a thorough selection process of both the right patient and the right center,” said investigator Andreas du Bois, MD, of the Kliniken Essen-Mitte (Germany).
The median survival gain for patients with platinum-free intervals of more than 6 months who undergo complete resection is nearly 16 months “and is worth going for,” he added.
Dr. du Bois presented these results as part of the American Society of Clinical Oncology virtual scientific program (Abstract 6000).
In another trial, SOC-1, that was also presented in the virtual program, investigators reported a progression-free survival advantage of 5.5 months for patients with recurrent ovarian cancer who underwent debulking surgery, compared with those who did not (Abstract 6001).
Different trials, different results
The invited discussant for Dr. du Bois’s presentation was Robert L. Coleman, MD, chief scientific officer of the U.S. Oncology Network in The Woodlands, Tex., who was the principal investigator of the GOG-0213 trial (N Engl J Med. 2019;381:1929-39).
That trial did not show an overall survival advantage to secondary surgical cytoreduction followed by chemotherapy, compared with chemotherapy alone, among 485 women with platinum-sensitive recurrent ovarian cancer.
Referring to both AGO DESKTOP III and SOC-1, Dr. Coleman noted that, “while only DESKTOP III met its primary endpoint of improving overall survival, both demonstrated a benefit on PFS [progression-free survival].” Both trials also support a triage algorithm for selecting the approximately 75% of patients who are likely to benefit from secondary cytoreductive surgery.
“However, the price paid for being wrong is substantial, with no benefit seen in progression-free survival and possibly a detriment in overall survival. Because of these observations, both [presenters of SOC-1 and AGO DESKTOP III data] recommended that procedures be limited to select women having surgery performed at sites of excellence,” Dr. Coleman said.
Potential explanations for the differential findings of a secondary surgery benefit in DESKTOP III and SOC-1 versus GOG-0213 include the use of a selection algorithm in the former versus investigator selection based on clinical parameters and imaging in the latter.
In addition, “while platinum-based therapy was the rule in all trials, the use of concomitant and maintenance bevacizumab, a regimen found to improve overall survival in GOG-0213, was used in substantially higher numbers of patients in that trial relative to the two current trials,” Dr. Coleman said.
The GOG-0213 trial also demonstrated an advantage for adjuvant therapy with platinum-based chemotherapy and bevacizumab, which was given to 84% of patients in GOG-0213. That trial had a median overall survival for patients who did not undergo surgery of 65.7 months, compared with 46 months in AGO DESKTOP III and 53.9 months in SOC-1, Dr. Coleman said.
Third time’s a charm
As its name implies, the AGO DESKTOP III trial is the third in a series. AGO DESKTOP I developed the hypothesis that a positive AGO score – consisting of an Eastern Cooperative Oncology Group performance status score of 0, complete resection during first-line therapy, and ascites less than 500 mL – could be predictive of favorable outcomes with debulking surgery (Ann Surg Oncol. 2006 Dec;13[12]:1702-10).
AGO DESKTOP II was a prospective, multicenter trial testing the score in patients with platinum-free intervals of more than 6 months (Int J Gynecol Cancer. 2011 Feb;21[2]:289-95). In this trial, 51% of patients had a positive AGO score, and the score was shown to predict, with 95% probability, complete resectability in two-thirds of these patients, Dr. Du Bois said.
In AGO DESKTOP III, 407 patients were prospectively randomized to second-line chemotherapy alone (n = 201) or to cytoreductive surgery (n = 206) followed by the same chemotherapy, with platinum-containing regimens highly recommended.
Patient characteristics were well balanced between the arms. Nearly all patients (99%) in each arm had prior platinum exposure, and 75% had a platinum-free interval of more than 12 months (a median of 21.1 months in the surgery arm versus 18.7 months in the no-surgery arm).
Complete resections extend OS
There were 8 patients (4%) in the chemotherapy-only arm and 14 (6.8%) in the surgery arm who were noncompliant with randomization. The complete resection rate was 74.2%.
Following randomization, 88.8% of patients in the surgery arm and 90% in the no-surgery arm received platinum-containing chemotherapy; 22.8% and 23.4%, respectively, received bevacizumab; and 3.9% and 6.0% received a poly (ADP-ribose) polymerase inhibitor.
The median overall survival in the intention-to-treat population was 53.7 months in the surgery arm and 46 months in the no-surgery arm, an absolute difference of 7.7 months (hazard ratio, 0.75; P = .02).
The median progression-free survival, assessed in the intention-to-treat population after database closure in January 2020, was 18.4 months with surgery and 14 months without (HR, 0.66; P < .001).
A post hoc analysis showed the importance of complete versus partial resection. The median overall survival was 61.9 months in patients with complete resections and 28.8 months for patients with residual tumor after cytoreductive surgery, an absolute difference of nearly 3 years (HR, 0.40; P < .001).
Comparing only those patients with complete resections with patients who did not undergo surgery, the respective median overall survival was 61.9 months and 46 months (HR, 0.57; P < .001).
AGO DESKTOP III was sponsored by the AGO study group in collaboration with other oncology groups, Medac, and GlaxoSmithKline. Dr. du Bois and Dr. Coleman disclosed relationships with many companies.
SOURCE: du Bois A et al. ASCO 2020, Abstract 6000.
The trial, AGO DESKTOP III/ENGOT ov20, is the first prospective, randomized study showing an overall survival benefit for debulking surgery in patients with recurrent ovarian cancer.
Among 406 patients in first relapse, the median overall survival was 53.7 months for those randomized to cytoreductive surgery plus chemotherapy and 46 months for patients randomized to chemotherapy alone (P = .02).
“The overall survival benefit was highest and exclusively seen in the cohort with complete resection, indicating the importance of a thorough selection process of both the right patient and the right center,” said investigator Andreas du Bois, MD, of the Kliniken Essen-Mitte (Germany).
The median survival gain for patients with platinum-free intervals of more than 6 months who undergo complete resection is nearly 16 months “and is worth going for,” he added.
Dr. du Bois presented these results as part of the American Society of Clinical Oncology virtual scientific program (Abstract 6000).
In another trial, SOC-1, that was also presented in the virtual program, investigators reported a progression-free survival advantage of 5.5 months for patients with recurrent ovarian cancer who underwent debulking surgery, compared with those who did not (Abstract 6001).
Different trials, different results
The invited discussant for Dr. du Bois’s presentation was Robert L. Coleman, MD, chief scientific officer of the U.S. Oncology Network in The Woodlands, Tex., who was the principal investigator of the GOG-0213 trial (N Engl J Med. 2019;381:1929-39).
That trial did not show an overall survival advantage to secondary surgical cytoreduction followed by chemotherapy, compared with chemotherapy alone, among 485 women with platinum-sensitive recurrent ovarian cancer.
Referring to both AGO DESKTOP III and SOC-1, Dr. Coleman noted that, “while only DESKTOP III met its primary endpoint of improving overall survival, both demonstrated a benefit on PFS [progression-free survival].” Both trials also support a triage algorithm for selecting the approximately 75% of patients who are likely to benefit from secondary cytoreductive surgery.
“However, the price paid for being wrong is substantial, with no benefit seen in progression-free survival and possibly a detriment in overall survival. Because of these observations, both [presenters of SOC-1 and AGO DESKTOP III data] recommended that procedures be limited to select women having surgery performed at sites of excellence,” Dr. Coleman said.
Potential explanations for the differential findings of a secondary surgery benefit in DESKTOP III and SOC-1 versus GOG-0213 include the use of a selection algorithm in the former versus investigator selection based on clinical parameters and imaging in the latter.
In addition, “while platinum-based therapy was the rule in all trials, the use of concomitant and maintenance bevacizumab, a regimen found to improve overall survival in GOG-0213, was used in substantially higher numbers of patients in that trial relative to the two current trials,” Dr. Coleman said.
The GOG-0213 trial also demonstrated an advantage for adjuvant therapy with platinum-based chemotherapy and bevacizumab, which was given to 84% of patients in GOG-0213. That trial had a median overall survival for patients who did not undergo surgery of 65.7 months, compared with 46 months in AGO DESKTOP III and 53.9 months in SOC-1, Dr. Coleman said.
Third time’s a charm
As its name implies, the AGO DESKTOP III trial is the third in a series. AGO DESKTOP I developed the hypothesis that a positive AGO score – consisting of an Eastern Cooperative Oncology Group performance status score of 0, complete resection during first-line therapy, and ascites less than 500 mL – could be predictive of favorable outcomes with debulking surgery (Ann Surg Oncol. 2006 Dec;13[12]:1702-10).
AGO DESKTOP II was a prospective, multicenter trial testing the score in patients with platinum-free intervals of more than 6 months (Int J Gynecol Cancer. 2011 Feb;21[2]:289-95). In this trial, 51% of patients had a positive AGO score, and the score was shown to predict, with 95% probability, complete resectability in two-thirds of these patients, Dr. Du Bois said.
In AGO DESKTOP III, 407 patients were prospectively randomized to second-line chemotherapy alone (n = 201) or to cytoreductive surgery (n = 206) followed by the same chemotherapy, with platinum-containing regimens highly recommended.
Patient characteristics were well balanced between the arms. Nearly all patients (99%) in each arm had prior platinum exposure, and 75% had a platinum-free interval of more than 12 months (a median of 21.1 months in the surgery arm versus 18.7 months in the no-surgery arm).
Complete resections extend OS
There were 8 patients (4%) in the chemotherapy-only arm and 14 (6.8%) in the surgery arm who were noncompliant with randomization. The complete resection rate was 74.2%.
Following randomization, 88.8% of patients in the surgery arm and 90% in the no-surgery arm received platinum-containing chemotherapy; 22.8% and 23.4%, respectively, received bevacizumab; and 3.9% and 6.0% received a poly (ADP-ribose) polymerase inhibitor.
The median overall survival in the intention-to-treat population was 53.7 months in the surgery arm and 46 months in the no-surgery arm, an absolute difference of 7.7 months (hazard ratio, 0.75; P = .02).
The median progression-free survival, assessed in the intention-to-treat population after database closure in January 2020, was 18.4 months with surgery and 14 months without (HR, 0.66; P < .001).
A post hoc analysis showed the importance of complete versus partial resection. The median overall survival was 61.9 months in patients with complete resections and 28.8 months for patients with residual tumor after cytoreductive surgery, an absolute difference of nearly 3 years (HR, 0.40; P < .001).
Comparing only those patients with complete resections with patients who did not undergo surgery, the respective median overall survival was 61.9 months and 46 months (HR, 0.57; P < .001).
AGO DESKTOP III was sponsored by the AGO study group in collaboration with other oncology groups, Medac, and GlaxoSmithKline. Dr. du Bois and Dr. Coleman disclosed relationships with many companies.
SOURCE: du Bois A et al. ASCO 2020, Abstract 6000.
FROM ASCO 2020
Updated BEACON: Doublet as good as triplet in metastatic CRC
The BEACON study tested both a doublet and a triplet of drugs for patients with previously treated BRAF V600E–mutated metastatic colorectal cancer (CRC).
New results from that trial, with an updated survival analysis, show that the doublet is sufficient and that patients can safely be treated with a combination of the BRAF inhibitor encorafenib (Braftovi, Array BioPharma) and the EGFR inhibitor monoclonal antibody cetuximab (Erbitux, Eli Lilly).
This means that the increased toxicity from the addition of the MEK inhibitor binimetinib (Mektovi, Array BioPharma) can be avoided and that good outcomes can be maintained.
The new results were presented as part of the virtual scientific program of the 2020 American Society of Clinical Oncology annual meeting.
Study discussant Michael S. Lee, MD, from the University of North Carolina Lineberger Comprehensive Cancer Center, Chapel Hill, said he “would consider encorafenib and cetuximab now the standard of care in the second line and beyond in BRAF-mutant colorectal cancer.
“I would give the doublet rather than the triplet because of the comparable survival and better side effect profile,” he said.
“This is immediately practice changing, given the FDA approval of encorafenib and cetuximab,” commented Autumn J. McRee, MD, UNC Lineberger Comprehensive Cancer Center.
This is a “clinically relevant” trial, and it demonstrates that the “poorest prognostic group in colorectal cancer now has viable options,” she said at a Highlights of the Day session.
“We will await the results of the ANCHOR-CRC trial to see if we should be using this targeted approach in earlier lines of therapy,” she added.
New survival data
The primary analysis of BEACON CRC, presented at the 2019 World Conference on Gastrointestinal Cancer, showed that use of the triplet therapy was associated with a 48% improvement in overall survival in comparison with standard chemotherapy.
Although that was also linked to improved quality of life, questions have been raised as to whether the benefits are worth the cost, and one commentator singled the study out for harsh criticism.
Scott Kopetz, MD, PhD, from the University of Texas MD Anderson Cancer Center, Houston, presented the updated survival results from BEACON CRC, which included data from an additional 6 months of follow-up.
“We know that the V600E mutation in BRAF occurs in about 10%-15% of patients and is associated with a poor prognosis,” Dr. Kopetz commented.
“BRAF inhibitors alone are not effective,” he noted. He said preclinical models point toward an approach that targets multiple pathways, including BRAF, MEK, and EGFR.
The BEACON study had three arms, each with 205 patients, as follows:
- Encorafenib plus binimetinib plus cetuximab
- Encorafenib plus cetixumab
- A control arm of FOLFIRI plus cetuximab or irinotecan plus cetuximab.
The three arms of the trial were relatively well balanced with respect to patient characteristics, Dr. Kopetz commented. The median age of the patients ranged from 60 to 62 years, and 48%-57% of the patients were women.
Of note, between 5% and 10% of the cases were characterized by high microsatellite instability, and 34%-35% of patients had received more than one prior line of therapy.
The data now presented at ASCO represent a post hoc updated analysis that includes 6 months of additional follow-up since the primary analysis was presented, Dr. Kopetz explained.
After a median follow-up of 12.8 months, 13% of triplet therapy patients, 14% of those who received doublet therapy, and 3% of control patients were still on treatment.
The updated analysis shows that median overall survival with the doublet therapy was 9.3 months versus 5.9 months for the control group (hazard ratio, 0.61). The benefit was seen across all subgroups, including those based on the number of prior regimens.
Dr. Kopetz pointed out that overall survival was numerically superior to that seen in the primary analysis, which was 8.4 months.
The updated survival analysis for the triplet therapy indicated that the median overall survival was 9.3 months versus 5.9 months in the control arm (HR, 0.60). Again, this was consistent across subgroups.
In the primary analysis, the median overall survival with the triplet therapy was 9.0 months.
The team also compared the triplet and doublet therapies, finding that, “in contrast to what was seen in the primary analysis ... we see numerically identical median overall survival with the two arms.” The result was sustained across subgroups.
However, there were indications that there may be survival benefits with the triplet in certain patient subgroups, including those with Eastern Cooperative Oncology Group performance status 1, those in whom three or more organs are involved, those with higher baseline levels of C-reactive protein, and those with partially resected or unresected disease.
Progression-free survival was comparable between the two treatment groups, at 4.5 months with the triplet therapy and 4.3 months with the doublet, compared with just 1.5 months in the control arm.
The updated analysis also showed that the objective response rate was 27% with triplet therapy versus 20% with the doublet and 2% in the control arm. In both the doublet and triplet arms, the majority of responses were partial.
