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AI tool reveals MS drug interactions, offers safer options
MILAN – , German researchers reported.
The team fed the medication plans of almost 630 patients into a deep neural network, which identified drug-drug interactions in more than 80% of cases, in particular when switching from one medication to another, alongside potential food interactions.
The tool was able to identify specific interactions that could be avoided if a drug was replaced with one with a similar pharmacologic profile, but a lower risk of adverse effects.
“Potential drug-drug interactions are a major safety concern in patients with MS,” said study presenter Michael Hecker, PhD, department of neurology, Rostock (Germany) University Medical Center.
Such deep learning–based methods are “useful” in screening for potential interactions both between drugs and with foods, they concluded.
The findings were presented at the 9th Joint ECTRIMS-ACTRIMS Meeting.
Unknown interactions
During his presentation, Dr. Hecker noted that most patients with MS take two or more drugs “to treat their disease and to mitigate their symptoms and comorbidities.” He pointed out, however, that patients who take multiple medications are at an increased risk for side effects, as one drug may affect the pharmacokinetic or pharmacodynamic properties of another.
“For instance, it may change its metabolism,” Dr. Hecker said, and therefore affect its mechanism of action and the response to the drug, with medications potentially having synergistic, antagonistic, or additive effects.
He explained that the online DrugBank database “provides a huge collection” of known drug-drug interactions for compounds that have a track record. “However, for other drugs, and especially those that are tested only in clinical trials, there’s no information about drug-drug and drug-food interactions,” Dr. Hecker said.
“Moreover, it is quite time-consuming to search a database for individual drug-drug interactions,” he added.
34 million parameters
Consequently, there is increasing interest in the use of deep neural networks to study drug-drug interactions, Dr. Hecker said. DeepDDI is the “state-of-the-art deep learning framework” for predicting interactions. It takes drug-drug or drug-food pairs and compares their structures to determine their similarity. This information is fed into a deep neural network with almost 34 million trainable parameters.
The framework then provides a prediction of any interactions in the same terms as the DrugBank, suggesting, for example, that Drug A may decrease the antihypertensive activities of Drug B.
For the current study, the researchers trained the deep neural network on the most recent release of the DrugBank database, finding it was able to replicate the drug-drug interactions in the database at an accuracy of 92.2% in the validation set and 92.1% in the testing set. They then put the medication plans of 627 patients with MS into the deep neural network.
The patients had a mean age of 48.6 years, 70.3% were women, and the median disease duration was 10 years. They were taking an average of 5.3 medications, and 62% were using disease-modifying therapies (DMT).
The team compared the structures of the drugs they were taking with those of 367 drugs used for the treatment of MS, as well as with structural data for 1,673 food compounds from the FooDB database.
Swapping drugs could reduce interactions
The overall prevalence of potential drug-drug interactions among the patients included in the study was 81.2%.
The researchers then determined the proportion of patients who would be at risk of additional drug-drug interaction if they switched from one DMT to another, or to a Bruton tyrosine kinase inhibitor, given all their other medications.
They found, for example, that more than 40% of patients who switched to the immunomodulator fingolimod (Gilenya) would be at increased risk for bradycardia.
Just under 40% of patients who changed their DMT to the purine analogue cladribine (Mavenclad) would have an increased risk, or worsening, of bleeding, as would approximately 25% of those who switched to the anthracenedione antineoplastic agent mitoxantrone (Novantrone).
Dr. Hecker also showed the deep neural network could make suggestions as to how critical drug-drug interactions could be avoided by replacing interacting drugs with alternatives that have similar pharmacological effects.
For example, carbamazepine (Tegretol, Equetro) could be replaced with topiramate (several brand names) to avoid hepatotoxicity in patients also taking acetaminophen, while liothyronine (Cytomel, Triostat) could replace levothyroxine in patients also taking teriflunomide (Aubagio).
Finally, Dr. Hecker reported there was a subset of 6,860 potential drug-food interactions with the patients’ medications, resulting in reduced or increased concentrations of the drugs, particularly with fish or mushroom consumption.
He conceded, however, there were several limitations to their study, including that it included only small-molecule drugs, and that they did not ask patients about their diet or if they had observed any undesired drug effects.
Furthermore, “only a small number” of the potential drug-drug or drug-food interactions they identified would be “clinically relevant.”
Dr. Hecker also pointed out that each drug has one record, but it is used for different indications, with different dosages, and has different side effects, depending how it is used. “The model does not distinguish this,” he said, and so some of the interactions it highlights could be related to other doses than the one used in MS, for example.
Promise for the future
Pavan Bhargava, MBBS, MD, associate professor of neurology, Johns Hopkins Precision Medicine Center of Excellence for Multiple Sclerosis, Baltimore, commented that, as with all AI tools, “it’s only as good as what we’re putting into it.”
Dr. Bhargava, who cochaired the session, said that “there’s limitations on the information in the databases” that are being fed into the deep neural network.
He also highlighted that, “at this point, it didn’t seem like it was coming up with much clinically useful information,” but noted that, “we may get to that point.”
“Right now, there’s promise,” Dr. Bhargava said, but “it’s still not quite there.”
No funding was declared. Dr. Hecker declares relationships with Bayer HealthCare, Biogen, Merck Healthcare, Novartis, and Teva. Several other coauthors also declared financial relationships with industry.
A version of this article first appeared on Medscape.com.
MILAN – , German researchers reported.
The team fed the medication plans of almost 630 patients into a deep neural network, which identified drug-drug interactions in more than 80% of cases, in particular when switching from one medication to another, alongside potential food interactions.
The tool was able to identify specific interactions that could be avoided if a drug was replaced with one with a similar pharmacologic profile, but a lower risk of adverse effects.
“Potential drug-drug interactions are a major safety concern in patients with MS,” said study presenter Michael Hecker, PhD, department of neurology, Rostock (Germany) University Medical Center.
Such deep learning–based methods are “useful” in screening for potential interactions both between drugs and with foods, they concluded.
The findings were presented at the 9th Joint ECTRIMS-ACTRIMS Meeting.
Unknown interactions
During his presentation, Dr. Hecker noted that most patients with MS take two or more drugs “to treat their disease and to mitigate their symptoms and comorbidities.” He pointed out, however, that patients who take multiple medications are at an increased risk for side effects, as one drug may affect the pharmacokinetic or pharmacodynamic properties of another.
“For instance, it may change its metabolism,” Dr. Hecker said, and therefore affect its mechanism of action and the response to the drug, with medications potentially having synergistic, antagonistic, or additive effects.