With regard to safety, Dr. Kopetz said that the updated data regarding adverse events were in general “consistent with the previously reported safety profile.”
He added it is “notable” that the triplet therapy “had slightly higher rates of GI toxicity and anemia,” which was not seen with the doublet, something that is “again associated with the known safety profile of a MEK inhibitor.”
The study was funded by Pfizer. Dr. Kopetz has stock and other ownership interests with numerous pharmaceutical companies. Other authors, as well as Dr. Lee and Dr. McRee, have also reported relevant financial relationships.
This article first appeared on Medscape.com.
The BEACON study tested both a doublet and a triplet of drugs for patients with previously treated BRAF V600E–mutated metastatic colorectal cancer (CRC).
New results from that trial, with an updated survival analysis, show that the doublet is sufficient and that patients can safely be treated with a combination of the BRAF inhibitor encorafenib (Braftovi, Array BioPharma) and the EGFR inhibitor monoclonal antibody cetuximab (Erbitux, Eli Lilly).
This means that the increased toxicity from the addition of the MEK inhibitor binimetinib (Mektovi, Array BioPharma) can be avoided and that good outcomes can be maintained.
The new results were presented as part of the virtual scientific program of the 2020 American Society of Clinical Oncology annual meeting.
Study discussant Michael S. Lee, MD, from the University of North Carolina Lineberger Comprehensive Cancer Center, Chapel Hill, said he “would consider encorafenib and cetuximab now the standard of care in the second line and beyond in BRAF-mutant colorectal cancer.
“I would give the doublet rather than the triplet because of the comparable survival and better side effect profile,” he said.
“This is immediately practice changing, given the FDA approval of encorafenib and cetuximab,” commented Autumn J. McRee, MD, UNC Lineberger Comprehensive Cancer Center.
This is a “clinically relevant” trial, and it demonstrates that the “poorest prognostic group in colorectal cancer now has viable options,” she said at a Highlights of the Day session.
“We will await the results of the ANCHOR-CRC trial to see if we should be using this targeted approach in earlier lines of therapy,” she added.
New survival data
The primary analysis of BEACON CRC, presented at the 2019 World Conference on Gastrointestinal Cancer, showed that use of the triplet therapy was associated with a 48% improvement in overall survival in comparison with standard chemotherapy.
Although that was also linked to improved quality of life, questions have been raised as to whether the benefits are worth the cost, and one commentator singled the study out for harsh criticism.
Scott Kopetz, MD, PhD, from the University of Texas MD Anderson Cancer Center, Houston, presented the updated survival results from BEACON CRC, which included data from an additional 6 months of follow-up.
“We know that the V600E mutation in BRAF occurs in about 10%-15% of patients and is associated with a poor prognosis,” Dr. Kopetz commented.
“BRAF inhibitors alone are not effective,” he noted. He said preclinical models point toward an approach that targets multiple pathways, including BRAF, MEK, and EGFR.
The BEACON study had three arms, each with 205 patients, as follows:
- Encorafenib plus binimetinib plus cetuximab
- Encorafenib plus cetixumab
- A control arm of FOLFIRI plus cetuximab or irinotecan plus cetuximab.
The three arms of the trial were relatively well balanced with respect to patient characteristics, Dr. Kopetz commented. The median age of the patients ranged from 60 to 62 years, and 48%-57% of the patients were women.
Of note, between 5% and 10% of the cases were characterized by high microsatellite instability, and 34%-35% of patients had received more than one prior line of therapy.
The data now presented at ASCO represent a post hoc updated analysis that includes 6 months of additional follow-up since the primary analysis was presented, Dr. Kopetz explained.
After a median follow-up of 12.8 months, 13% of triplet therapy patients, 14% of those who received doublet therapy, and 3% of control patients were still on treatment.
The updated analysis shows that median overall survival with the doublet therapy was 9.3 months versus 5.9 months for the control group (hazard ratio, 0.61). The benefit was seen across all subgroups, including those based on the number of prior regimens.
Dr. Kopetz pointed out that overall survival was numerically superior to that seen in the primary analysis, which was 8.4 months.
The updated survival analysis for the triplet therapy indicated that the median overall survival was 9.3 months versus 5.9 months in the control arm (HR, 0.60). Again, this was consistent across subgroups.
In the primary analysis, the median overall survival with the triplet therapy was 9.0 months.
The team also compared the triplet and doublet therapies, finding that, “in contrast to what was seen in the primary analysis ... we see numerically identical median overall survival with the two arms.” The result was sustained across subgroups.
However, there were indications that there may be survival benefits with the triplet in certain patient subgroups, including those with Eastern Cooperative Oncology Group performance status 1, those in whom three or more organs are involved, those with higher baseline levels of C-reactive protein, and those with partially resected or unresected disease.
Progression-free survival was comparable between the two treatment groups, at 4.5 months with the triplet therapy and 4.3 months with the doublet, compared with just 1.5 months in the control arm.
The updated analysis also showed that the objective response rate was 27% with triplet therapy versus 20% with the doublet and 2% in the control arm. In both the doublet and triplet arms, the majority of responses were partial.
With regard to safety, Dr. Kopetz said that the updated data regarding adverse events were in general “consistent with the previously reported safety profile.”
He added it is “notable” that the triplet therapy “had slightly higher rates of GI toxicity and anemia,” which was not seen with the doublet, something that is “again associated with the known safety profile of a MEK inhibitor.”
The study was funded by Pfizer. Dr. Kopetz has stock and other ownership interests with numerous pharmaceutical companies. Other authors, as well as Dr. Lee and Dr. McRee, have also reported relevant financial relationships.
This article first appeared on Medscape.com.
The BEACON study tested both a doublet and a triplet of drugs for patients with previously treated BRAF V600E–mutated metastatic colorectal cancer (CRC).
New results from that trial, with an updated survival analysis, show that the doublet is sufficient and that patients can safely be treated with a combination of the BRAF inhibitor encorafenib (Braftovi, Array BioPharma) and the EGFR inhibitor monoclonal antibody cetuximab (Erbitux, Eli Lilly).
This means that the increased toxicity from the addition of the MEK inhibitor binimetinib (Mektovi, Array BioPharma) can be avoided and that good outcomes can be maintained.
The new results were presented as part of the virtual scientific program of the 2020 American Society of Clinical Oncology annual meeting.
Study discussant Michael S. Lee, MD, from the University of North Carolina Lineberger Comprehensive Cancer Center, Chapel Hill, said he “would consider encorafenib and cetuximab now the standard of care in the second line and beyond in BRAF-mutant colorectal cancer.
“I would give the doublet rather than the triplet because of the comparable survival and better side effect profile,” he said.
“This is immediately practice changing, given the FDA approval of encorafenib and cetuximab,” commented Autumn J. McRee, MD, UNC Lineberger Comprehensive Cancer Center.
This is a “clinically relevant” trial, and it demonstrates that the “poorest prognostic group in colorectal cancer now has viable options,” she said at a Highlights of the Day session.
“We will await the results of the ANCHOR-CRC trial to see if we should be using this targeted approach in earlier lines of therapy,” she added.
New survival data
The primary analysis of BEACON CRC, presented at the 2019 World Conference on Gastrointestinal Cancer, showed that use of the triplet therapy was associated with a 48% improvement in overall survival in comparison with standard chemotherapy.
Although that was also linked to improved quality of life, questions have been raised as to whether the benefits are worth the cost, and one commentator singled the study out for harsh criticism.
Scott Kopetz, MD, PhD, from the University of Texas MD Anderson Cancer Center, Houston, presented the updated survival results from BEACON CRC, which included data from an additional 6 months of follow-up.
“We know that the V600E mutation in BRAF occurs in about 10%-15% of patients and is associated with a poor prognosis,” Dr. Kopetz commented.
“BRAF inhibitors alone are not effective,” he noted. He said preclinical models point toward an approach that targets multiple pathways, including BRAF, MEK, and EGFR.
The BEACON study had three arms, each with 205 patients, as follows:
- Encorafenib plus binimetinib plus cetuximab
- Encorafenib plus cetixumab
- A control arm of FOLFIRI plus cetuximab or irinotecan plus cetuximab.
The three arms of the trial were relatively well balanced with respect to patient characteristics, Dr. Kopetz commented. The median age of the patients ranged from 60 to 62 years, and 48%-57% of the patients were women.
Of note, between 5% and 10% of the cases were characterized by high microsatellite instability, and 34%-35% of patients had received more than one prior line of therapy.
The data now presented at ASCO represent a post hoc updated analysis that includes 6 months of additional follow-up since the primary analysis was presented, Dr. Kopetz explained.
After a median follow-up of 12.8 months, 13% of triplet therapy patients, 14% of those who received doublet therapy, and 3% of control patients were still on treatment.
The updated analysis shows that median overall survival with the doublet therapy was 9.3 months versus 5.9 months for the control group (hazard ratio, 0.61). The benefit was seen across all subgroups, including those based on the number of prior regimens.
Dr. Kopetz pointed out that overall survival was numerically superior to that seen in the primary analysis, which was 8.4 months.
The updated survival analysis for the triplet therapy indicated that the median overall survival was 9.3 months versus 5.9 months in the control arm (HR, 0.60). Again, this was consistent across subgroups.
In the primary analysis, the median overall survival with the triplet therapy was 9.0 months.
The team also compared the triplet and doublet therapies, finding that, “in contrast to what was seen in the primary analysis ... we see numerically identical median overall survival with the two arms.” The result was sustained across subgroups.
However, there were indications that there may be survival benefits with the triplet in certain patient subgroups, including those with Eastern Cooperative Oncology Group performance status 1, those in whom three or more organs are involved, those with higher baseline levels of C-reactive protein, and those with partially resected or unresected disease.
Progression-free survival was comparable between the two treatment groups, at 4.5 months with the triplet therapy and 4.3 months with the doublet, compared with just 1.5 months in the control arm.
The updated analysis also showed that the objective response rate was 27% with triplet therapy versus 20% with the doublet and 2% in the control arm. In both the doublet and triplet arms, the majority of responses were partial.
With regard to safety, Dr. Kopetz said that the updated data regarding adverse events were in general “consistent with the previously reported safety profile.”
He added it is “notable” that the triplet therapy “had slightly higher rates of GI toxicity and anemia,” which was not seen with the doublet, something that is “again associated with the known safety profile of a MEK inhibitor.”
The study was funded by Pfizer. Dr. Kopetz has stock and other ownership interests with numerous pharmaceutical companies. Other authors, as well as Dr. Lee and Dr. McRee, have also reported relevant financial relationships.
This article first appeared on Medscape.com.
FROM ASCO 2020
Germline testing in advanced cancer can lead to targeted treatment
The study involved 11,974 patients with various tumor types. All the patients underwent germline genetic testing from 2015 to 2019 at the Memorial Sloan Kettering Cancer Center (MSKCC) in New York, using the next-generation sequencing panel MSK-IMPACT.
This testing showed that 17.1% of patients had variants in cancer predisposition genes, and 7.1%-8.6% had variants that could potentially be targeted.
“Of course, these numbers are not static,” commented lead author Zsofia K. Stadler, MD, a medical oncologist at MSKCC. “And with the emergence of novel targeted treatments with new FDA indications, the therapeutic actionability of germline variants is likely to increase over time.
“Our study demonstrates the first comprehensive assessment of the clinical utility of germline alterations for therapeutic actionability in a population of patients with advanced cancer,” she added.
Dr. Stadler presented the study results during a virtual scientific program of the American Society of Clinical Oncology 2020.
Testing for somatic mutations is evolving as the standard of care in many cancer types, and somatic genomic testing is rapidly becoming an integral part of the regimen for patients with advanced disease. Some studies suggest that 9%-11% of patients harbor actionable genetic alterations, as determined on the basis of tumor profiling.
“The take-home message from this is that now, more than ever before, germline testing is indicated for the selection of cancer treatment,” said Erin Wysong Hofstatter, MD, from Yale University, New Haven, Conn., in a Highlights of the Day session.
An emerging indication for germline testing is the selection of treatment in the advanced setting, she noted. “And it is important to know your test. Remember that tumor sequencing is not a substitute for comprehensive germline testing.”
Implications in cancer treatment
For their study, Dr. Stadler and colleagues reviewed the medical records of patients with likely pathogenic/pathogenic germline (LP/P) alterations in genes that had known therapeutic targets so as to identify germline-targeted treatment either in a clinical or research setting.
“Since 2015, patients undergoing MSK-IMPACT may also choose to provide additional consent for secondary germline genetic analysis, wherein up to 88 genes known to be associated with cancer predisposition are analyzed,” she said. “Likely pathogenic and pathogenic germline alterations identified are disclosed to the patient and treating physician via the Clinical Genetic Service.”
A total of 2043 (17.1%) patients who harbored LP/P variants in a cancer predisposition gene were identified. Of these, 11% of patients harbored pathogenic alterations in high or moderate penetrance cancer predisposition genes. When the analysis was limited to genes with targeted therapeutic actionability, or what the authors defined as tier 1 and tier 2 genes, 7.1% of patients (n = 849) harbored a targetable pathogenic germline alteration.
BRCA alterations accounted for half (52%) of the findings, and 20% were associated with Lynch syndrome.
The tier 2 genes, which included PALB2, ATM, RAD51C, and RAD51D, accounted for about a quarter of the findings. Dr. Hofstatter noted that, using strict criteria, 7.1% of patients (n = 849) were found to harbor a pathogenic alteration and a targetable gene. Using less stringent criteria, additional tier 3 genes and additional genes associated with DNA homologous recombination repair brought the number up to 8.6% (n = 1,003).
Therapeutic action
For determining therapeutic actionability, the strict criteria were used; 593 patients (4.95%) with recurrent or metastatic disease were identified. For these patients, consideration of a targeted therapy, either as part of standard care or as part of an investigation or research protocol, was important.
Of this group, 44% received therapy targeting the germline alteration. Regarding specific genes, 50% of BRCA1/2 carriers and 58% of Lynch syndrome patients received targeted treatment. With respect to tier 2 genes, 40% of patients with PALB2, 19% with ATM, and 37% with RAD51C or 51D received a poly (ADP-ribose) polymerase (PARP) inhibitor.
Among patients with a BRCA1/2 mutation who received a PARP inhibitor, 55.1% had breast or ovarian cancer, and 44.8% had other tumor types, including pancreas, prostate, bile duct, gastric cancers. These patients received the drug in a research setting.
For patients with PALB2 alterations who received PARP inhibitors, 53.3% had breast or pancreas cancer, and 46.7% had cancer of the prostate, ovary, or an unknown primary.
Looking ahead
The discussant for the paper, Funda Meric-Bernstam, MD, chair of the Department of Investigational Cancer Therapeutics at the University of Texas MD Anderson Cancer Center, Houston, pointed out that most of the BRCA-positive patients had cancers traditionally associated with the mutation. “There were no patients with PTEN mutations treated, and interestingly, no patients with NF1 were treated,” she said. “But actionability is evolving, as the MEK inhibitor selumitinib was recently approved for NF1.”
Some questions remain unanswered, she noted, such as: “What percentage of patients undergoing tumor-normal testing signed a germline protocol?” and “Does the population introduce a bias – such as younger patients, family history, and so on?”
It is also unknown what percentage of germline alterations were known in comparison with those identified through tumor/normal testing. Also of importance is the fact that in this study, the results of germline testing were delivered in an academic setting, she emphasized. “What if they were delivered elsewhere? What would be the impact of identifying these alterations in an environment with less access to trials?
“But to be fair, it is not easy to seek the germline mutations,” Dr. Meric-Bernstam continued. “These studies were done under institutional review board protocols, and it is important to note that most profiling is done as standard of care without consenting and soliciting patient preference on the return of germline results.”
An infrastructure is needed to return/counsel/offer cascade testing, and “analyses need to be facilitated to ensure that findings can be acted upon in a timely fashion,” she added.
The study was supported by MSKCC internal funding. Dr. Stadler reported relationships (institutional) with Adverum, Alimera Sciences, Allergan, Biomarin, Fortress Biotech, Genentech/Roche, Novartis, Optos, Regeneron, Regenxbio, and Spark Therapeutics. Dr. Meric-Bernstram reported relationships with numerous pharmaceutical companies.
This article first appeared on Medscape.com.
The study involved 11,974 patients with various tumor types. All the patients underwent germline genetic testing from 2015 to 2019 at the Memorial Sloan Kettering Cancer Center (MSKCC) in New York, using the next-generation sequencing panel MSK-IMPACT.
This testing showed that 17.1% of patients had variants in cancer predisposition genes, and 7.1%-8.6% had variants that could potentially be targeted.
“Of course, these numbers are not static,” commented lead author Zsofia K. Stadler, MD, a medical oncologist at MSKCC. “And with the emergence of novel targeted treatments with new FDA indications, the therapeutic actionability of germline variants is likely to increase over time.
“Our study demonstrates the first comprehensive assessment of the clinical utility of germline alterations for therapeutic actionability in a population of patients with advanced cancer,” she added.
Dr. Stadler presented the study results during a virtual scientific program of the American Society of Clinical Oncology 2020.
Testing for somatic mutations is evolving as the standard of care in many cancer types, and somatic genomic testing is rapidly becoming an integral part of the regimen for patients with advanced disease. Some studies suggest that 9%-11% of patients harbor actionable genetic alterations, as determined on the basis of tumor profiling.
“The take-home message from this is that now, more than ever before, germline testing is indicated for the selection of cancer treatment,” said Erin Wysong Hofstatter, MD, from Yale University, New Haven, Conn., in a Highlights of the Day session.
An emerging indication for germline testing is the selection of treatment in the advanced setting, she noted. “And it is important to know your test. Remember that tumor sequencing is not a substitute for comprehensive germline testing.”
Implications in cancer treatment
For their study, Dr. Stadler and colleagues reviewed the medical records of patients with likely pathogenic/pathogenic germline (LP/P) alterations in genes that had known therapeutic targets so as to identify germline-targeted treatment either in a clinical or research setting.
“Since 2015, patients undergoing MSK-IMPACT may also choose to provide additional consent for secondary germline genetic analysis, wherein up to 88 genes known to be associated with cancer predisposition are analyzed,” she said. “Likely pathogenic and pathogenic germline alterations identified are disclosed to the patient and treating physician via the Clinical Genetic Service.”
A total of 2043 (17.1%) patients who harbored LP/P variants in a cancer predisposition gene were identified. Of these, 11% of patients harbored pathogenic alterations in high or moderate penetrance cancer predisposition genes. When the analysis was limited to genes with targeted therapeutic actionability, or what the authors defined as tier 1 and tier 2 genes, 7.1% of patients (n = 849) harbored a targetable pathogenic germline alteration.
BRCA alterations accounted for half (52%) of the findings, and 20% were associated with Lynch syndrome.
The tier 2 genes, which included PALB2, ATM, RAD51C, and RAD51D, accounted for about a quarter of the findings. Dr. Hofstatter noted that, using strict criteria, 7.1% of patients (n = 849) were found to harbor a pathogenic alteration and a targetable gene. Using less stringent criteria, additional tier 3 genes and additional genes associated with DNA homologous recombination repair brought the number up to 8.6% (n = 1,003).
Therapeutic action
For determining therapeutic actionability, the strict criteria were used; 593 patients (4.95%) with recurrent or metastatic disease were identified. For these patients, consideration of a targeted therapy, either as part of standard care or as part of an investigation or research protocol, was important.
Of this group, 44% received therapy targeting the germline alteration. Regarding specific genes, 50% of BRCA1/2 carriers and 58% of Lynch syndrome patients received targeted treatment. With respect to tier 2 genes, 40% of patients with PALB2, 19% with ATM, and 37% with RAD51C or 51D received a poly (ADP-ribose) polymerase (PARP) inhibitor.
Among patients with a BRCA1/2 mutation who received a PARP inhibitor, 55.1% had breast or ovarian cancer, and 44.8% had other tumor types, including pancreas, prostate, bile duct, gastric cancers. These patients received the drug in a research setting.
For patients with PALB2 alterations who received PARP inhibitors, 53.3% had breast or pancreas cancer, and 46.7% had cancer of the prostate, ovary, or an unknown primary.
Looking ahead
The discussant for the paper, Funda Meric-Bernstam, MD, chair of the Department of Investigational Cancer Therapeutics at the University of Texas MD Anderson Cancer Center, Houston, pointed out that most of the BRCA-positive patients had cancers traditionally associated with the mutation. “There were no patients with PTEN mutations treated, and interestingly, no patients with NF1 were treated,” she said. “But actionability is evolving, as the MEK inhibitor selumitinib was recently approved for NF1.”
Some questions remain unanswered, she noted, such as: “What percentage of patients undergoing tumor-normal testing signed a germline protocol?” and “Does the population introduce a bias – such as younger patients, family history, and so on?”
It is also unknown what percentage of germline alterations were known in comparison with those identified through tumor/normal testing. Also of importance is the fact that in this study, the results of germline testing were delivered in an academic setting, she emphasized. “What if they were delivered elsewhere? What would be the impact of identifying these alterations in an environment with less access to trials?
“But to be fair, it is not easy to seek the germline mutations,” Dr. Meric-Bernstam continued. “These studies were done under institutional review board protocols, and it is important to note that most profiling is done as standard of care without consenting and soliciting patient preference on the return of germline results.”
An infrastructure is needed to return/counsel/offer cascade testing, and “analyses need to be facilitated to ensure that findings can be acted upon in a timely fashion,” she added.
The study was supported by MSKCC internal funding. Dr. Stadler reported relationships (institutional) with Adverum, Alimera Sciences, Allergan, Biomarin, Fortress Biotech, Genentech/Roche, Novartis, Optos, Regeneron, Regenxbio, and Spark Therapeutics. Dr. Meric-Bernstram reported relationships with numerous pharmaceutical companies.
This article first appeared on Medscape.com.
The study involved 11,974 patients with various tumor types. All the patients underwent germline genetic testing from 2015 to 2019 at the Memorial Sloan Kettering Cancer Center (MSKCC) in New York, using the next-generation sequencing panel MSK-IMPACT.
This testing showed that 17.1% of patients had variants in cancer predisposition genes, and 7.1%-8.6% had variants that could potentially be targeted.
“Of course, these numbers are not static,” commented lead author Zsofia K. Stadler, MD, a medical oncologist at MSKCC. “And with the emergence of novel targeted treatments with new FDA indications, the therapeutic actionability of germline variants is likely to increase over time.
“Our study demonstrates the first comprehensive assessment of the clinical utility of germline alterations for therapeutic actionability in a population of patients with advanced cancer,” she added.
Dr. Stadler presented the study results during a virtual scientific program of the American Society of Clinical Oncology 2020.
Testing for somatic mutations is evolving as the standard of care in many cancer types, and somatic genomic testing is rapidly becoming an integral part of the regimen for patients with advanced disease. Some studies suggest that 9%-11% of patients harbor actionable genetic alterations, as determined on the basis of tumor profiling.
“The take-home message from this is that now, more than ever before, germline testing is indicated for the selection of cancer treatment,” said Erin Wysong Hofstatter, MD, from Yale University, New Haven, Conn., in a Highlights of the Day session.
An emerging indication for germline testing is the selection of treatment in the advanced setting, she noted. “And it is important to know your test. Remember that tumor sequencing is not a substitute for comprehensive germline testing.”
Implications in cancer treatment
For their study, Dr. Stadler and colleagues reviewed the medical records of patients with likely pathogenic/pathogenic germline (LP/P) alterations in genes that had known therapeutic targets so as to identify germline-targeted treatment either in a clinical or research setting.
“Since 2015, patients undergoing MSK-IMPACT may also choose to provide additional consent for secondary germline genetic analysis, wherein up to 88 genes known to be associated with cancer predisposition are analyzed,” she said. “Likely pathogenic and pathogenic germline alterations identified are disclosed to the patient and treating physician via the Clinical Genetic Service.”
A total of 2043 (17.1%) patients who harbored LP/P variants in a cancer predisposition gene were identified. Of these, 11% of patients harbored pathogenic alterations in high or moderate penetrance cancer predisposition genes. When the analysis was limited to genes with targeted therapeutic actionability, or what the authors defined as tier 1 and tier 2 genes, 7.1% of patients (n = 849) harbored a targetable pathogenic germline alteration.
BRCA alterations accounted for half (52%) of the findings, and 20% were associated with Lynch syndrome.
The tier 2 genes, which included PALB2, ATM, RAD51C, and RAD51D, accounted for about a quarter of the findings. Dr. Hofstatter noted that, using strict criteria, 7.1% of patients (n = 849) were found to harbor a pathogenic alteration and a targetable gene. Using less stringent criteria, additional tier 3 genes and additional genes associated with DNA homologous recombination repair brought the number up to 8.6% (n = 1,003).
Therapeutic action
For determining therapeutic actionability, the strict criteria were used; 593 patients (4.95%) with recurrent or metastatic disease were identified. For these patients, consideration of a targeted therapy, either as part of standard care or as part of an investigation or research protocol, was important.
Of this group, 44% received therapy targeting the germline alteration. Regarding specific genes, 50% of BRCA1/2 carriers and 58% of Lynch syndrome patients received targeted treatment. With respect to tier 2 genes, 40% of patients with PALB2, 19% with ATM, and 37% with RAD51C or 51D received a poly (ADP-ribose) polymerase (PARP) inhibitor.
Among patients with a BRCA1/2 mutation who received a PARP inhibitor, 55.1% had breast or ovarian cancer, and 44.8% had other tumor types, including pancreas, prostate, bile duct, gastric cancers. These patients received the drug in a research setting.
For patients with PALB2 alterations who received PARP inhibitors, 53.3% had breast or pancreas cancer, and 46.7% had cancer of the prostate, ovary, or an unknown primary.
Looking ahead
The discussant for the paper, Funda Meric-Bernstam, MD, chair of the Department of Investigational Cancer Therapeutics at the University of Texas MD Anderson Cancer Center, Houston, pointed out that most of the BRCA-positive patients had cancers traditionally associated with the mutation. “There were no patients with PTEN mutations treated, and interestingly, no patients with NF1 were treated,” she said. “But actionability is evolving, as the MEK inhibitor selumitinib was recently approved for NF1.”
Some questions remain unanswered, she noted, such as: “What percentage of patients undergoing tumor-normal testing signed a germline protocol?” and “Does the population introduce a bias – such as younger patients, family history, and so on?”
It is also unknown what percentage of germline alterations were known in comparison with those identified through tumor/normal testing. Also of importance is the fact that in this study, the results of germline testing were delivered in an academic setting, she emphasized. “What if they were delivered elsewhere? What would be the impact of identifying these alterations in an environment with less access to trials?
“But to be fair, it is not easy to seek the germline mutations,” Dr. Meric-Bernstam continued. “These studies were done under institutional review board protocols, and it is important to note that most profiling is done as standard of care without consenting and soliciting patient preference on the return of germline results.”
An infrastructure is needed to return/counsel/offer cascade testing, and “analyses need to be facilitated to ensure that findings can be acted upon in a timely fashion,” she added.
The study was supported by MSKCC internal funding. Dr. Stadler reported relationships (institutional) with Adverum, Alimera Sciences, Allergan, Biomarin, Fortress Biotech, Genentech/Roche, Novartis, Optos, Regeneron, Regenxbio, and Spark Therapeutics. Dr. Meric-Bernstram reported relationships with numerous pharmaceutical companies.
This article first appeared on Medscape.com.
FROM ASCO 2020
Dietary intervention cuts mood swings, other bipolar symptoms
A nutritional intervention with a focus on fatty acids appears to reduce mood swings in patients with bipolar disorder (BD) when used as an adjunct to pharmacotherapy, early research suggests.
In a single-center study, patients with BD who received a diet consisting of high omega-3 plus low omega-6 fatty acids (H3-L6), in addition to usual care, showed significant reductions in mood variability, irritability, and pain, compared with their counterparts who received a diet with usual levels of omega-3 and omega-6 fatty acids commonly consumed in regular U.S. diets.
“Our findings need replication and validation in other studies,” study coinvestigator Erika Saunders, MD, professor and chair of the department of psychiatry and behavioral health at Penn State Health, Hershey, said in an interview.
“While we got really exciting findings, it’s far from confirmatory or the last word on the subject. The fatty acids do two broad things. They incorporate into the membranes of neurons in the brain and they also create signaling molecules throughout the brain and the body that interact with the immune system and the inflammatory system. And we suspect that it is through those mechanisms that this composition of fatty acids is having an effect on mood stability, but lots more work needs to be done to figure that out,” Dr. Saunders added.
The findings were presented at the American Society of Clinical Psychopharmacology 2020 Virtual Conference.
Fewer mood swings
Many patients with bipolar disorder do not achieve complete mood stability with medication, making the need for additional treatments imperative, she added.
“We were interested in looking at treatments that improved mood stability in bipolar disorder that are well tolerated by patients and that can be added to pharmacological treatments. We studied this particular nutritional intervention because biologically it does some of the same things that effective medications for bipolar disorder do and it has been investigated as an effective treatment for conditions like migraine headaches, which has a lot of overlap and comorbidity with bipolar disorder.”
The researchers randomized 41 patients with BD to receive the nutritional intervention of high omega-3 plus low omega-6 (H3-L6) and 41 patients with BD to receive a control diet of usual US levels of omega-3 and omega-6 fatty acids.
The patients were aged 20-75 years (mean age, 43.5 +/– 13.9 years) and 83% were women. They had similar mean levels of mood symptoms and pain.
All patients received group-specific study foods and oils, as well as intensive dietary counseling from a dietitian, access to a website with recipes, and guidance for eating in restaurants. All participants were blinded to the composition of the food that they were eating.
Both the interventional diet and the control diet were tailored for the purposes of the study, noted coinvestigator Sarah Shahriar, a research assistant at Penn State.
“The interventional group had more fatty fish such as salmon and tuna, while the control group had more white fish and fish with less fatty acid content. The interventional group also received a different type of cooking oil, which was a blend of olive and macadamia-nut oil, which was specially formulated by a research nutritional service at the University of North Carolina,” Ms. Shahriar said in an interview.
“They also decreased their red meat consumption and received specially formulated snack foods, which were specifically prepared by [the university’s] research nutritional service. It is important to point out that these diets were for a very specific purpose. We are not saying in any way shape or form that this particular nutritional intervention is good in general,” she added.
After 12 weeks, significant reductions were seen in mood variability, energy, irritability, and pain in the H3-L6 group (P < .001). The only symptom that was significantly lowered in the control group was impulsive thoughts (P = .004).