He explained that the online DrugBank database “provides a huge collection” of known drug-drug interactions for compounds that have a track record. “However, for other drugs, and especially those that are tested only in clinical trials, there’s no information about drug-drug and drug-food interactions,” Dr. Hecker said.
“Moreover, it is quite time-consuming to search a database for individual drug-drug interactions,” he added.
34 million parameters
Consequently, there is increasing interest in the use of deep neural networks to study drug-drug interactions, Dr. Hecker said. DeepDDI is the “state-of-the-art deep learning framework” for predicting interactions. It takes drug-drug or drug-food pairs and compares their structures to determine their similarity. This information is fed into a deep neural network with almost 34 million trainable parameters.
The framework then provides a prediction of any interactions in the same terms as the DrugBank, suggesting, for example, that Drug A may decrease the antihypertensive activities of Drug B.
For the current study, the researchers trained the deep neural network on the most recent release of the DrugBank database, finding it was able to replicate the drug-drug interactions in the database at an accuracy of 92.2% in the validation set and 92.1% in the testing set. They then put the medication plans of 627 patients with MS into the deep neural network.
The patients had a mean age of 48.6 years, 70.3% were women, and the median disease duration was 10 years. They were taking an average of 5.3 medications, and 62% were using disease-modifying therapies (DMT).
The team compared the structures of the drugs they were taking with those of 367 drugs used for the treatment of MS, as well as with structural data for 1,673 food compounds from the FooDB database.
Swapping drugs could reduce interactions
The overall prevalence of potential drug-drug interactions among the patients included in the study was 81.2%.
The researchers then determined the proportion of patients who would be at risk of additional drug-drug interaction if they switched from one DMT to another, or to a Bruton tyrosine kinase inhibitor, given all their other medications.
They found, for example, that more than 40% of patients who switched to the immunomodulator fingolimod (Gilenya) would be at increased risk for bradycardia.
Just under 40% of patients who changed their DMT to the purine analogue cladribine (Mavenclad) would have an increased risk, or worsening, of bleeding, as would approximately 25% of those who switched to the anthracenedione antineoplastic agent mitoxantrone (Novantrone).
Dr. Hecker also showed the deep neural network could make suggestions as to how critical drug-drug interactions could be avoided by replacing interacting drugs with alternatives that have similar pharmacological effects.
For example, carbamazepine (Tegretol, Equetro) could be replaced with topiramate (several brand names) to avoid hepatotoxicity in patients also taking acetaminophen, while liothyronine (Cytomel, Triostat) could replace levothyroxine in patients also taking teriflunomide (Aubagio).
Finally, Dr. Hecker reported there was a subset of 6,860 potential drug-food interactions with the patients’ medications, resulting in reduced or increased concentrations of the drugs, particularly with fish or mushroom consumption.
He conceded, however, there were several limitations to their study, including that it included only small-molecule drugs, and that they did not ask patients about their diet or if they had observed any undesired drug effects.
Furthermore, “only a small number” of the potential drug-drug or drug-food interactions they identified would be “clinically relevant.”
Dr. Hecker also pointed out that each drug has one record, but it is used for different indications, with different dosages, and has different side effects, depending how it is used. “The model does not distinguish this,” he said, and so some of the interactions it highlights could be related to other doses than the one used in MS, for example.
Promise for the future
Pavan Bhargava, MBBS, MD, associate professor of neurology, Johns Hopkins Precision Medicine Center of Excellence for Multiple Sclerosis, Baltimore, commented that, as with all AI tools, “it’s only as good as what we’re putting into it.”
Dr. Bhargava, who cochaired the session, said that “there’s limitations on the information in the databases” that are being fed into the deep neural network.
He also highlighted that, “at this point, it didn’t seem like it was coming up with much clinically useful information,” but noted that, “we may get to that point.”
“Right now, there’s promise,” Dr. Bhargava said, but “it’s still not quite there.”
No funding was declared. Dr. Hecker declares relationships with Bayer HealthCare, Biogen, Merck Healthcare, Novartis, and Teva. Several other coauthors also declared financial relationships with industry.
A version of this article first appeared on Medscape.com.
MILAN – , German researchers reported.
The team fed the medication plans of almost 630 patients into a deep neural network, which identified drug-drug interactions in more than 80% of cases, in particular when switching from one medication to another, alongside potential food interactions.
The tool was able to identify specific interactions that could be avoided if a drug was replaced with one with a similar pharmacologic profile, but a lower risk of adverse effects.
“Potential drug-drug interactions are a major safety concern in patients with MS,” said study presenter Michael Hecker, PhD, department of neurology, Rostock (Germany) University Medical Center.
Such deep learning–based methods are “useful” in screening for potential interactions both between drugs and with foods, they concluded.
The findings were presented at the 9th Joint ECTRIMS-ACTRIMS Meeting.
Unknown interactions
During his presentation, Dr. Hecker noted that most patients with MS take two or more drugs “to treat their disease and to mitigate their symptoms and comorbidities.” He pointed out, however, that patients who take multiple medications are at an increased risk for side effects, as one drug may affect the pharmacokinetic or pharmacodynamic properties of another.
“For instance, it may change its metabolism,” Dr. Hecker said, and therefore affect its mechanism of action and the response to the drug, with medications potentially having synergistic, antagonistic, or additive effects.
He explained that the online DrugBank database “provides a huge collection” of known drug-drug interactions for compounds that have a track record. “However, for other drugs, and especially those that are tested only in clinical trials, there’s no information about drug-drug and drug-food interactions,” Dr. Hecker said.
“Moreover, it is quite time-consuming to search a database for individual drug-drug interactions,” he added.
34 million parameters
Consequently, there is increasing interest in the use of deep neural networks to study drug-drug interactions, Dr. Hecker said. DeepDDI is the “state-of-the-art deep learning framework” for predicting interactions. It takes drug-drug or drug-food pairs and compares their structures to determine their similarity. This information is fed into a deep neural network with almost 34 million trainable parameters.
The framework then provides a prediction of any interactions in the same terms as the DrugBank, suggesting, for example, that Drug A may decrease the antihypertensive activities of Drug B.
For the current study, the researchers trained the deep neural network on the most recent release of the DrugBank database, finding it was able to replicate the drug-drug interactions in the database at an accuracy of 92.2% in the validation set and 92.1% in the testing set. They then put the medication plans of 627 patients with MS into the deep neural network.