“The best message for doctors to tell their patients at this point is one of general nutritional health and the importance of nutrition in overall body and brain health, and that [this] can be a very important component of mood,” Dr. Saunders said.
Diet matters
“Highly unsaturated fatty acids are important components of neuronal cell membranes and in cell signaling,” Jessica M. Gannon, MD, University of Pittsburgh, who was not part of the study, said in an interview.
“Omega-6 fatty acids are precursors to proinflammatory compounds. Omega-3 fatty acids eicosapentaenoic acid and docosahexaenoic acid are thought to be competitive inhibitors of omega-6 and thought to have anti-inflammatory effects. Supplementation with omega-3 has been explored in cardiovascular disease, diabetes, and in rheumatologic disorders as well as in a host of psychiatric disorders, including bipolar disorders, where a possible treatment effect has been suggested,” Dr. Gannon said.
Dietary interventions targeting not only increasing omega-3 but also decreasing consumption of omega-6 rich foods could be both effective and attractive to patients invested in a healthy lifestyle for promotion of mental health, especially when they are not optimally controlled by prescribed medications, she added.
“This study suggests that such an intervention could prove beneficial, although significant patient support may be necessary to assure adherence to the diet. I would agree that future studies would be worth pursuing,” Dr. Gannon said.
The investigators and Dr. Gannon have reported no relevant financial relationships.
A version of this article originally appeared on Medscape.com.
A nutritional intervention with a focus on fatty acids appears to reduce mood swings in patients with bipolar disorder (BD) when used as an adjunct to pharmacotherapy, early research suggests.
In a single-center study, patients with BD who received a diet consisting of high omega-3 plus low omega-6 fatty acids (H3-L6), in addition to usual care, showed significant reductions in mood variability, irritability, and pain, compared with their counterparts who received a diet with usual levels of omega-3 and omega-6 fatty acids commonly consumed in regular U.S. diets.
“Our findings need replication and validation in other studies,” study coinvestigator Erika Saunders, MD, professor and chair of the department of psychiatry and behavioral health at Penn State Health, Hershey, said in an interview.
“While we got really exciting findings, it’s far from confirmatory or the last word on the subject. The fatty acids do two broad things. They incorporate into the membranes of neurons in the brain and they also create signaling molecules throughout the brain and the body that interact with the immune system and the inflammatory system. And we suspect that it is through those mechanisms that this composition of fatty acids is having an effect on mood stability, but lots more work needs to be done to figure that out,” Dr. Saunders added.
The findings were presented at the American Society of Clinical Psychopharmacology 2020 Virtual Conference.
Fewer mood swings
Many patients with bipolar disorder do not achieve complete mood stability with medication, making the need for additional treatments imperative, she added.
“We were interested in looking at treatments that improved mood stability in bipolar disorder that are well tolerated by patients and that can be added to pharmacological treatments. We studied this particular nutritional intervention because biologically it does some of the same things that effective medications for bipolar disorder do and it has been investigated as an effective treatment for conditions like migraine headaches, which has a lot of overlap and comorbidity with bipolar disorder.”
The researchers randomized 41 patients with BD to receive the nutritional intervention of high omega-3 plus low omega-6 (H3-L6) and 41 patients with BD to receive a control diet of usual US levels of omega-3 and omega-6 fatty acids.
The patients were aged 20-75 years (mean age, 43.5 +/– 13.9 years) and 83% were women. They had similar mean levels of mood symptoms and pain.
All patients received group-specific study foods and oils, as well as intensive dietary counseling from a dietitian, access to a website with recipes, and guidance for eating in restaurants. All participants were blinded to the composition of the food that they were eating.
Both the interventional diet and the control diet were tailored for the purposes of the study, noted coinvestigator Sarah Shahriar, a research assistant at Penn State.
“The interventional group had more fatty fish such as salmon and tuna, while the control group had more white fish and fish with less fatty acid content. The interventional group also received a different type of cooking oil, which was a blend of olive and macadamia-nut oil, which was specially formulated by a research nutritional service at the University of North Carolina,” Ms. Shahriar said in an interview.
“They also decreased their red meat consumption and received specially formulated snack foods, which were specifically prepared by [the university’s] research nutritional service. It is important to point out that these diets were for a very specific purpose. We are not saying in any way shape or form that this particular nutritional intervention is good in general,” she added.
After 12 weeks, significant reductions were seen in mood variability, energy, irritability, and pain in the H3-L6 group (P < .001). The only symptom that was significantly lowered in the control group was impulsive thoughts (P = .004).
“The best message for doctors to tell their patients at this point is one of general nutritional health and the importance of nutrition in overall body and brain health, and that [this] can be a very important component of mood,” Dr. Saunders said.
Diet matters
“Highly unsaturated fatty acids are important components of neuronal cell membranes and in cell signaling,” Jessica M. Gannon, MD, University of Pittsburgh, who was not part of the study, said in an interview.
“Omega-6 fatty acids are precursors to proinflammatory compounds. Omega-3 fatty acids eicosapentaenoic acid and docosahexaenoic acid are thought to be competitive inhibitors of omega-6 and thought to have anti-inflammatory effects. Supplementation with omega-3 has been explored in cardiovascular disease, diabetes, and in rheumatologic disorders as well as in a host of psychiatric disorders, including bipolar disorders, where a possible treatment effect has been suggested,” Dr. Gannon said.
Dietary interventions targeting not only increasing omega-3 but also decreasing consumption of omega-6 rich foods could be both effective and attractive to patients invested in a healthy lifestyle for promotion of mental health, especially when they are not optimally controlled by prescribed medications, she added.
“This study suggests that such an intervention could prove beneficial, although significant patient support may be necessary to assure adherence to the diet. I would agree that future studies would be worth pursuing,” Dr. Gannon said.
The investigators and Dr. Gannon have reported no relevant financial relationships.
A version of this article originally appeared on Medscape.com.
A nutritional intervention with a focus on fatty acids appears to reduce mood swings in patients with bipolar disorder (BD) when used as an adjunct to pharmacotherapy, early research suggests.
In a single-center study, patients with BD who received a diet consisting of high omega-3 plus low omega-6 fatty acids (H3-L6), in addition to usual care, showed significant reductions in mood variability, irritability, and pain, compared with their counterparts who received a diet with usual levels of omega-3 and omega-6 fatty acids commonly consumed in regular U.S. diets.
“Our findings need replication and validation in other studies,” study coinvestigator Erika Saunders, MD, professor and chair of the department of psychiatry and behavioral health at Penn State Health, Hershey, said in an interview.
“While we got really exciting findings, it’s far from confirmatory or the last word on the subject. The fatty acids do two broad things. They incorporate into the membranes of neurons in the brain and they also create signaling molecules throughout the brain and the body that interact with the immune system and the inflammatory system. And we suspect that it is through those mechanisms that this composition of fatty acids is having an effect on mood stability, but lots more work needs to be done to figure that out,” Dr. Saunders added.
The findings were presented at the American Society of Clinical Psychopharmacology 2020 Virtual Conference.
Fewer mood swings
Many patients with bipolar disorder do not achieve complete mood stability with medication, making the need for additional treatments imperative, she added.
“We were interested in looking at treatments that improved mood stability in bipolar disorder that are well tolerated by patients and that can be added to pharmacological treatments. We studied this particular nutritional intervention because biologically it does some of the same things that effective medications for bipolar disorder do and it has been investigated as an effective treatment for conditions like migraine headaches, which has a lot of overlap and comorbidity with bipolar disorder.”
The researchers randomized 41 patients with BD to receive the nutritional intervention of high omega-3 plus low omega-6 (H3-L6) and 41 patients with BD to receive a control diet of usual US levels of omega-3 and omega-6 fatty acids.
The patients were aged 20-75 years (mean age, 43.5 +/– 13.9 years) and 83% were women. They had similar mean levels of mood symptoms and pain.
All patients received group-specific study foods and oils, as well as intensive dietary counseling from a dietitian, access to a website with recipes, and guidance for eating in restaurants. All participants were blinded to the composition of the food that they were eating.
Both the interventional diet and the control diet were tailored for the purposes of the study, noted coinvestigator Sarah Shahriar, a research assistant at Penn State.
“The interventional group had more fatty fish such as salmon and tuna, while the control group had more white fish and fish with less fatty acid content. The interventional group also received a different type of cooking oil, which was a blend of olive and macadamia-nut oil, which was specially formulated by a research nutritional service at the University of North Carolina,” Ms. Shahriar said in an interview.
“They also decreased their red meat consumption and received specially formulated snack foods, which were specifically prepared by [the university’s] research nutritional service. It is important to point out that these diets were for a very specific purpose. We are not saying in any way shape or form that this particular nutritional intervention is good in general,” she added.
After 12 weeks, significant reductions were seen in mood variability, energy, irritability, and pain in the H3-L6 group (P < .001). The only symptom that was significantly lowered in the control group was impulsive thoughts (P = .004).
“The best message for doctors to tell their patients at this point is one of general nutritional health and the importance of nutrition in overall body and brain health, and that [this] can be a very important component of mood,” Dr. Saunders said.
Diet matters
“Highly unsaturated fatty acids are important components of neuronal cell membranes and in cell signaling,” Jessica M. Gannon, MD, University of Pittsburgh, who was not part of the study, said in an interview.
“Omega-6 fatty acids are precursors to proinflammatory compounds. Omega-3 fatty acids eicosapentaenoic acid and docosahexaenoic acid are thought to be competitive inhibitors of omega-6 and thought to have anti-inflammatory effects. Supplementation with omega-3 has been explored in cardiovascular disease, diabetes, and in rheumatologic disorders as well as in a host of psychiatric disorders, including bipolar disorders, where a possible treatment effect has been suggested,” Dr. Gannon said.
Dietary interventions targeting not only increasing omega-3 but also decreasing consumption of omega-6 rich foods could be both effective and attractive to patients invested in a healthy lifestyle for promotion of mental health, especially when they are not optimally controlled by prescribed medications, she added.
“This study suggests that such an intervention could prove beneficial, although significant patient support may be necessary to assure adherence to the diet. I would agree that future studies would be worth pursuing,” Dr. Gannon said.
The investigators and Dr. Gannon have reported no relevant financial relationships.
A version of this article originally appeared on Medscape.com.
TILs and PET-CT can predict pCR in HER2-positive metastatic breast cancer
In an update of the PREDIX-HER2 trial, trastuzumab emtansine (T-DM1) remained equivalent to standard neoadjuvant chemotherapy plus dual-targeted HER2 therapy in producing pathologic complete remissions (pCRs) among patients with HER2-positive, metastatic breast cancer.
The new data also suggest tumor-infiltrating lymphocytes (TILs) and dramatic improvements in PET-CT scans can predict favorable outcomes in both treatment groups. Though these findings will be useful for research purposes, they likely won’t influence routine clinical practice.
Thomas Hatschek, MD, PhD, of Karolinska Institutet in Stockholm, presented the updated results from PREDIX-HER2 during the European Society for Medical Oncology: Breast Cancer virtual meeting.
PREDIX-HER2 included patients with HER2-positive breast cancer and tumor size greater than 20 mm or lymph node metastases.
Patients received neoadjuvant therapy (NAT) with docetaxel and trastuzumab plus pertuzumab (DTP) or T-DM1 every 3 weeks for a planned total of six courses. The protocol permitted switching to the competing treatment for progression, lack of response, or drug-related severe toxicity.
Postoperatively, all patients received triweekly epirubicin plus cyclophosphamide – four courses for the T-DM1 arm and two courses for the DTP arm. All patients then received triweekly adjuvant trastuzumab for 11 courses. The 62% of patients whose tumors were hormone receptor (HR)–positive received standard endocrine therapy postoperatively.
Updated results, predictors of pCR
At the 2019 ASCO annual meeting, PREDIX-HER2 investigators reported that, when compared with DTP, T-DM1 produced the same likelihood of pCR with less toxicity (ASCO 2019, Abstract 501). Updated data presented at ESMO Breast Cancer 2020 showed similar results.
The pCR rate was 45.5% in the DTP arm and 43.9% in the T-DM1 arm (P = .824). pCR rates were higher for HR-negative tumors – 63.6% in the DTP arm and 59% in the T-DM1 arm – than for HR-positive tumors – 36.4% in the DTP arm and 33.9% in the TDM-1 arm.
Three patients had disease progression with T-DM1, and none progressed with DTP. However, almost twice as many patients switched from DTP to T-DM1, compared with the other sequence.
Dr. Hatschek reported that the presence of at least 10% TILs predicted pCR in both treatment groups. Among patients who achieved a pCR, 52.2% had at least 10% TILs in baseline biopsies, and 30.4% had less than 10% TILs.
In addition, a decrease of FDG maximum standardized uptake value by more than 75% on protocol-required PET-CT scans was highly predictive of pCR. Among patients who achieved a pCR, 70.3% had a maximum standardized uptake value decrease of more than 75%, and 22.5% had a decrease of 75% or less.
At median follow-up of 28.5 months, event-free survival was similar between the treatment arms. Overall, there were 13 cases of progression, relapse, contralateral breast cancer, distant metastases, or death from any cause. There were five such events in the DTP arm and eight in the TDM-1 arm.
Dr. Hatschek concluded that neoadjuvant T-DM1 may be as effective as standard NAT in all clinical subgroups evaluated. Both TILs and PET-CT showed the potential to predict pCR and merit further study in the NAT setting.
An imperfect surrogate
By definition, a surrogate is “one appointed to act in place of another.” In the case of PREDIX-HER2 and most other NAT studies in HER2-positive breast cancer patients, pCR is a surrogate for the endpoint about which doctors and patients really care – cancer-free survival.
As such, pCR is not a perfect surrogate. Reproducibly, pCR has been highly predictive of disease-free survival and overall survival, especially in the HR-negative subset of HER2-positive patients.
However, despite improvements with dual targeting of HER2 in the TRYPHAENA trial (Eur J Cancer. 2018;89:27-35) and the use of T-DM1 for patients failing to achieve pCR in the immediately practice-changing KATHERINE trial (N Engl J Med. 2019;380:617-28), eventual relapse is seen in 10%-20% of patients in various clinical-pathologic subgroups.
In PREDIX-HER2, the pCR rate for node-positive patients was considerably lower with T-DM1 than with DTP (54.1% vs. 38%), noted Valentina Guarneri, MD, of the University of Padova (Italy), in her discussion of the trial at ESMO Breast Cancer 2020.
Patients with larger initial tumor size and multiple involved axillary nodes at diagnosis remain at increased risk of death because of cancer relapse.
Central nervous system relapse remains a vexing problem. Among patients with triple-positive breast cancer, relapses may occur late, despite pCR.
Patients whose tumors transform from HER2 positive to HER2 negative with NAT, seen in approximately 8% of cases in the KATHERINE trial (ESMO Breast Cancer 2020, Abstract 96O), may be another poor-risk group.
Clinical implications
PREDIX-HER2 is an important study. At the early time point of 2.4 years (especially early since most patients were HR-positive), if pCR is achieved, event-free survival is excellent with T-DM1 or an aggressive multiagent cytotoxic combination plus dual HER2 targeting followed by anthracyclines.
It is ideal to have clinical-pathologic tests to distinguish those patients destined to achieve the surrogate endpoint of pCR from those who will not achieve it.
Despite linkage of TILs to improved outcome for triple-negative and HER2-enriched molecular subtypes (Lancet Oncol. 2018 Jan;19[1]:40-50), analysis of TILs is not standard practice in HER2-positive breast cancer in community settings. Optimal cutoffs are not well established, and TILs have not been linked to the choice of particular treatment options.
Currently, PET-CT scans are not part of National Comprehensive Cancer Network guidelines for pretreatment evaluation, except in patients for whom there is clinical suspicion of distant disease.
For those reasons, the main results of PREDIX-HER2 remain research tools that will focus our attention on the clinical-pathologic correlations Dr. Hatschek highlighted, but the results should have no influence on routine clinical practice at this time.
PREDIX-HER2 was funded by the Swedish Cancer Society, Radiumhemmet of Karolinska Institutet, Region Stockholm, and Roche Sweden. Dr. Hatschek disclosed relationships with Roche Sweden, Pfizer Sweden, and Pierre Fabre Sweden. Dr. Guarneri disclosed relationships with Roche, Novartis, and Eli Lilly.
Dr. Lyss was a community-based medical oncologist and clinical researcher for more than 35 years before his recent retirement. His clinical and research interests were focused on breast and lung cancers as well as expanding clinical trial access to medically underserved populations. He is based in St. Louis. He has no conflicts of interest.
SOURCE: Hatschek T et al. ESMO Breast Cancer 2020, Abstract 97O.
In an update of the PREDIX-HER2 trial, trastuzumab emtansine (T-DM1) remained equivalent to standard neoadjuvant chemotherapy plus dual-targeted HER2 therapy in producing pathologic complete remissions (pCRs) among patients with HER2-positive, metastatic breast cancer.
The new data also suggest tumor-infiltrating lymphocytes (TILs) and dramatic improvements in PET-CT scans can predict favorable outcomes in both treatment groups. Though these findings will be useful for research purposes, they likely won’t influence routine clinical practice.
Thomas Hatschek, MD, PhD, of Karolinska Institutet in Stockholm, presented the updated results from PREDIX-HER2 during the European Society for Medical Oncology: Breast Cancer virtual meeting.
PREDIX-HER2 included patients with HER2-positive breast cancer and tumor size greater than 20 mm or lymph node metastases.
Patients received neoadjuvant therapy (NAT) with docetaxel and trastuzumab plus pertuzumab (DTP) or T-DM1 every 3 weeks for a planned total of six courses. The protocol permitted switching to the competing treatment for progression, lack of response, or drug-related severe toxicity.
Postoperatively, all patients received triweekly epirubicin plus cyclophosphamide – four courses for the T-DM1 arm and two courses for the DTP arm. All patients then received triweekly adjuvant trastuzumab for 11 courses. The 62% of patients whose tumors were hormone receptor (HR)–positive received standard endocrine therapy postoperatively.
Updated results, predictors of pCR
At the 2019 ASCO annual meeting, PREDIX-HER2 investigators reported that, when compared with DTP, T-DM1 produced the same likelihood of pCR with less toxicity (ASCO 2019, Abstract 501). Updated data presented at ESMO Breast Cancer 2020 showed similar results.
The pCR rate was 45.5% in the DTP arm and 43.9% in the T-DM1 arm (P = .824). pCR rates were higher for HR-negative tumors – 63.6% in the DTP arm and 59% in the T-DM1 arm – than for HR-positive tumors – 36.4% in the DTP arm and 33.9% in the TDM-1 arm.
Three patients had disease progression with T-DM1, and none progressed with DTP. However, almost twice as many patients switched from DTP to T-DM1, compared with the other sequence.
Dr. Hatschek reported that the presence of at least 10% TILs predicted pCR in both treatment groups. Among patients who achieved a pCR, 52.2% had at least 10% TILs in baseline biopsies, and 30.4% had less than 10% TILs.
In addition, a decrease of FDG maximum standardized uptake value by more than 75% on protocol-required PET-CT scans was highly predictive of pCR. Among patients who achieved a pCR, 70.3% had a maximum standardized uptake value decrease of more than 75%, and 22.5% had a decrease of 75% or less.
At median follow-up of 28.5 months, event-free survival was similar between the treatment arms. Overall, there were 13 cases of progression, relapse, contralateral breast cancer, distant metastases, or death from any cause. There were five such events in the DTP arm and eight in the TDM-1 arm.
Dr. Hatschek concluded that neoadjuvant T-DM1 may be as effective as standard NAT in all clinical subgroups evaluated. Both TILs and PET-CT showed the potential to predict pCR and merit further study in the NAT setting.
An imperfect surrogate
By definition, a surrogate is “one appointed to act in place of another.” In the case of PREDIX-HER2 and most other NAT studies in HER2-positive breast cancer patients, pCR is a surrogate for the endpoint about which doctors and patients really care – cancer-free survival.
As such, pCR is not a perfect surrogate. Reproducibly, pCR has been highly predictive of disease-free survival and overall survival, especially in the HR-negative subset of HER2-positive patients.
However, despite improvements with dual targeting of HER2 in the TRYPHAENA trial (Eur J Cancer. 2018;89:27-35) and the use of T-DM1 for patients failing to achieve pCR in the immediately practice-changing KATHERINE trial (N Engl J Med. 2019;380:617-28), eventual relapse is seen in 10%-20% of patients in various clinical-pathologic subgroups.
In PREDIX-HER2, the pCR rate for node-positive patients was considerably lower with T-DM1 than with DTP (54.1% vs. 38%), noted Valentina Guarneri, MD, of the University of Padova (Italy), in her discussion of the trial at ESMO Breast Cancer 2020.
Patients with larger initial tumor size and multiple involved axillary nodes at diagnosis remain at increased risk of death because of cancer relapse.
Central nervous system relapse remains a vexing problem. Among patients with triple-positive breast cancer, relapses may occur late, despite pCR.
Patients whose tumors transform from HER2 positive to HER2 negative with NAT, seen in approximately 8% of cases in the KATHERINE trial (ESMO Breast Cancer 2020, Abstract 96O), may be another poor-risk group.
Clinical implications
PREDIX-HER2 is an important study. At the early time point of 2.4 years (especially early since most patients were HR-positive), if pCR is achieved, event-free survival is excellent with T-DM1 or an aggressive multiagent cytotoxic combination plus dual HER2 targeting followed by anthracyclines.
It is ideal to have clinical-pathologic tests to distinguish those patients destined to achieve the surrogate endpoint of pCR from those who will not achieve it.
Despite linkage of TILs to improved outcome for triple-negative and HER2-enriched molecular subtypes (Lancet Oncol. 2018 Jan;19[1]:40-50), analysis of TILs is not standard practice in HER2-positive breast cancer in community settings. Optimal cutoffs are not well established, and TILs have not been linked to the choice of particular treatment options.
Currently, PET-CT scans are not part of National Comprehensive Cancer Network guidelines for pretreatment evaluation, except in patients for whom there is clinical suspicion of distant disease.
For those reasons, the main results of PREDIX-HER2 remain research tools that will focus our attention on the clinical-pathologic correlations Dr. Hatschek highlighted, but the results should have no influence on routine clinical practice at this time.
PREDIX-HER2 was funded by the Swedish Cancer Society, Radiumhemmet of Karolinska Institutet, Region Stockholm, and Roche Sweden. Dr. Hatschek disclosed relationships with Roche Sweden, Pfizer Sweden, and Pierre Fabre Sweden. Dr. Guarneri disclosed relationships with Roche, Novartis, and Eli Lilly.
Dr. Lyss was a community-based medical oncologist and clinical researcher for more than 35 years before his recent retirement. His clinical and research interests were focused on breast and lung cancers as well as expanding clinical trial access to medically underserved populations. He is based in St. Louis. He has no conflicts of interest.
SOURCE: Hatschek T et al. ESMO Breast Cancer 2020, Abstract 97O.
In an update of the PREDIX-HER2 trial, trastuzumab emtansine (T-DM1) remained equivalent to standard neoadjuvant chemotherapy plus dual-targeted HER2 therapy in producing pathologic complete remissions (pCRs) among patients with HER2-positive, metastatic breast cancer.
The new data also suggest tumor-infiltrating lymphocytes (TILs) and dramatic improvements in PET-CT scans can predict favorable outcomes in both treatment groups. Though these findings will be useful for research purposes, they likely won’t influence routine clinical practice.
Thomas Hatschek, MD, PhD, of Karolinska Institutet in Stockholm, presented the updated results from PREDIX-HER2 during the European Society for Medical Oncology: Breast Cancer virtual meeting.
PREDIX-HER2 included patients with HER2-positive breast cancer and tumor size greater than 20 mm or lymph node metastases.
Patients received neoadjuvant therapy (NAT) with docetaxel and trastuzumab plus pertuzumab (DTP) or T-DM1 every 3 weeks for a planned total of six courses. The protocol permitted switching to the competing treatment for progression, lack of response, or drug-related severe toxicity.
Postoperatively, all patients received triweekly epirubicin plus cyclophosphamide – four courses for the T-DM1 arm and two courses for the DTP arm. All patients then received triweekly adjuvant trastuzumab for 11 courses. The 62% of patients whose tumors were hormone receptor (HR)–positive received standard endocrine therapy postoperatively.
Updated results, predictors of pCR
At the 2019 ASCO annual meeting, PREDIX-HER2 investigators reported that, when compared with DTP, T-DM1 produced the same likelihood of pCR with less toxicity (ASCO 2019, Abstract 501). Updated data presented at ESMO Breast Cancer 2020 showed similar results.
The pCR rate was 45.5% in the DTP arm and 43.9% in the T-DM1 arm (P = .824). pCR rates were higher for HR-negative tumors – 63.6% in the DTP arm and 59% in the T-DM1 arm – than for HR-positive tumors – 36.4% in the DTP arm and 33.9% in the TDM-1 arm.
Three patients had disease progression with T-DM1, and none progressed with DTP. However, almost twice as many patients switched from DTP to T-DM1, compared with the other sequence.
Dr. Hatschek reported that the presence of at least 10% TILs predicted pCR in both treatment groups. Among patients who achieved a pCR, 52.2% had at least 10% TILs in baseline biopsies, and 30.4% had less than 10% TILs.
In addition, a decrease of FDG maximum standardized uptake value by more than 75% on protocol-required PET-CT scans was highly predictive of pCR. Among patients who achieved a pCR, 70.3% had a maximum standardized uptake value decrease of more than 75%, and 22.5% had a decrease of 75% or less.
At median follow-up of 28.5 months, event-free survival was similar between the treatment arms. Overall, there were 13 cases of progression, relapse, contralateral breast cancer, distant metastases, or death from any cause. There were five such events in the DTP arm and eight in the TDM-1 arm.
Dr. Hatschek concluded that neoadjuvant T-DM1 may be as effective as standard NAT in all clinical subgroups evaluated. Both TILs and PET-CT showed the potential to predict pCR and merit further study in the NAT setting.
An imperfect surrogate
By definition, a surrogate is “one appointed to act in place of another.” In the case of PREDIX-HER2 and most other NAT studies in HER2-positive breast cancer patients, pCR is a surrogate for the endpoint about which doctors and patients really care – cancer-free survival.
As such, pCR is not a perfect surrogate. Reproducibly, pCR has been highly predictive of disease-free survival and overall survival, especially in the HR-negative subset of HER2-positive patients.
However, despite improvements with dual targeting of HER2 in the TRYPHAENA trial (Eur J Cancer. 2018;89:27-35) and the use of T-DM1 for patients failing to achieve pCR in the immediately practice-changing KATHERINE trial (N Engl J Med. 2019;380:617-28), eventual relapse is seen in 10%-20% of patients in various clinical-pathologic subgroups.
In PREDIX-HER2, the pCR rate for node-positive patients was considerably lower with T-DM1 than with DTP (54.1% vs. 38%), noted Valentina Guarneri, MD, of the University of Padova (Italy), in her discussion of the trial at ESMO Breast Cancer 2020.
Patients with larger initial tumor size and multiple involved axillary nodes at diagnosis remain at increased risk of death because of cancer relapse.
Central nervous system relapse remains a vexing problem. Among patients with triple-positive breast cancer, relapses may occur late, despite pCR.
Patients whose tumors transform from HER2 positive to HER2 negative with NAT, seen in approximately 8% of cases in the KATHERINE trial (ESMO Breast Cancer 2020, Abstract 96O), may be another poor-risk group.
Clinical implications
PREDIX-HER2 is an important study. At the early time point of 2.4 years (especially early since most patients were HR-positive), if pCR is achieved, event-free survival is excellent with T-DM1 or an aggressive multiagent cytotoxic combination plus dual HER2 targeting followed by anthracyclines.
It is ideal to have clinical-pathologic tests to distinguish those patients destined to achieve the surrogate endpoint of pCR from those who will not achieve it.
Despite linkage of TILs to improved outcome for triple-negative and HER2-enriched molecular subtypes (Lancet Oncol. 2018 Jan;19[1]:40-50), analysis of TILs is not standard practice in HER2-positive breast cancer in community settings. Optimal cutoffs are not well established, and TILs have not been linked to the choice of particular treatment options.
Currently, PET-CT scans are not part of National Comprehensive Cancer Network guidelines for pretreatment evaluation, except in patients for whom there is clinical suspicion of distant disease.
For those reasons, the main results of PREDIX-HER2 remain research tools that will focus our attention on the clinical-pathologic correlations Dr. Hatschek highlighted, but the results should have no influence on routine clinical practice at this time.
PREDIX-HER2 was funded by the Swedish Cancer Society, Radiumhemmet of Karolinska Institutet, Region Stockholm, and Roche Sweden. Dr. Hatschek disclosed relationships with Roche Sweden, Pfizer Sweden, and Pierre Fabre Sweden. Dr. Guarneri disclosed relationships with Roche, Novartis, and Eli Lilly.
Dr. Lyss was a community-based medical oncologist and clinical researcher for more than 35 years before his recent retirement. His clinical and research interests were focused on breast and lung cancers as well as expanding clinical trial access to medically underserved populations. He is based in St. Louis. He has no conflicts of interest.
SOURCE: Hatschek T et al. ESMO Breast Cancer 2020, Abstract 97O.
FROM ESMO BREAST CANCER 2020
Need HER2-positive testing in CRC; trastuzumab deruxtecan shows benefit
Testing for HER2 in patients with colorectal cancer (CRC) should become a new standard of care, say experts discussing new results from a phase 2 trial showing benefit with trastuzumab deruxtecan (T-DXd, marketed as Enhertu, AstraZeneca/Daiichi Sankyo).
This drug is approved in the United States for use in the treatment of unresectable or metastatic HER2-positive breast cancer in patients who have already received two or more prior anti–HER2-based regimens in the metastatic setting.
Results come from a phase 2 study, dubbed DESTINY-CRC01, in patients with previously treated HER2+ advanced CRC.
The results show that, in patients with the highest degree of HER2 positivity, T-DXd was associated with an objective response rate of over 45% and a median progression-free survival (PFS) of almost 7 months.
They “demonstrate, in our opinion, the potential of T-DXd as a treatment option” for patients with advanced HER2-positive colorectal cancer that is refractory to standard therapies, said lead investigator Salvatore Siena, MD, from Niguarda Cancer Center, in Milan, Italy.
He presented the results at the 2020 annual meeting of the American Society of Clinical Oncology, held virtually because of the coronavirus pandemic.