The patients had a mean age of 48.6 years, 70.3% were women, and the median disease duration was 10 years. They were taking an average of 5.3 medications, and 62% were using disease-modifying therapies (DMT).
The team compared the structures of the drugs they were taking with those of 367 drugs used for the treatment of MS, as well as with structural data for 1,673 food compounds from the FooDB database.
Swapping drugs could reduce interactions
The overall prevalence of potential drug-drug interactions among the patients included in the study was 81.2%.
The researchers then determined the proportion of patients who would be at risk of additional drug-drug interaction if they switched from one DMT to another, or to a Bruton tyrosine kinase inhibitor, given all their other medications.
They found, for example, that more than 40% of patients who switched to the immunomodulator fingolimod (Gilenya) would be at increased risk for bradycardia.
Just under 40% of patients who changed their DMT to the purine analogue cladribine (Mavenclad) would have an increased risk, or worsening, of bleeding, as would approximately 25% of those who switched to the anthracenedione antineoplastic agent mitoxantrone (Novantrone).
Dr. Hecker also showed the deep neural network could make suggestions as to how critical drug-drug interactions could be avoided by replacing interacting drugs with alternatives that have similar pharmacological effects.
For example, carbamazepine (Tegretol, Equetro) could be replaced with topiramate (several brand names) to avoid hepatotoxicity in patients also taking acetaminophen, while liothyronine (Cytomel, Triostat) could replace levothyroxine in patients also taking teriflunomide (Aubagio).
Finally, Dr. Hecker reported there was a subset of 6,860 potential drug-food interactions with the patients’ medications, resulting in reduced or increased concentrations of the drugs, particularly with fish or mushroom consumption.
He conceded, however, there were several limitations to their study, including that it included only small-molecule drugs, and that they did not ask patients about their diet or if they had observed any undesired drug effects.
Furthermore, “only a small number” of the potential drug-drug or drug-food interactions they identified would be “clinically relevant.”
Dr. Hecker also pointed out that each drug has one record, but it is used for different indications, with different dosages, and has different side effects, depending how it is used. “The model does not distinguish this,” he said, and so some of the interactions it highlights could be related to other doses than the one used in MS, for example.
Promise for the future
Pavan Bhargava, MBBS, MD, associate professor of neurology, Johns Hopkins Precision Medicine Center of Excellence for Multiple Sclerosis, Baltimore, commented that, as with all AI tools, “it’s only as good as what we’re putting into it.”
Dr. Bhargava, who cochaired the session, said that “there’s limitations on the information in the databases” that are being fed into the deep neural network.
He also highlighted that, “at this point, it didn’t seem like it was coming up with much clinically useful information,” but noted that, “we may get to that point.”
“Right now, there’s promise,” Dr. Bhargava said, but “it’s still not quite there.”
No funding was declared. Dr. Hecker declares relationships with Bayer HealthCare, Biogen, Merck Healthcare, Novartis, and Teva. Several other coauthors also declared financial relationships with industry.
A version of this article first appeared on Medscape.com.
FROM ECTRIMS 2023
Ocrelizumab benefit confirmed in older patients with MS
MILAN – they say.
The researchers studied about 700 patients with MS aged 60 years and older from an international database, comparing outcomes with the anti-CD20 monoclonal antibody ocrelizumab versus those for interferon/glatiramer acetate (BRACE). They found ocrelizumab significantly reduced the annual rate of relapses, although after adjustments, patients overall faced a relapse rate of less than 0.1 per year. There were also no significant differences in either disability progression or improvement between the two treatments.
“We believe this study is unique in that ocrelizumab demonstrates a very clear differential treatment benefit in this age group,” said study presenter Yi Chao Foong, MD, department of neuroscience, Monash University, Melbourne. “However, this has to be balanced against the fact that overall relapse activity is extremely low in people with MS over the age of 60. We believe that this study adds valuable, real-world data for nuanced benefit versus risk DMT discussions with for older adults with MS.”
The findings were presented at the 9th Joint ECTRIMS-ACTRIMS meeting.
Lack of data in older patients
Dr. Fong explained the comparative efficacy of disease-modifying therapies (DMTs) has not been demonstrated in older people with MS, as all landmark trials to date have excluded people older than age 60 years. He underlined, however, that the inflammatory aspect of MS reduces with age, when neurodegenerative processes begin to predominate.
“This, combined with increased risk of acute infections in older adults have raised concerns over the benefit ratios of DMTs in this age group,” Dr. Fong said.
This has led to several de-escalation studies in older patients already on treatment for MS, but with “varied results.”
One study, published earlier in 2023, was unable to conclude whether DMT discontinuation was noninferior to continuation in older patients with no recent relapse or new MRI activity.
To investigate further, the Australian team used the MSBase database to study patients with a confirmed MS diagnosis who had started or switched to ocrelizumab or BRACE when older than 60 years of age.
They were also required to have undergone an Expanded Disability Status Scale (EDSS) assessment around the time of the initiation of DMT. In all, 675 patients met the inclusion criteria, of whom 248 started with ocrelizumab and 427 with BRACE.
The treatment groups were well balanced, although baseline EDSS scores were higher in patients given ocrelizumab, at 5.22 versus 3.89 with BRACE (P = .05), and they had a lower relapse rate prior in the year (P = .01) and 2 years (P = .02) prior to baseline.
Only relapse rates reduced
With more than 571 patient-years of follow-up, there were eight relapses in patients treated with ocrelizumab, compared with 182 relapses during 2238 patient-years among those given BRACE.
The team then performed propensity matching based on patient age, disease duration, sex, baseline EDSS, prior relapses, and prior DMTs.
They found that, over a median follow-up of 2.47 years for ocrelizumab and 4.48 years for BRACE, there was a lower rate of relapse with ocrelizumab, at a weighted annualized relapse rate of 0.01 versus 0.08 (P < .0001). This, they calculated, equated to an ARR ratio in favor of ocrelizumab of 0.15 (P < .01).
The time to first relapse was also longer for ocrelizumab versus BRACE, at a weighted hazard ratio for relapse of 0.11 (P < .001) and with, as Dr. Fong highlighted, separation of the curves at 5 months.
Over a follow-up duration of 3.6 years, there was, however, no significant difference in confirmed disability progression between the two treatments (P = .31), with similar results seen for confirmed disability improvement (P = .92).
Dr. Fong noted the study was limited by an inherent treatment indication bias, affecting the sensitivity analysis and weighing, while assessment of confirmed disability progression and confirmed disability improvement was hampered by the relatively short follow-up period and the lack of data on comorbidities.