At the same time, results from another study, this time in gastric cancer patients, were published online in the New England Journal of Medicine.
Interstitial lung disease as adverse event
The safety profile of T-DXd seen in the colorectal trial “is consistent with what has been previously reported,” said Siena, adding that most of the adverse events were low grade. But he noted there was also a serious adverse effect – interstitial lung disease (ILD). This occurred in 6% of patients, two of whom died. This is “an important risk and requires careful monitoring and proper intervention,” he emphasized.
The ILD adverse effect in this study is “a concern…and something to consider,” commented discussant for the study Michael S. Lee, MD, Lineberger Comprehensive Cancer Center, University of North Carolina, Chapel Hill. But he added that these are the “the best data so far for subsequent anti-HER2 therapy in colorectal cancer”.
Also, the dose of drug used in this trial was higher than that approved for breast cancer, and the incidence of ILD “begs the question of whether we should be using a lower dose in this patient population,” said Autumn J. McRee, MD, also from Lineberger, in a highlights session at the meeting.
“The question here really is whether an HER2-specific approach is superior to what we would offer to these patients in the standard of care setting,” McRee said.
She noted that the patients in DESTINY-CRC01 were “heavily pretreated…and if you think about what our options are in the refractory setting, we do have two approved treatments: regorafenib [Stivarga, Bayer] and TAS-102 [Lonsurf, Taiho Oncology].”
The current data suggest, however, that T-DXd is associated with a trend toward higher response rates and improved survival outcomes, as well as lower monthly costs.
“Without a doubt, this trial is clinically relevant,” she said, adding that it’s “important not to miss these patients.”
“They are rare…but I would argue that testing for HER2 amplification in colorectal cancer should be considered standard of care,” she said.
She added that, based on the current evidence, the trial “may be” practice changing, although it is “still to be determined how to sequence HER2 targeted therapies.”
Study details
The trial was conducted in 78 patients with previously treated unresectable and/or metastatic CRC that was HER2 expressing, RAS/BRAF wild type, and patients had to have received at least two prior regimens, including prior anti-HER2 treatment. Patients with current or suspected ILD were excluded.
Patients were divided into three cohorts based on the degree of HER2 positivity:
- HER2+ with immunohistochemistry (IHC) scoring 3+ or IHC2+/in-situ-hybridization (ISH)+ (cohort A, n = 53)
- HER2 IHC2+/ISH– (cohort B, n = 7)
- HER2 IHC1+ (cohort C, n = 18)
All patients received T-DXd at 6.4 mg/kg intravenously every 3 weeks until progression or intolerable toxicity.
Across the three cohorts, the median age was 58.5 years, and nearly half (47.4%) of patients were female. The vast majority (98.7%) of patents had ECOG performance status 0 or 1, and the primary tumor site was the left colon or rectum in 89.7%.
Siena noted that “the median number of prior lines of standard therapies was four, ranging from two to 11.” All patients had previously received irinotecan and oxaliplatin, and 20.5% had received an anti-HER2 drug.
At the data cutoff on August 9, 2019, 38.5% of patients remained on treatment. The reason for discontinuation was progressive disease in 41%, and clinical progression in 9%.
Siena reported that the overall response rate, as confirmed by independent central review, was 45.3% in cohort A, with all but one of the 24 responders having a partial response. No responses were recorded in cohorts B and C.
Stable disease was seen in 37.7% of cohort A patients, giving a disease control rate of 83%. The median duration of response was not reached.
Median PFS was 6.9 months in cohort A, and the medial overall survival was not reached.
In terms of safety, 50.9% of patients in cohort A and 48.7% patients overall experienced drug-related treatment emergent adverse events, with 22.6% and 17.9%, respectively, having serious drug-related events.
The most common treatment-emergent adverse events were nausea, anemia, reduced neutrophil count, fatigue, and decreased appetite.
There were two deaths related to the study drug, as determined by investigator assessment: one from pneumonitis and one as a result of ILD, with both occurring in cohort A.
Looking specifically at ILD, Siena said there were five events – two grade 2, one grade 3, and two grade 5 – at a median time to reported onset of 80 days. All patients received corticosteroids, as per the study protocol, and two recovered.
Study discussant Lee commented that biomarker testing, such as for HER2, “is part of our standard of care for colorectal cancer,” although studies such as the current one are providing new data to “better refine” treatment approaches.
Lee said that, overall, T-DXd had a response rate and PFS survival “that looked similar to prior data from previous single arm phase 2 studies,” with response rates generally ranging from 30% to 50%, “and this compares favorably with other standard of care options” for chemotherapy-refractory patients.
Nevertheless, there are several ongoing questions related to the treatment of HER2 amplified metastatic CRC patients, some of which are being addressed in the ongoing SWOG S1613 study.
Lee said that, for now, he would recommend that patients with HER2 amplification enroll in a clinical trial, if possible. “However, if that’s not feasible, there are a range of options to consider,” including trastuzumab plus lapatinib (Tykerb, Novartis), or trastuzumab plus pembrolizumab (Keytruda, Merck).
However, “none of these options are FDA approved so there will be issues potentially with financial toxicity and other regulatory issues,” he said.
The study was funded by Daiichi Sankyo Co, Ltd.
Siena reports stock and other ownership interests with Guardant Health and Myriad Genetics; a consulting or advisory role with Amgen, Bayer, Bristol-Myers Squibb, CheckmAb, Clovis Oncology, Daiichi Sankyo, Incyte, Merck, Novartis, Roche/Genentech, Seattle Genetics; research funding from MSD Oncology (Inst); patents, royalties, and other intellectual property from Amgen; and travel, accommodations, expenses from Amgen, Bayer, and Roche. Other coauthors report potential conflicts of interest. The full list can be found with the original article.
Lee reports: Research Funding – Amgen (Inst); Bristol-Myers Squibb (Inst); EMD Serono (Inst); Exelixis (Inst); Genentech/Roche (Inst); Pfizer (Inst); Travel, Accommodations, Expenses – Genentech/Roche.
McRee reports honoraria from Cor2Ed and Onc Live; research funding from AstraZeneca (Inst), BioMed Valley Discoveries (Inst), Boston Biomedical (Inst), Inovio Pharmaceuticals (Inst), Merck (Inst), Novartis (Inst), Rgenix (Inst), and Takeda (Inst); and travel, accommodations, expenses from Cor2Ed.
This article first appeared on Medscape.com.
Testing for HER2 in patients with colorectal cancer (CRC) should become a new standard of care, say experts discussing new results from a phase 2 trial showing benefit with trastuzumab deruxtecan (T-DXd, marketed as Enhertu, AstraZeneca/Daiichi Sankyo).
This drug is approved in the United States for use in the treatment of unresectable or metastatic HER2-positive breast cancer in patients who have already received two or more prior anti–HER2-based regimens in the metastatic setting.
Results come from a phase 2 study, dubbed DESTINY-CRC01, in patients with previously treated HER2+ advanced CRC.
The results show that, in patients with the highest degree of HER2 positivity, T-DXd was associated with an objective response rate of over 45% and a median progression-free survival (PFS) of almost 7 months.
They “demonstrate, in our opinion, the potential of T-DXd as a treatment option” for patients with advanced HER2-positive colorectal cancer that is refractory to standard therapies, said lead investigator Salvatore Siena, MD, from Niguarda Cancer Center, in Milan, Italy.
He presented the results at the 2020 annual meeting of the American Society of Clinical Oncology, held virtually because of the coronavirus pandemic.
At the same time, results from another study, this time in gastric cancer patients, were published online in the New England Journal of Medicine.
Interstitial lung disease as adverse event
The safety profile of T-DXd seen in the colorectal trial “is consistent with what has been previously reported,” said Siena, adding that most of the adverse events were low grade. But he noted there was also a serious adverse effect – interstitial lung disease (ILD). This occurred in 6% of patients, two of whom died. This is “an important risk and requires careful monitoring and proper intervention,” he emphasized.
The ILD adverse effect in this study is “a concern…and something to consider,” commented discussant for the study Michael S. Lee, MD, Lineberger Comprehensive Cancer Center, University of North Carolina, Chapel Hill. But he added that these are the “the best data so far for subsequent anti-HER2 therapy in colorectal cancer”.
Also, the dose of drug used in this trial was higher than that approved for breast cancer, and the incidence of ILD “begs the question of whether we should be using a lower dose in this patient population,” said Autumn J. McRee, MD, also from Lineberger, in a highlights session at the meeting.
“The question here really is whether an HER2-specific approach is superior to what we would offer to these patients in the standard of care setting,” McRee said.
She noted that the patients in DESTINY-CRC01 were “heavily pretreated…and if you think about what our options are in the refractory setting, we do have two approved treatments: regorafenib [Stivarga, Bayer] and TAS-102 [Lonsurf, Taiho Oncology].”
The current data suggest, however, that T-DXd is associated with a trend toward higher response rates and improved survival outcomes, as well as lower monthly costs.
“Without a doubt, this trial is clinically relevant,” she said, adding that it’s “important not to miss these patients.”
“They are rare…but I would argue that testing for HER2 amplification in colorectal cancer should be considered standard of care,” she said.
She added that, based on the current evidence, the trial “may be” practice changing, although it is “still to be determined how to sequence HER2 targeted therapies.”
Study details
The trial was conducted in 78 patients with previously treated unresectable and/or metastatic CRC that was HER2 expressing, RAS/BRAF wild type, and patients had to have received at least two prior regimens, including prior anti-HER2 treatment. Patients with current or suspected ILD were excluded.
Patients were divided into three cohorts based on the degree of HER2 positivity:
- HER2+ with immunohistochemistry (IHC) scoring 3+ or IHC2+/in-situ-hybridization (ISH)+ (cohort A, n = 53)
- HER2 IHC2+/ISH– (cohort B, n = 7)
- HER2 IHC1+ (cohort C, n = 18)
All patients received T-DXd at 6.4 mg/kg intravenously every 3 weeks until progression or intolerable toxicity.
Across the three cohorts, the median age was 58.5 years, and nearly half (47.4%) of patients were female. The vast majority (98.7%) of patents had ECOG performance status 0 or 1, and the primary tumor site was the left colon or rectum in 89.7%.
Siena noted that “the median number of prior lines of standard therapies was four, ranging from two to 11.” All patients had previously received irinotecan and oxaliplatin, and 20.5% had received an anti-HER2 drug.
At the data cutoff on August 9, 2019, 38.5% of patients remained on treatment. The reason for discontinuation was progressive disease in 41%, and clinical progression in 9%.
Siena reported that the overall response rate, as confirmed by independent central review, was 45.3% in cohort A, with all but one of the 24 responders having a partial response. No responses were recorded in cohorts B and C.
Stable disease was seen in 37.7% of cohort A patients, giving a disease control rate of 83%. The median duration of response was not reached.
Median PFS was 6.9 months in cohort A, and the medial overall survival was not reached.
In terms of safety, 50.9% of patients in cohort A and 48.7% patients overall experienced drug-related treatment emergent adverse events, with 22.6% and 17.9%, respectively, having serious drug-related events.
The most common treatment-emergent adverse events were nausea, anemia, reduced neutrophil count, fatigue, and decreased appetite.
There were two deaths related to the study drug, as determined by investigator assessment: one from pneumonitis and one as a result of ILD, with both occurring in cohort A.
Looking specifically at ILD, Siena said there were five events – two grade 2, one grade 3, and two grade 5 – at a median time to reported onset of 80 days. All patients received corticosteroids, as per the study protocol, and two recovered.
Study discussant Lee commented that biomarker testing, such as for HER2, “is part of our standard of care for colorectal cancer,” although studies such as the current one are providing new data to “better refine” treatment approaches.
Lee said that, overall, T-DXd had a response rate and PFS survival “that looked similar to prior data from previous single arm phase 2 studies,” with response rates generally ranging from 30% to 50%, “and this compares favorably with other standard of care options” for chemotherapy-refractory patients.
Nevertheless, there are several ongoing questions related to the treatment of HER2 amplified metastatic CRC patients, some of which are being addressed in the ongoing SWOG S1613 study.
Lee said that, for now, he would recommend that patients with HER2 amplification enroll in a clinical trial, if possible. “However, if that’s not feasible, there are a range of options to consider,” including trastuzumab plus lapatinib (Tykerb, Novartis), or trastuzumab plus pembrolizumab (Keytruda, Merck).
However, “none of these options are FDA approved so there will be issues potentially with financial toxicity and other regulatory issues,” he said.
The study was funded by Daiichi Sankyo Co, Ltd.
Siena reports stock and other ownership interests with Guardant Health and Myriad Genetics; a consulting or advisory role with Amgen, Bayer, Bristol-Myers Squibb, CheckmAb, Clovis Oncology, Daiichi Sankyo, Incyte, Merck, Novartis, Roche/Genentech, Seattle Genetics; research funding from MSD Oncology (Inst); patents, royalties, and other intellectual property from Amgen; and travel, accommodations, expenses from Amgen, Bayer, and Roche. Other coauthors report potential conflicts of interest. The full list can be found with the original article.
Lee reports: Research Funding – Amgen (Inst); Bristol-Myers Squibb (Inst); EMD Serono (Inst); Exelixis (Inst); Genentech/Roche (Inst); Pfizer (Inst); Travel, Accommodations, Expenses – Genentech/Roche.
McRee reports honoraria from Cor2Ed and Onc Live; research funding from AstraZeneca (Inst), BioMed Valley Discoveries (Inst), Boston Biomedical (Inst), Inovio Pharmaceuticals (Inst), Merck (Inst), Novartis (Inst), Rgenix (Inst), and Takeda (Inst); and travel, accommodations, expenses from Cor2Ed.
This article first appeared on Medscape.com.
Testing for HER2 in patients with colorectal cancer (CRC) should become a new standard of care, say experts discussing new results from a phase 2 trial showing benefit with trastuzumab deruxtecan (T-DXd, marketed as Enhertu, AstraZeneca/Daiichi Sankyo).
This drug is approved in the United States for use in the treatment of unresectable or metastatic HER2-positive breast cancer in patients who have already received two or more prior anti–HER2-based regimens in the metastatic setting.
Results come from a phase 2 study, dubbed DESTINY-CRC01, in patients with previously treated HER2+ advanced CRC.
The results show that, in patients with the highest degree of HER2 positivity, T-DXd was associated with an objective response rate of over 45% and a median progression-free survival (PFS) of almost 7 months.
They “demonstrate, in our opinion, the potential of T-DXd as a treatment option” for patients with advanced HER2-positive colorectal cancer that is refractory to standard therapies, said lead investigator Salvatore Siena, MD, from Niguarda Cancer Center, in Milan, Italy.
He presented the results at the 2020 annual meeting of the American Society of Clinical Oncology, held virtually because of the coronavirus pandemic.
At the same time, results from another study, this time in gastric cancer patients, were published online in the New England Journal of Medicine.
Interstitial lung disease as adverse event
The safety profile of T-DXd seen in the colorectal trial “is consistent with what has been previously reported,” said Siena, adding that most of the adverse events were low grade. But he noted there was also a serious adverse effect – interstitial lung disease (ILD). This occurred in 6% of patients, two of whom died. This is “an important risk and requires careful monitoring and proper intervention,” he emphasized.
The ILD adverse effect in this study is “a concern…and something to consider,” commented discussant for the study Michael S. Lee, MD, Lineberger Comprehensive Cancer Center, University of North Carolina, Chapel Hill. But he added that these are the “the best data so far for subsequent anti-HER2 therapy in colorectal cancer”.
Also, the dose of drug used in this trial was higher than that approved for breast cancer, and the incidence of ILD “begs the question of whether we should be using a lower dose in this patient population,” said Autumn J. McRee, MD, also from Lineberger, in a highlights session at the meeting.
“The question here really is whether an HER2-specific approach is superior to what we would offer to these patients in the standard of care setting,” McRee said.
She noted that the patients in DESTINY-CRC01 were “heavily pretreated…and if you think about what our options are in the refractory setting, we do have two approved treatments: regorafenib [Stivarga, Bayer] and TAS-102 [Lonsurf, Taiho Oncology].”
The current data suggest, however, that T-DXd is associated with a trend toward higher response rates and improved survival outcomes, as well as lower monthly costs.
“Without a doubt, this trial is clinically relevant,” she said, adding that it’s “important not to miss these patients.”
“They are rare…but I would argue that testing for HER2 amplification in colorectal cancer should be considered standard of care,” she said.
She added that, based on the current evidence, the trial “may be” practice changing, although it is “still to be determined how to sequence HER2 targeted therapies.”
Study details
The trial was conducted in 78 patients with previously treated unresectable and/or metastatic CRC that was HER2 expressing, RAS/BRAF wild type, and patients had to have received at least two prior regimens, including prior anti-HER2 treatment. Patients with current or suspected ILD were excluded.
Patients were divided into three cohorts based on the degree of HER2 positivity:
- HER2+ with immunohistochemistry (IHC) scoring 3+ or IHC2+/in-situ-hybridization (ISH)+ (cohort A, n = 53)
- HER2 IHC2+/ISH– (cohort B, n = 7)
- HER2 IHC1+ (cohort C, n = 18)
All patients received T-DXd at 6.4 mg/kg intravenously every 3 weeks until progression or intolerable toxicity.
Across the three cohorts, the median age was 58.5 years, and nearly half (47.4%) of patients were female. The vast majority (98.7%) of patents had ECOG performance status 0 or 1, and the primary tumor site was the left colon or rectum in 89.7%.
Siena noted that “the median number of prior lines of standard therapies was four, ranging from two to 11.” All patients had previously received irinotecan and oxaliplatin, and 20.5% had received an anti-HER2 drug.
At the data cutoff on August 9, 2019, 38.5% of patients remained on treatment. The reason for discontinuation was progressive disease in 41%, and clinical progression in 9%.
Siena reported that the overall response rate, as confirmed by independent central review, was 45.3% in cohort A, with all but one of the 24 responders having a partial response. No responses were recorded in cohorts B and C.
Stable disease was seen in 37.7% of cohort A patients, giving a disease control rate of 83%. The median duration of response was not reached.
Median PFS was 6.9 months in cohort A, and the medial overall survival was not reached.
In terms of safety, 50.9% of patients in cohort A and 48.7% patients overall experienced drug-related treatment emergent adverse events, with 22.6% and 17.9%, respectively, having serious drug-related events.
The most common treatment-emergent adverse events were nausea, anemia, reduced neutrophil count, fatigue, and decreased appetite.
There were two deaths related to the study drug, as determined by investigator assessment: one from pneumonitis and one as a result of ILD, with both occurring in cohort A.
Looking specifically at ILD, Siena said there were five events – two grade 2, one grade 3, and two grade 5 – at a median time to reported onset of 80 days. All patients received corticosteroids, as per the study protocol, and two recovered.
Study discussant Lee commented that biomarker testing, such as for HER2, “is part of our standard of care for colorectal cancer,” although studies such as the current one are providing new data to “better refine” treatment approaches.
Lee said that, overall, T-DXd had a response rate and PFS survival “that looked similar to prior data from previous single arm phase 2 studies,” with response rates generally ranging from 30% to 50%, “and this compares favorably with other standard of care options” for chemotherapy-refractory patients.
Nevertheless, there are several ongoing questions related to the treatment of HER2 amplified metastatic CRC patients, some of which are being addressed in the ongoing SWOG S1613 study.
Lee said that, for now, he would recommend that patients with HER2 amplification enroll in a clinical trial, if possible. “However, if that’s not feasible, there are a range of options to consider,” including trastuzumab plus lapatinib (Tykerb, Novartis), or trastuzumab plus pembrolizumab (Keytruda, Merck).
However, “none of these options are FDA approved so there will be issues potentially with financial toxicity and other regulatory issues,” he said.
The study was funded by Daiichi Sankyo Co, Ltd.
Siena reports stock and other ownership interests with Guardant Health and Myriad Genetics; a consulting or advisory role with Amgen, Bayer, Bristol-Myers Squibb, CheckmAb, Clovis Oncology, Daiichi Sankyo, Incyte, Merck, Novartis, Roche/Genentech, Seattle Genetics; research funding from MSD Oncology (Inst); patents, royalties, and other intellectual property from Amgen; and travel, accommodations, expenses from Amgen, Bayer, and Roche. Other coauthors report potential conflicts of interest. The full list can be found with the original article.
Lee reports: Research Funding – Amgen (Inst); Bristol-Myers Squibb (Inst); EMD Serono (Inst); Exelixis (Inst); Genentech/Roche (Inst); Pfizer (Inst); Travel, Accommodations, Expenses – Genentech/Roche.
McRee reports honoraria from Cor2Ed and Onc Live; research funding from AstraZeneca (Inst), BioMed Valley Discoveries (Inst), Boston Biomedical (Inst), Inovio Pharmaceuticals (Inst), Merck (Inst), Novartis (Inst), Rgenix (Inst), and Takeda (Inst); and travel, accommodations, expenses from Cor2Ed.
This article first appeared on Medscape.com.
FROM ASCO 2020
MCC response varies based on immunosuppression type, especially CLL
Patients with Merkel cell carcinoma and chronic immunosuppression may fare better or worse on immunotherapy based on the reason for immunosuppression, according to recent research at the annual meeting of the Society for Investigative Dermatology, held virtually.
About 10% of patients with Merkel cell carcinoma (MCC) are immunosuppressed at diagnosis, and these patients tend to have a more aggressive disease course and worse disease-specific survival compared with immunocompetent patients, Lauren Zawacki, a research assistant in the Nghiem Lab at the University of Washington, Seattle, said in her presentation. Although patients are receiving immune checkpoint inhibitors such as anti-PD-1 and anti-PD-L1 as treatments, the efficacy and side effects on immunosuppressed patients have not been well studied because many of these patients are not eligible for clinical trials.
Ms. Zawacki and colleagues analyzed data from a prospective Seattle registry of 1,442 patients with MCC, identifying 179 patients with MCC who had chronic immunosuppression due to chronic lymphocytic leukemia (CLL), solid organ transplants, autoimmune disorders, other hematological malignancies, and HIV and AIDS. Non-Hodgkin lymphoma comprised 7 of 8 patients in the group with other hematological malignancies, and Crohn’s disease made up 5 of 6 patients in the autoimmune disorder group. Of the 179 patients with MCC and immunosuppression, 31 patients were treated with either anti-PD-1 or anti-PD-L1 therapy.
There was an objective response rate of 52%, with 14 patients having a complete response, 2 patients having a partial response, and 15 patients experiencing disease progression. Of the patients with disease progression, 11 died of MCC. The response rate in immunocompromised patients is similar to results seen by her group in immunocompetent patients (Nghiem P et al. N Engl J Med 2016; 374:2542-52), said Ms. Zawacki. “While the overall objective response rate is comparable between immunocompetent and immunosuppressed patients, the response rates vary greatly between the different types of immunosuppression,” she said.
When grouping response rates by immunosuppression type, they found 2 of 11 patients with CLL (18%) and 2 of 6 patients with autoimmune disease (33%) had an objective response, while 2 of 3 patients with HIV/AIDS (66%) and 7 of 7 patients with other hematologic malignancies (100%) had an objective response.
“While the numbers of the cohort are small, there still seems to be a considerable difference in the response rate between the different types of immune suppression, which is critical when we’re treating patients who typically have a more aggressive disease course,” said Ms. Zawacki.
In particular, the finding of no patients with MCC and CLL achieving a complete response interested Ms. Zawacki and her colleagues, since about one-fourth of patients in the Seattle registry have this combination of disease. “Not only did none of the CLL patients have a complete response, but 7 out of the 11 patients with CLL died from MCC,” she explained. When examining further, the researchers found 45% of patients in this group discontinued because of side effects of immunotherapy and had a median time to recurrence of 1.5 months. “This finding suggests that CLL in particular plays a large role in impairing the function of the immune system, leading to not only a more aggressive disease course, but a poorer response to immunotherapy,” she said.
“There is a significant need for improved interventions for patients with CLL and autoimmune disorders,” she added. “Research for immunosuppressed patients is critical given the associated aggressive disease course and their lack of inclusion in clinical trials.”
Ms. Zawacki acknowledged the small number of patients in the study as a limitation, and patients who received follow-up at outside facilities may have received slightly different care, which could impact adverse event reporting or reasons for study discontinuation.
“A multi-institutional study would be beneficial to expand the number of patients in that cohort and to help confirm the trend observed in this study. In addition, future studies should assess the role of combination systemic therapy, such as neutron radiation and immunotherapy together in order to see if the objective response can be approved among immunosuppressed patients,” she said.
This study was supported by funding from the MCC Patient Gift Fund, the National Cancer Institute, and a grant from NIH. Ms. Zawacki reports no relevant conflicts of interest.
SOURCE: Zawacki L. SID 2020, Abstract 497.
Patients with Merkel cell carcinoma and chronic immunosuppression may fare better or worse on immunotherapy based on the reason for immunosuppression, according to recent research at the annual meeting of the Society for Investigative Dermatology, held virtually.
About 10% of patients with Merkel cell carcinoma (MCC) are immunosuppressed at diagnosis, and these patients tend to have a more aggressive disease course and worse disease-specific survival compared with immunocompetent patients, Lauren Zawacki, a research assistant in the Nghiem Lab at the University of Washington, Seattle, said in her presentation. Although patients are receiving immune checkpoint inhibitors such as anti-PD-1 and anti-PD-L1 as treatments, the efficacy and side effects on immunosuppressed patients have not been well studied because many of these patients are not eligible for clinical trials.
Ms. Zawacki and colleagues analyzed data from a prospective Seattle registry of 1,442 patients with MCC, identifying 179 patients with MCC who had chronic immunosuppression due to chronic lymphocytic leukemia (CLL), solid organ transplants, autoimmune disorders, other hematological malignancies, and HIV and AIDS. Non-Hodgkin lymphoma comprised 7 of 8 patients in the group with other hematological malignancies, and Crohn’s disease made up 5 of 6 patients in the autoimmune disorder group. Of the 179 patients with MCC and immunosuppression, 31 patients were treated with either anti-PD-1 or anti-PD-L1 therapy.
There was an objective response rate of 52%, with 14 patients having a complete response, 2 patients having a partial response, and 15 patients experiencing disease progression. Of the patients with disease progression, 11 died of MCC. The response rate in immunocompromised patients is similar to results seen by her group in immunocompetent patients (Nghiem P et al. N Engl J Med 2016; 374:2542-52), said Ms. Zawacki. “While the overall objective response rate is comparable between immunocompetent and immunosuppressed patients, the response rates vary greatly between the different types of immunosuppression,” she said.
When grouping response rates by immunosuppression type, they found 2 of 11 patients with CLL (18%) and 2 of 6 patients with autoimmune disease (33%) had an objective response, while 2 of 3 patients with HIV/AIDS (66%) and 7 of 7 patients with other hematologic malignancies (100%) had an objective response.
“While the numbers of the cohort are small, there still seems to be a considerable difference in the response rate between the different types of immune suppression, which is critical when we’re treating patients who typically have a more aggressive disease course,” said Ms. Zawacki.
In particular, the finding of no patients with MCC and CLL achieving a complete response interested Ms. Zawacki and her colleagues, since about one-fourth of patients in the Seattle registry have this combination of disease. “Not only did none of the CLL patients have a complete response, but 7 out of the 11 patients with CLL died from MCC,” she explained. When examining further, the researchers found 45% of patients in this group discontinued because of side effects of immunotherapy and had a median time to recurrence of 1.5 months. “This finding suggests that CLL in particular plays a large role in impairing the function of the immune system, leading to not only a more aggressive disease course, but a poorer response to immunotherapy,” she said.
“There is a significant need for improved interventions for patients with CLL and autoimmune disorders,” she added. “Research for immunosuppressed patients is critical given the associated aggressive disease course and their lack of inclusion in clinical trials.”
Ms. Zawacki acknowledged the small number of patients in the study as a limitation, and patients who received follow-up at outside facilities may have received slightly different care, which could impact adverse event reporting or reasons for study discontinuation.
“A multi-institutional study would be beneficial to expand the number of patients in that cohort and to help confirm the trend observed in this study. In addition, future studies should assess the role of combination systemic therapy, such as neutron radiation and immunotherapy together in order to see if the objective response can be approved among immunosuppressed patients,” she said.
This study was supported by funding from the MCC Patient Gift Fund, the National Cancer Institute, and a grant from NIH. Ms. Zawacki reports no relevant conflicts of interest.
SOURCE: Zawacki L. SID 2020, Abstract 497.
Patients with Merkel cell carcinoma and chronic immunosuppression may fare better or worse on immunotherapy based on the reason for immunosuppression, according to recent research at the annual meeting of the Society for Investigative Dermatology, held virtually.
About 10% of patients with Merkel cell carcinoma (MCC) are immunosuppressed at diagnosis, and these patients tend to have a more aggressive disease course and worse disease-specific survival compared with immunocompetent patients, Lauren Zawacki, a research assistant in the Nghiem Lab at the University of Washington, Seattle, said in her presentation. Although patients are receiving immune checkpoint inhibitors such as anti-PD-1 and anti-PD-L1 as treatments, the efficacy and side effects on immunosuppressed patients have not been well studied because many of these patients are not eligible for clinical trials.
Ms. Zawacki and colleagues analyzed data from a prospective Seattle registry of 1,442 patients with MCC, identifying 179 patients with MCC who had chronic immunosuppression due to chronic lymphocytic leukemia (CLL), solid organ transplants, autoimmune disorders, other hematological malignancies, and HIV and AIDS. Non-Hodgkin lymphoma comprised 7 of 8 patients in the group with other hematological malignancies, and Crohn’s disease made up 5 of 6 patients in the autoimmune disorder group. Of the 179 patients with MCC and immunosuppression, 31 patients were treated with either anti-PD-1 or anti-PD-L1 therapy.
There was an objective response rate of 52%, with 14 patients having a complete response, 2 patients having a partial response, and 15 patients experiencing disease progression. Of the patients with disease progression, 11 died of MCC. The response rate in immunocompromised patients is similar to results seen by her group in immunocompetent patients (Nghiem P et al. N Engl J Med 2016; 374:2542-52), said Ms. Zawacki. “While the overall objective response rate is comparable between immunocompetent and immunosuppressed patients, the response rates vary greatly between the different types of immunosuppression,” she said.
When grouping response rates by immunosuppression type, they found 2 of 11 patients with CLL (18%) and 2 of 6 patients with autoimmune disease (33%) had an objective response, while 2 of 3 patients with HIV/AIDS (66%) and 7 of 7 patients with other hematologic malignancies (100%) had an objective response.