He also highlighted the lack of safety data for the study population, as well as the lack of MRI.
Muddling the data
Approached for comment, Pavan Bhargava, MBBS, MD, associate professor of neurology, Johns Hopkins Precision Medicine Center of Excellence for Multiple Sclerosis, Baltimore, pointed out the study is based on retrospective data.
“The main question that we normally come up against in clinical practice, once people are older, is: What do you do with their treatment?” he asked.
This, Dr. Bhargava said, was the question that was addressed in the previous de-escalation studies.
The current study “actually answered a completely different question: If you were starting or changing a treatment after 60, which one would be better to choose?” This is a “much rarer scenario,” he said.
The results nevertheless showed what is seen in younger patients; in other words, “a more efficacious treatment is more effective at reducing relapses than a less efficacious treatment, even though overall the number of relapses is quite low,” Dr. Bhargava said.
“The other problem,” he added, is the study included “not just relapsing but also progressive patients, so that kind of muddles the data a little bit.”
Consequently, “it’s hard to really make a definitive conclusion” from the results, Dr. Bhargava concluded.
No funding was declared. Dr. Fong declares relationships with Biogen, National Health and Medical Research Council, Multiple Sclerosis Research Australia, and the Australian and New Zealand Association of Neurologists. Several coauthors also declared financial relationships with industry.
A version of this article first appeared on Medscape.com.
MILAN – they say.
The researchers studied about 700 patients with MS aged 60 years and older from an international database, comparing outcomes with the anti-CD20 monoclonal antibody ocrelizumab versus those for interferon/glatiramer acetate (BRACE). They found ocrelizumab significantly reduced the annual rate of relapses, although after adjustments, patients overall faced a relapse rate of less than 0.1 per year. There were also no significant differences in either disability progression or improvement between the two treatments.
“We believe this study is unique in that ocrelizumab demonstrates a very clear differential treatment benefit in this age group,” said study presenter Yi Chao Foong, MD, department of neuroscience, Monash University, Melbourne. “However, this has to be balanced against the fact that overall relapse activity is extremely low in people with MS over the age of 60. We believe that this study adds valuable, real-world data for nuanced benefit versus risk DMT discussions with for older adults with MS.”
The findings were presented at the 9th Joint ECTRIMS-ACTRIMS meeting.
Lack of data in older patients
Dr. Fong explained the comparative efficacy of disease-modifying therapies (DMTs) has not been demonstrated in older people with MS, as all landmark trials to date have excluded people older than age 60 years. He underlined, however, that the inflammatory aspect of MS reduces with age, when neurodegenerative processes begin to predominate.
“This, combined with increased risk of acute infections in older adults have raised concerns over the benefit ratios of DMTs in this age group,” Dr. Fong said.
This has led to several de-escalation studies in older patients already on treatment for MS, but with “varied results.”
One study, published earlier in 2023, was unable to conclude whether DMT discontinuation was noninferior to continuation in older patients with no recent relapse or new MRI activity.
To investigate further, the Australian team used the MSBase database to study patients with a confirmed MS diagnosis who had started or switched to ocrelizumab or BRACE when older than 60 years of age.
They were also required to have undergone an Expanded Disability Status Scale (EDSS) assessment around the time of the initiation of DMT. In all, 675 patients met the inclusion criteria, of whom 248 started with ocrelizumab and 427 with BRACE.
The treatment groups were well balanced, although baseline EDSS scores were higher in patients given ocrelizumab, at 5.22 versus 3.89 with BRACE (P = .05), and they had a lower relapse rate prior in the year (P = .01) and 2 years (P = .02) prior to baseline.
Only relapse rates reduced
With more than 571 patient-years of follow-up, there were eight relapses in patients treated with ocrelizumab, compared with 182 relapses during 2238 patient-years among those given BRACE.
The team then performed propensity matching based on patient age, disease duration, sex, baseline EDSS, prior relapses, and prior DMTs.
They found that, over a median follow-up of 2.47 years for ocrelizumab and 4.48 years for BRACE, there was a lower rate of relapse with ocrelizumab, at a weighted annualized relapse rate of 0.01 versus 0.08 (P < .0001). This, they calculated, equated to an ARR ratio in favor of ocrelizumab of 0.15 (P < .01).
The time to first relapse was also longer for ocrelizumab versus BRACE, at a weighted hazard ratio for relapse of 0.11 (P < .001) and with, as Dr. Fong highlighted, separation of the curves at 5 months.
Over a follow-up duration of 3.6 years, there was, however, no significant difference in confirmed disability progression between the two treatments (P = .31), with similar results seen for confirmed disability improvement (P = .92).
Dr. Fong noted the study was limited by an inherent treatment indication bias, affecting the sensitivity analysis and weighing, while assessment of confirmed disability progression and confirmed disability improvement was hampered by the relatively short follow-up period and the lack of data on comorbidities.
He also highlighted the lack of safety data for the study population, as well as the lack of MRI.
Muddling the data
Approached for comment, Pavan Bhargava, MBBS, MD, associate professor of neurology, Johns Hopkins Precision Medicine Center of Excellence for Multiple Sclerosis, Baltimore, pointed out the study is based on retrospective data.
“The main question that we normally come up against in clinical practice, once people are older, is: What do you do with their treatment?” he asked.
This, Dr. Bhargava said, was the question that was addressed in the previous de-escalation studies.
The current study “actually answered a completely different question: If you were starting or changing a treatment after 60, which one would be better to choose?” This is a “much rarer scenario,” he said.
The results nevertheless showed what is seen in younger patients; in other words, “a more efficacious treatment is more effective at reducing relapses than a less efficacious treatment, even though overall the number of relapses is quite low,” Dr. Bhargava said.
“The other problem,” he added, is the study included “not just relapsing but also progressive patients, so that kind of muddles the data a little bit.”
Consequently, “it’s hard to really make a definitive conclusion” from the results, Dr. Bhargava concluded.
No funding was declared. Dr. Fong declares relationships with Biogen, National Health and Medical Research Council, Multiple Sclerosis Research Australia, and the Australian and New Zealand Association of Neurologists. Several coauthors also declared financial relationships with industry.
A version of this article first appeared on Medscape.com.
MILAN – they say.
The researchers studied about 700 patients with MS aged 60 years and older from an international database, comparing outcomes with the anti-CD20 monoclonal antibody ocrelizumab versus those for interferon/glatiramer acetate (BRACE). They found ocrelizumab significantly reduced the annual rate of relapses, although after adjustments, patients overall faced a relapse rate of less than 0.1 per year. There were also no significant differences in either disability progression or improvement between the two treatments.
“We believe this study is unique in that ocrelizumab demonstrates a very clear differential treatment benefit in this age group,” said study presenter Yi Chao Foong, MD, department of neuroscience, Monash University, Melbourne. “However, this has to be balanced against the fact that overall relapse activity is extremely low in people with MS over the age of 60. We believe that this study adds valuable, real-world data for nuanced benefit versus risk DMT discussions with for older adults with MS.”
The findings were presented at the 9th Joint ECTRIMS-ACTRIMS meeting.
Lack of data in older patients
Dr. Fong explained the comparative efficacy of disease-modifying therapies (DMTs) has not been demonstrated in older people with MS, as all landmark trials to date have excluded people older than age 60 years. He underlined, however, that the inflammatory aspect of MS reduces with age, when neurodegenerative processes begin to predominate.
“This, combined with increased risk of acute infections in older adults have raised concerns over the benefit ratios of DMTs in this age group,” Dr. Fong said.
This has led to several de-escalation studies in older patients already on treatment for MS, but with “varied results.”
One study, published earlier in 2023, was unable to conclude whether DMT discontinuation was noninferior to continuation in older patients with no recent relapse or new MRI activity.
To investigate further, the Australian team used the MSBase database to study patients with a confirmed MS diagnosis who had started or switched to ocrelizumab or BRACE when older than 60 years of age.
They were also required to have undergone an Expanded Disability Status Scale (EDSS) assessment around the time of the initiation of DMT. In all, 675 patients met the inclusion criteria, of whom 248 started with ocrelizumab and 427 with BRACE.
The treatment groups were well balanced, although baseline EDSS scores were higher in patients given ocrelizumab, at 5.22 versus 3.89 with BRACE (P = .05), and they had a lower relapse rate prior in the year (P = .01) and 2 years (P = .02) prior to baseline.
Only relapse rates reduced
With more than 571 patient-years of follow-up, there were eight relapses in patients treated with ocrelizumab, compared with 182 relapses during 2238 patient-years among those given BRACE.
The team then performed propensity matching based on patient age, disease duration, sex, baseline EDSS, prior relapses, and prior DMTs.
They found that, over a median follow-up of 2.47 years for ocrelizumab and 4.48 years for BRACE, there was a lower rate of relapse with ocrelizumab, at a weighted annualized relapse rate of 0.01 versus 0.08 (P < .0001). This, they calculated, equated to an ARR ratio in favor of ocrelizumab of 0.15 (P < .01).
The time to first relapse was also longer for ocrelizumab versus BRACE, at a weighted hazard ratio for relapse of 0.11 (P < .001) and with, as Dr. Fong highlighted, separation of the curves at 5 months.
Over a follow-up duration of 3.6 years, there was, however, no significant difference in confirmed disability progression between the two treatments (P = .31), with similar results seen for confirmed disability improvement (P = .92).
Dr. Fong noted the study was limited by an inherent treatment indication bias, affecting the sensitivity analysis and weighing, while assessment of confirmed disability progression and confirmed disability improvement was hampered by the relatively short follow-up period and the lack of data on comorbidities.
He also highlighted the lack of safety data for the study population, as well as the lack of MRI.
Muddling the data
Approached for comment, Pavan Bhargava, MBBS, MD, associate professor of neurology, Johns Hopkins Precision Medicine Center of Excellence for Multiple Sclerosis, Baltimore, pointed out the study is based on retrospective data.
“The main question that we normally come up against in clinical practice, once people are older, is: What do you do with their treatment?” he asked.
This, Dr. Bhargava said, was the question that was addressed in the previous de-escalation studies.
The current study “actually answered a completely different question: If you were starting or changing a treatment after 60, which one would be better to choose?” This is a “much rarer scenario,” he said.
The results nevertheless showed what is seen in younger patients; in other words, “a more efficacious treatment is more effective at reducing relapses than a less efficacious treatment, even though overall the number of relapses is quite low,” Dr. Bhargava said.
“The other problem,” he added, is the study included “not just relapsing but also progressive patients, so that kind of muddles the data a little bit.”
Consequently, “it’s hard to really make a definitive conclusion” from the results, Dr. Bhargava concluded.
No funding was declared. Dr. Fong declares relationships with Biogen, National Health and Medical Research Council, Multiple Sclerosis Research Australia, and the Australian and New Zealand Association of Neurologists. Several coauthors also declared financial relationships with industry.
A version of this article first appeared on Medscape.com.
AT ECTRIMS 2023
Confirmed: Intermittent use of benzodiazepines is the safest option
BARCELONA – results of a large-scale study show.
Investigators matched more than 57,000 chronic benzodiazepine users with nearly 114,000 intermittent users and found that, at 1 year, chronic users had an 8% increased risk for emergency department visits and/or hospitalizations for falls.
Chronic users also had a 25% increased risk for hip fracture, a 4% raised risk for ED visits and/or hospitalizations for any reason, and a 23% increased risk for death.
Study investigator Simon J.C. Davies, MD, PhD, MSc, Centre for Addiction & Mental Health, Toronto, said that the research shows that, where possible, patients older than 65 years with anxiety or insomnia who are taking benzodiazepines should not stay on these medications continuously.
However, he acknowledged that, “in practical terms, there will be some who can’t change or do not want to change” their treatment.
The findings were presented at the annual meeting of the European College of Neuropsychopharmacology.
Wide range of adverse outcomes
The authors noted that benzodiazepines are used to treat anxiety and insomnia but are associated with a range of adverse outcomes, including falls, fractures, cognitive impairment, and mortality as well as tolerance and dose escalation.
“These risks are especially relevant in older adults,” they added, noting that some guidelines recommend avoiding the drugs in this population, whereas other suggest short-term benzodiazepine use for a maximum of 4 weeks.
Despite this, “benzodiazepines are widely prescribed in older adults.” One study showed that almost 15% of adults aged 65 years or older received at least one benzodiazepine prescription.
Moreover, chronic use is more common in older versus younger patients.
Benzodiazepine use among older adults “used to be higher,” Dr. Davies said in an interview, at around 20%, but the “numbers have come down,” partly because of the introduction of benzodiazepine-like sleep medications but also because of educational efforts.