“While the numbers of the cohort are small, there still seems to be a considerable difference in the response rate between the different types of immune suppression, which is critical when we’re treating patients who typically have a more aggressive disease course,” said Ms. Zawacki.
In particular, the finding of no patients with MCC and CLL achieving a complete response interested Ms. Zawacki and her colleagues, since about one-fourth of patients in the Seattle registry have this combination of disease. “Not only did none of the CLL patients have a complete response, but 7 out of the 11 patients with CLL died from MCC,” she explained. When examining further, the researchers found 45% of patients in this group discontinued because of side effects of immunotherapy and had a median time to recurrence of 1.5 months. “This finding suggests that CLL in particular plays a large role in impairing the function of the immune system, leading to not only a more aggressive disease course, but a poorer response to immunotherapy,” she said.
“There is a significant need for improved interventions for patients with CLL and autoimmune disorders,” she added. “Research for immunosuppressed patients is critical given the associated aggressive disease course and their lack of inclusion in clinical trials.”
Ms. Zawacki acknowledged the small number of patients in the study as a limitation, and patients who received follow-up at outside facilities may have received slightly different care, which could impact adverse event reporting or reasons for study discontinuation.
“A multi-institutional study would be beneficial to expand the number of patients in that cohort and to help confirm the trend observed in this study. In addition, future studies should assess the role of combination systemic therapy, such as neutron radiation and immunotherapy together in order to see if the objective response can be approved among immunosuppressed patients,” she said.
This study was supported by funding from the MCC Patient Gift Fund, the National Cancer Institute, and a grant from NIH. Ms. Zawacki reports no relevant conflicts of interest.
SOURCE: Zawacki L. SID 2020, Abstract 497.
FROM SID 2020
Erythema and sclerosis predict chronic GVHD clinical response, survival
Erythema associated with chronic graft-versus-host disease (GVHD) after allogenic stem cell transplantation is likely to resolve regardless of when it appears, while sclerosis that develops more than 3 months after a chronic GVHD diagnosis is less likely to resolve, according to research presented during a plenary session at the annual meeting of the Society for Investigative Dermatology, held virtually.
In addition, greater improvement in erythema, as measured by body surface area (BSA) in the study was significantly associated with higher patient survival, Laura X. Baker, BS, a medical student at Vanderbilt University, and coinvestigators at Vanderbilt Dermatology Translational Research Clinic in Nashville, Tenn., said in her presentation.
This new significant association between erythema response and survival could inform future studies,” she said. “Our findings highlight the importance of thorough skin exams in chronic GVHD patients.”
Ms. Baker and colleagues performed a prospective, observational study of 242 patients with chronic GVHD and cutaneous manifestations, enrolled in the Chronic GVHD Consortium across nine centers between 2007 and 2012.
Patients had either erythema or sclerosis at the time of enrollment, which was considered incident if erythema or sclerosis appeared less than 3 months after diagnosis of chronic GVHD, or prevalent if erythema or sclerosis appeared 3 months or later after a chronic GVHD diagnosis. All patients were enrolled in the Chronic GVHD Consortium within 3 years of a transplant and were receiving systemic immunosuppressive therapy.
Transplant clinicians examined patients every 6 months, assessing clinical parameters such as skin involvement. Ms. Baker and colleagues used the 2005 National Institutes of Health (NIH) criteria to assess a complete response, a partial response, or no cutaneous response using measurements made by the transplant clinicians. The NIH criteria recommend calculating the change in BSA at the first follow-up visit to determine these changes (Pavletic S et al. Biol Blood Marrow Transplant. 2006 Mar;12[3]:252-66). Researchers also developed a Cox regression model to evaluate overall survival and non-relapse mortality.
Among those with erythema, 133 patients had incident cases and 52 had prevalent cases of cutaneous chronic GVHD. At first follow-up after a finding of cutaneous involvement, the mean BSA was 4.5%, but the median BSA was zero, “meaning that more than half of the patients had complete disappearance of any erythema by the first follow-up,” Ms. Baker said. By the second follow-up visit, 74% of patients with erythema had complete responses, 9% achieved a partial response, and 18% had no response. A similar complete response rate was seen among patients with prevalent cases.
Among patients with sclerosis, there were 43 incident and 47 prevalent cases. Among patients with incident sclerosis, 68% achieved a clear response, 2% a partial response, and 30% no response. But only 28% of those with prevalent sclerosis had a complete response, 4% had a partial response, and 68% had no response.
Most erythema showed a complete response by the first follow-up, and it was not dependent on time from cGVHD diagnosis, Ms. Baker said. However, while most sclerosis within 3 months of cGVHD diagnosis showed a response, sclerosis present beyond the initial 3 months did not generally respond by the first follow-up.
“These findings could inform clinical care and expectations in addition to guiding the selection of outcome measures and endpoint definitions in clinical trials,” she added.
The researchers also looked at overall survival and nonrelapse mortality among patients with incident and prevalent erythema. After adjustment for age and BSA at enrollment, patients with incident cases of erythema with a complete response had significantly better odds of overall survival compared with patients who had no clinical response (hazard ratio, 0.50; 95% confidence interval; 0.25-1.00; P = .05).
Overall survival was greater in patients with prevalent cases of erythema (HR, 0.29; 95% CI, 0.09-0.87; P = .03). Nonrelapse mortality was also significantly lower among prevalent cases with complete or partial clinical response for erythema (HR, 0.19; 95% CI, 0.06-0.64; P = .01).
In a subgroup analysis, 113 patients with incident cases of erythema that had other organ cGVHD had significantly greater overall survival than did patients without a clinical response (HR, 0.20; 95% CI, 0.08-0.46; P < .005). Median survival distance after the first follow-up between patients with and without a clinical response was 28.9 months among incident cases, and 33.7 months among prevalent erythema cases.
“We knew that erythema is not a direct cause of mortality,” Ms. Baker said. Our results suggest the association between erythema response and survival is important and could inform future study.”
The researchers noted their study was limited by transplant clinicians measuring BSA rather than dermatologists, patients being treated at top transplant centers, and their GVHD diagnosis being within 3 years of a transplant, which could limit generalizability of the findings.
This study was funded by a career development award from the U.S. Department of Veterans Affairs and grants from the National Institutes of Health/National Cancer Institute.
SOURCE: Baker L. SID 2020, Abstract 434.
Erythema associated with chronic graft-versus-host disease (GVHD) after allogenic stem cell transplantation is likely to resolve regardless of when it appears, while sclerosis that develops more than 3 months after a chronic GVHD diagnosis is less likely to resolve, according to research presented during a plenary session at the annual meeting of the Society for Investigative Dermatology, held virtually.
In addition, greater improvement in erythema, as measured by body surface area (BSA) in the study was significantly associated with higher patient survival, Laura X. Baker, BS, a medical student at Vanderbilt University, and coinvestigators at Vanderbilt Dermatology Translational Research Clinic in Nashville, Tenn., said in her presentation.
This new significant association between erythema response and survival could inform future studies,” she said. “Our findings highlight the importance of thorough skin exams in chronic GVHD patients.”
Ms. Baker and colleagues performed a prospective, observational study of 242 patients with chronic GVHD and cutaneous manifestations, enrolled in the Chronic GVHD Consortium across nine centers between 2007 and 2012.
Patients had either erythema or sclerosis at the time of enrollment, which was considered incident if erythema or sclerosis appeared less than 3 months after diagnosis of chronic GVHD, or prevalent if erythema or sclerosis appeared 3 months or later after a chronic GVHD diagnosis. All patients were enrolled in the Chronic GVHD Consortium within 3 years of a transplant and were receiving systemic immunosuppressive therapy.
Transplant clinicians examined patients every 6 months, assessing clinical parameters such as skin involvement. Ms. Baker and colleagues used the 2005 National Institutes of Health (NIH) criteria to assess a complete response, a partial response, or no cutaneous response using measurements made by the transplant clinicians. The NIH criteria recommend calculating the change in BSA at the first follow-up visit to determine these changes (Pavletic S et al. Biol Blood Marrow Transplant. 2006 Mar;12[3]:252-66). Researchers also developed a Cox regression model to evaluate overall survival and non-relapse mortality.
Among those with erythema, 133 patients had incident cases and 52 had prevalent cases of cutaneous chronic GVHD. At first follow-up after a finding of cutaneous involvement, the mean BSA was 4.5%, but the median BSA was zero, “meaning that more than half of the patients had complete disappearance of any erythema by the first follow-up,” Ms. Baker said. By the second follow-up visit, 74% of patients with erythema had complete responses, 9% achieved a partial response, and 18% had no response. A similar complete response rate was seen among patients with prevalent cases.
Among patients with sclerosis, there were 43 incident and 47 prevalent cases. Among patients with incident sclerosis, 68% achieved a clear response, 2% a partial response, and 30% no response. But only 28% of those with prevalent sclerosis had a complete response, 4% had a partial response, and 68% had no response.
Most erythema showed a complete response by the first follow-up, and it was not dependent on time from cGVHD diagnosis, Ms. Baker said. However, while most sclerosis within 3 months of cGVHD diagnosis showed a response, sclerosis present beyond the initial 3 months did not generally respond by the first follow-up.
“These findings could inform clinical care and expectations in addition to guiding the selection of outcome measures and endpoint definitions in clinical trials,” she added.
The researchers also looked at overall survival and nonrelapse mortality among patients with incident and prevalent erythema. After adjustment for age and BSA at enrollment, patients with incident cases of erythema with a complete response had significantly better odds of overall survival compared with patients who had no clinical response (hazard ratio, 0.50; 95% confidence interval; 0.25-1.00; P = .05).
Overall survival was greater in patients with prevalent cases of erythema (HR, 0.29; 95% CI, 0.09-0.87; P = .03). Nonrelapse mortality was also significantly lower among prevalent cases with complete or partial clinical response for erythema (HR, 0.19; 95% CI, 0.06-0.64; P = .01).
In a subgroup analysis, 113 patients with incident cases of erythema that had other organ cGVHD had significantly greater overall survival than did patients without a clinical response (HR, 0.20; 95% CI, 0.08-0.46; P < .005). Median survival distance after the first follow-up between patients with and without a clinical response was 28.9 months among incident cases, and 33.7 months among prevalent erythema cases.
“We knew that erythema is not a direct cause of mortality,” Ms. Baker said. Our results suggest the association between erythema response and survival is important and could inform future study.”
The researchers noted their study was limited by transplant clinicians measuring BSA rather than dermatologists, patients being treated at top transplant centers, and their GVHD diagnosis being within 3 years of a transplant, which could limit generalizability of the findings.
This study was funded by a career development award from the U.S. Department of Veterans Affairs and grants from the National Institutes of Health/National Cancer Institute.
SOURCE: Baker L. SID 2020, Abstract 434.
Erythema associated with chronic graft-versus-host disease (GVHD) after allogenic stem cell transplantation is likely to resolve regardless of when it appears, while sclerosis that develops more than 3 months after a chronic GVHD diagnosis is less likely to resolve, according to research presented during a plenary session at the annual meeting of the Society for Investigative Dermatology, held virtually.
In addition, greater improvement in erythema, as measured by body surface area (BSA) in the study was significantly associated with higher patient survival, Laura X. Baker, BS, a medical student at Vanderbilt University, and coinvestigators at Vanderbilt Dermatology Translational Research Clinic in Nashville, Tenn., said in her presentation.
This new significant association between erythema response and survival could inform future studies,” she said. “Our findings highlight the importance of thorough skin exams in chronic GVHD patients.”
Ms. Baker and colleagues performed a prospective, observational study of 242 patients with chronic GVHD and cutaneous manifestations, enrolled in the Chronic GVHD Consortium across nine centers between 2007 and 2012.
Patients had either erythema or sclerosis at the time of enrollment, which was considered incident if erythema or sclerosis appeared less than 3 months after diagnosis of chronic GVHD, or prevalent if erythema or sclerosis appeared 3 months or later after a chronic GVHD diagnosis. All patients were enrolled in the Chronic GVHD Consortium within 3 years of a transplant and were receiving systemic immunosuppressive therapy.
Transplant clinicians examined patients every 6 months, assessing clinical parameters such as skin involvement. Ms. Baker and colleagues used the 2005 National Institutes of Health (NIH) criteria to assess a complete response, a partial response, or no cutaneous response using measurements made by the transplant clinicians. The NIH criteria recommend calculating the change in BSA at the first follow-up visit to determine these changes (Pavletic S et al. Biol Blood Marrow Transplant. 2006 Mar;12[3]:252-66). Researchers also developed a Cox regression model to evaluate overall survival and non-relapse mortality.
Among those with erythema, 133 patients had incident cases and 52 had prevalent cases of cutaneous chronic GVHD. At first follow-up after a finding of cutaneous involvement, the mean BSA was 4.5%, but the median BSA was zero, “meaning that more than half of the patients had complete disappearance of any erythema by the first follow-up,” Ms. Baker said. By the second follow-up visit, 74% of patients with erythema had complete responses, 9% achieved a partial response, and 18% had no response. A similar complete response rate was seen among patients with prevalent cases.
Among patients with sclerosis, there were 43 incident and 47 prevalent cases. Among patients with incident sclerosis, 68% achieved a clear response, 2% a partial response, and 30% no response. But only 28% of those with prevalent sclerosis had a complete response, 4% had a partial response, and 68% had no response.
Most erythema showed a complete response by the first follow-up, and it was not dependent on time from cGVHD diagnosis, Ms. Baker said. However, while most sclerosis within 3 months of cGVHD diagnosis showed a response, sclerosis present beyond the initial 3 months did not generally respond by the first follow-up.
“These findings could inform clinical care and expectations in addition to guiding the selection of outcome measures and endpoint definitions in clinical trials,” she added.
The researchers also looked at overall survival and nonrelapse mortality among patients with incident and prevalent erythema. After adjustment for age and BSA at enrollment, patients with incident cases of erythema with a complete response had significantly better odds of overall survival compared with patients who had no clinical response (hazard ratio, 0.50; 95% confidence interval; 0.25-1.00; P = .05).
Overall survival was greater in patients with prevalent cases of erythema (HR, 0.29; 95% CI, 0.09-0.87; P = .03). Nonrelapse mortality was also significantly lower among prevalent cases with complete or partial clinical response for erythema (HR, 0.19; 95% CI, 0.06-0.64; P = .01).
In a subgroup analysis, 113 patients with incident cases of erythema that had other organ cGVHD had significantly greater overall survival than did patients without a clinical response (HR, 0.20; 95% CI, 0.08-0.46; P < .005). Median survival distance after the first follow-up between patients with and without a clinical response was 28.9 months among incident cases, and 33.7 months among prevalent erythema cases.
“We knew that erythema is not a direct cause of mortality,” Ms. Baker said. Our results suggest the association between erythema response and survival is important and could inform future study.”
The researchers noted their study was limited by transplant clinicians measuring BSA rather than dermatologists, patients being treated at top transplant centers, and their GVHD diagnosis being within 3 years of a transplant, which could limit generalizability of the findings.
This study was funded by a career development award from the U.S. Department of Veterans Affairs and grants from the National Institutes of Health/National Cancer Institute.
SOURCE: Baker L. SID 2020, Abstract 434.
FROM SID 2020