“There are certainly campaigns in Ontario to educate physicians,” Dr. Davies said, “but I think more broadly people are aware of the activity of these drugs, and the tolerance and other issues.”
To compare the risk associated with chronic versus intermittent use of benzodiazepines in older adults, the team performed a population-based cohort study using linked health care databases in Ontario.
They focused on adults aged 65 years or older with a first benzodiazepine prescription after at least 1 year without taking the drugs.
Chronic benzodiazepine use was defined as 120 days of prescriptions over the first 180 days after the index prescription. Patients who met these criteria were matched with intermittent users in a 2:1 ratio by age and sex.
Patients were then propensity matched using 24 variables, including health system use in the year prior to the index prescription, clinical diagnoses, prior psychiatric health system use, falls, and income level.
The team identified 57,072 chronic benzodiazepine users and 312,468 intermittent users, of whom, 57,041 and 113,839, respectively, were propensity matched.
As expected, chronic users were prescribed benzodiazepines for more days than were the intermittent users over both the initial 180-day exposure period, at 141 days versus 33 days, and again during a further 180-day follow-up period, at 181 days versus 19 days.
Over the follow-up period, the daily lorazepam dose-equivalents of chronic users four times that of intermittent users.
Hospitalizations and/or ED visits for falls were higher among patients in the chronic benzodiazepine group, at 4.6% versus 3.2% in those who took the drugs intermittently.
After adjusting for benzodiazepine dose, the team found that chronic benzodiazepine use was associated with a significant increase in the risk for falls leading to hospital presentation over the 360-day study period, compared with intermittent use (hazard ratio, 1.08; P = .0124).
Sex differences
In addition, chronic use was linked to a significantly increased risk for hip fracture (HR, 1.25; P = .0095), and long-term care admission (HR, 1.32; P < .0001).
There was also a significant increase in ED visits and/or hospitalizations for any reason with chronic benzodiazepine use versus intermittent use (HR, 1.04; P = .0007), and an increase in the risk for death (HR, 1.23; P < .0001).
A nonsignificant increased risk for wrist fracture was also associated with chronic use of benzodiazepines (HR, 1.02; P = .8683).
Further analysis revealed some sex differences. For instance, men had a marked increase in the risk for hip fracture with chronic use (HR, 1.50; P = .0154), whereas the risk was not significant in women (HR, 1.16; P = .1332). In addition, mortality risk associated with chronic use was higher in men than in women (HR, 1.39; P < .0001 vs. HR, 1.10; P = .2245).
The decision to discontinue chronic benzodiazepine use can be challenging, said Dr. Davies. “If you’re advising people to stop, what happens to the treatment of their anxiety?”
He said that there are many other treatment options for anxiety that don’t come with tolerance or risk for addiction.
“My position would be that intermittent use is perfectly acceptable while you bide your time to explore other treatments. They may be pharmacological; they may, of course, be lifestyle changes, psychotherapies, and so on,” said Dr. Davies.
If, however, patients feel that chronic benzodiazepine use is their only option, this research informs that decision by quantifying the risks.
“We’ve always known that there was a problem, but there haven’t been high-quality epidemiological studies like this that allowed us to say what the numbers are,” said Dr. Davies.
Confirmatory research
In a comment, Christoph U. Correll, MD, professor of psychiatry at Hofstra University, Hempstead, N.Y., noted that the risk associated with benzodiazepine use, especially in older people, has been demonstrated repeatedly.
“In that context, it is not surprising that less continuous exposure to an established risk factor attenuates the risk for these adverse outcomes,” he said.
Dr. Correll, who was not involved in the study pointed out there is nevertheless a “risk of residual confounding by indication.”
In other words, “people with intermittent benzodiazepine use may have less severe underlying illness and better healthy lifestyle behaviors than those requiring chronic benzodiazepine administration.”
Also commenting on the research, Christian Vinkers, MD, PhD, psychiatrist and professor of stress and resilience, Amsterdam University Medical Centre, said that it confirms “once again that long-term benzodiazepine use should not be encouraged.”
“The risk of falls, as well as cognitive side effects and impaired driving skills, with the risk of road accidents, make chronic overuse of benzodiazepines a public health issue. Of course, there is a small group of patients who should have access to long-term use, but it is reasonable to assume that this group is currently too large,” he added.
The study was funded through a grant from the University of Toronto Department of Psychiatry Excellence Funds. No relevant financial relationships were declared.
A version of this article first appeared on Medscape.com.
BARCELONA – results of a large-scale study show.
Investigators matched more than 57,000 chronic benzodiazepine users with nearly 114,000 intermittent users and found that, at 1 year, chronic users had an 8% increased risk for emergency department visits and/or hospitalizations for falls.
Chronic users also had a 25% increased risk for hip fracture, a 4% raised risk for ED visits and/or hospitalizations for any reason, and a 23% increased risk for death.
Study investigator Simon J.C. Davies, MD, PhD, MSc, Centre for Addiction & Mental Health, Toronto, said that the research shows that, where possible, patients older than 65 years with anxiety or insomnia who are taking benzodiazepines should not stay on these medications continuously.
However, he acknowledged that, “in practical terms, there will be some who can’t change or do not want to change” their treatment.
The findings were presented at the annual meeting of the European College of Neuropsychopharmacology.
Wide range of adverse outcomes
The authors noted that benzodiazepines are used to treat anxiety and insomnia but are associated with a range of adverse outcomes, including falls, fractures, cognitive impairment, and mortality as well as tolerance and dose escalation.
“These risks are especially relevant in older adults,” they added, noting that some guidelines recommend avoiding the drugs in this population, whereas other suggest short-term benzodiazepine use for a maximum of 4 weeks.
Despite this, “benzodiazepines are widely prescribed in older adults.” One study showed that almost 15% of adults aged 65 years or older received at least one benzodiazepine prescription.
Moreover, chronic use is more common in older versus younger patients.
Benzodiazepine use among older adults “used to be higher,” Dr. Davies said in an interview, at around 20%, but the “numbers have come down,” partly because of the introduction of benzodiazepine-like sleep medications but also because of educational efforts.
“There are certainly campaigns in Ontario to educate physicians,” Dr. Davies said, “but I think more broadly people are aware of the activity of these drugs, and the tolerance and other issues.”
To compare the risk associated with chronic versus intermittent use of benzodiazepines in older adults, the team performed a population-based cohort study using linked health care databases in Ontario.
They focused on adults aged 65 years or older with a first benzodiazepine prescription after at least 1 year without taking the drugs.
Chronic benzodiazepine use was defined as 120 days of prescriptions over the first 180 days after the index prescription. Patients who met these criteria were matched with intermittent users in a 2:1 ratio by age and sex.
Patients were then propensity matched using 24 variables, including health system use in the year prior to the index prescription, clinical diagnoses, prior psychiatric health system use, falls, and income level.
The team identified 57,072 chronic benzodiazepine users and 312,468 intermittent users, of whom, 57,041 and 113,839, respectively, were propensity matched.
As expected, chronic users were prescribed benzodiazepines for more days than were the intermittent users over both the initial 180-day exposure period, at 141 days versus 33 days, and again during a further 180-day follow-up period, at 181 days versus 19 days.
Over the follow-up period, the daily lorazepam dose-equivalents of chronic users four times that of intermittent users.
Hospitalizations and/or ED visits for falls were higher among patients in the chronic benzodiazepine group, at 4.6% versus 3.2% in those who took the drugs intermittently.
After adjusting for benzodiazepine dose, the team found that chronic benzodiazepine use was associated with a significant increase in the risk for falls leading to hospital presentation over the 360-day study period, compared with intermittent use (hazard ratio, 1.08; P = .0124).
Sex differences
In addition, chronic use was linked to a significantly increased risk for hip fracture (HR, 1.25; P = .0095), and long-term care admission (HR, 1.32; P < .0001).
There was also a significant increase in ED visits and/or hospitalizations for any reason with chronic benzodiazepine use versus intermittent use (HR, 1.04; P = .0007), and an increase in the risk for death (HR, 1.23; P < .0001).
A nonsignificant increased risk for wrist fracture was also associated with chronic use of benzodiazepines (HR, 1.02; P = .8683).
Further analysis revealed some sex differences. For instance, men had a marked increase in the risk for hip fracture with chronic use (HR, 1.50; P = .0154), whereas the risk was not significant in women (HR, 1.16; P = .1332). In addition, mortality risk associated with chronic use was higher in men than in women (HR, 1.39; P < .0001 vs. HR, 1.10; P = .2245).
The decision to discontinue chronic benzodiazepine use can be challenging, said Dr. Davies. “If you’re advising people to stop, what happens to the treatment of their anxiety?”
He said that there are many other treatment options for anxiety that don’t come with tolerance or risk for addiction.
“My position would be that intermittent use is perfectly acceptable while you bide your time to explore other treatments. They may be pharmacological; they may, of course, be lifestyle changes, psychotherapies, and so on,” said Dr. Davies.
If, however, patients feel that chronic benzodiazepine use is their only option, this research informs that decision by quantifying the risks.
“We’ve always known that there was a problem, but there haven’t been high-quality epidemiological studies like this that allowed us to say what the numbers are,” said Dr. Davies.
Confirmatory research
In a comment, Christoph U. Correll, MD, professor of psychiatry at Hofstra University, Hempstead, N.Y., noted that the risk associated with benzodiazepine use, especially in older people, has been demonstrated repeatedly.
“In that context, it is not surprising that less continuous exposure to an established risk factor attenuates the risk for these adverse outcomes,” he said.
Dr. Correll, who was not involved in the study pointed out there is nevertheless a “risk of residual confounding by indication.”
In other words, “people with intermittent benzodiazepine use may have less severe underlying illness and better healthy lifestyle behaviors than those requiring chronic benzodiazepine administration.”
Also commenting on the research, Christian Vinkers, MD, PhD, psychiatrist and professor of stress and resilience, Amsterdam University Medical Centre, said that it confirms “once again that long-term benzodiazepine use should not be encouraged.”
“The risk of falls, as well as cognitive side effects and impaired driving skills, with the risk of road accidents, make chronic overuse of benzodiazepines a public health issue. Of course, there is a small group of patients who should have access to long-term use, but it is reasonable to assume that this group is currently too large,” he added.
The study was funded through a grant from the University of Toronto Department of Psychiatry Excellence Funds. No relevant financial relationships were declared.
A version of this article first appeared on Medscape.com.
BARCELONA – results of a large-scale study show.
Investigators matched more than 57,000 chronic benzodiazepine users with nearly 114,000 intermittent users and found that, at 1 year, chronic users had an 8% increased risk for emergency department visits and/or hospitalizations for falls.
Chronic users also had a 25% increased risk for hip fracture, a 4% raised risk for ED visits and/or hospitalizations for any reason, and a 23% increased risk for death.
Study investigator Simon J.C. Davies, MD, PhD, MSc, Centre for Addiction & Mental Health, Toronto, said that the research shows that, where possible, patients older than 65 years with anxiety or insomnia who are taking benzodiazepines should not stay on these medications continuously.
However, he acknowledged that, “in practical terms, there will be some who can’t change or do not want to change” their treatment.
The findings were presented at the annual meeting of the European College of Neuropsychopharmacology.
Wide range of adverse outcomes
The authors noted that benzodiazepines are used to treat anxiety and insomnia but are associated with a range of adverse outcomes, including falls, fractures, cognitive impairment, and mortality as well as tolerance and dose escalation.
“These risks are especially relevant in older adults,” they added, noting that some guidelines recommend avoiding the drugs in this population, whereas other suggest short-term benzodiazepine use for a maximum of 4 weeks.
Despite this, “benzodiazepines are widely prescribed in older adults.” One study showed that almost 15% of adults aged 65 years or older received at least one benzodiazepine prescription.
Moreover, chronic use is more common in older versus younger patients.
Benzodiazepine use among older adults “used to be higher,” Dr. Davies said in an interview, at around 20%, but the “numbers have come down,” partly because of the introduction of benzodiazepine-like sleep medications but also because of educational efforts.
“There are certainly campaigns in Ontario to educate physicians,” Dr. Davies said, “but I think more broadly people are aware of the activity of these drugs, and the tolerance and other issues.”
To compare the risk associated with chronic versus intermittent use of benzodiazepines in older adults, the team performed a population-based cohort study using linked health care databases in Ontario.
They focused on adults aged 65 years or older with a first benzodiazepine prescription after at least 1 year without taking the drugs.
Chronic benzodiazepine use was defined as 120 days of prescriptions over the first 180 days after the index prescription. Patients who met these criteria were matched with intermittent users in a 2:1 ratio by age and sex.
Patients were then propensity matched using 24 variables, including health system use in the year prior to the index prescription, clinical diagnoses, prior psychiatric health system use, falls, and income level.
The team identified 57,072 chronic benzodiazepine users and 312,468 intermittent users, of whom, 57,041 and 113,839, respectively, were propensity matched.
As expected, chronic users were prescribed benzodiazepines for more days than were the intermittent users over both the initial 180-day exposure period, at 141 days versus 33 days, and again during a further 180-day follow-up period, at 181 days versus 19 days.
Over the follow-up period, the daily lorazepam dose-equivalents of chronic users four times that of intermittent users.
Hospitalizations and/or ED visits for falls were higher among patients in the chronic benzodiazepine group, at 4.6% versus 3.2% in those who took the drugs intermittently.
After adjusting for benzodiazepine dose, the team found that chronic benzodiazepine use was associated with a significant increase in the risk for falls leading to hospital presentation over the 360-day study period, compared with intermittent use (hazard ratio, 1.08; P = .0124).
Sex differences
In addition, chronic use was linked to a significantly increased risk for hip fracture (HR, 1.25; P = .0095), and long-term care admission (HR, 1.32; P < .0001).
There was also a significant increase in ED visits and/or hospitalizations for any reason with chronic benzodiazepine use versus intermittent use (HR, 1.04; P = .0007), and an increase in the risk for death (HR, 1.23; P < .0001).
A nonsignificant increased risk for wrist fracture was also associated with chronic use of benzodiazepines (HR, 1.02; P = .8683).
Further analysis revealed some sex differences. For instance, men had a marked increase in the risk for hip fracture with chronic use (HR, 1.50; P = .0154), whereas the risk was not significant in women (HR, 1.16; P = .1332). In addition, mortality risk associated with chronic use was higher in men than in women (HR, 1.39; P < .0001 vs. HR, 1.10; P = .2245).
The decision to discontinue chronic benzodiazepine use can be challenging, said Dr. Davies. “If you’re advising people to stop, what happens to the treatment of their anxiety?”
He said that there are many other treatment options for anxiety that don’t come with tolerance or risk for addiction.
“My position would be that intermittent use is perfectly acceptable while you bide your time to explore other treatments. They may be pharmacological; they may, of course, be lifestyle changes, psychotherapies, and so on,” said Dr. Davies.
If, however, patients feel that chronic benzodiazepine use is their only option, this research informs that decision by quantifying the risks.
“We’ve always known that there was a problem, but there haven’t been high-quality epidemiological studies like this that allowed us to say what the numbers are,” said Dr. Davies.
Confirmatory research
In a comment, Christoph U. Correll, MD, professor of psychiatry at Hofstra University, Hempstead, N.Y., noted that the risk associated with benzodiazepine use, especially in older people, has been demonstrated repeatedly.
“In that context, it is not surprising that less continuous exposure to an established risk factor attenuates the risk for these adverse outcomes,” he said.
Dr. Correll, who was not involved in the study pointed out there is nevertheless a “risk of residual confounding by indication.”
In other words, “people with intermittent benzodiazepine use may have less severe underlying illness and better healthy lifestyle behaviors than those requiring chronic benzodiazepine administration.”
Also commenting on the research, Christian Vinkers, MD, PhD, psychiatrist and professor of stress and resilience, Amsterdam University Medical Centre, said that it confirms “once again that long-term benzodiazepine use should not be encouraged.”
“The risk of falls, as well as cognitive side effects and impaired driving skills, with the risk of road accidents, make chronic overuse of benzodiazepines a public health issue. Of course, there is a small group of patients who should have access to long-term use, but it is reasonable to assume that this group is currently too large,” he added.
The study was funded through a grant from the University of Toronto Department of Psychiatry Excellence Funds. No relevant financial relationships were declared.
A version of this article first appeared on Medscape.com.
AT ECNP 2023
Esketamine bests quetiapine for severe depression in head-to-head trial
BARCELONA – (TRD), results of a large, multicenter, head-to-head phase 3 trial show.
Results from the ESCAPE-TRD study, which included 675 participants with TRD, show that esketamine was associated with significantly increased rates of both depression and functional remission, compared with quetiapine.
More than 675 patients were randomly assigned to receive one of the two drugs along with ongoing treatment with an SSRI or a serotonin-norepinephrine reuptake inhibitor (SNRI).
Esketamine increased remission rates at 2 and 8 months over quetiapine by 72% and raised functional remission rates at 8 months by 88% while decreasing adverse event rates.
The findings were presented at the annual meeting of the European College of Neuropsychopharmacology and were published online in the New England Journal of Medicine.
New hope
The results provide “some hope for our patients suffering from TRD, which, given the data, is somewhat of a misnomer,” said study investigator Andreas Reif, MD, professor of psychiatry, psychosomatic medicine, and psychotherapy, University Hospital Frankfurt–Goethe University, Frankfurt am Main, Germany, and president-elect of the ECNP.
“These patients are not resistant, they just have resistance to monoaminergic drugs,” he added. Esketamine, he said, is a “new weapon in our armamentarium.”
Dr. Reif said TRD is a serious condition that affects approximately 20%-30% of those with major depressive disorder and has “substantial impact” on patients’ lives, including quality of life and level of functioning.
“We know that esketamine nasal spray is effective in TRD. However, up to now, there were only placebo-controlled trials in addition to ongoing antidepressant treatment,” Dr. Reif noted. Consequently, he added, a head-to-head comparison with an active agent with proven efficacy was “urgently needed.”
For the trial, patients from 171 sites in 24 countries with TRD, defined as a less than 25% improvement in symptoms with two or more consecutive treatments of adequate dosage and duration, were randomly assigned to receive esketamine nasal spray (n = 336) or quetiapine (n = 340) extended release together with ongoing SSRI or SNRI therapy.
Both esketamine and quetiapine were flexibly dosed. The primary endpoint was rates of remission at week 8 on the Montgomery-Åsberg Depression Rating Scale (MADRS). After week 8, patients entered a maintenance phase that lasted to week 32.
Dr. Reif said the study population was representative of a typical TRD population.
The average duration of the current depression episode was more than 5 years, and the average MADRS score was above 30.
Key findings
Results showed that those who received esketamine in combination with an SSRI or SNRI experienced a significantly higher rate of remission at week 8, compared with those treated with quetiapine (27.1% vs. 17.6%; P = .003). This equated to an adjusted odds ratio for remission of 1.74 (P = .003).
Use of esketamine was also associated with a higher rate of remission at week 8, and patients remained relapse free at week 32 (21.7% vs. 14.1% with quetiapine; odds ratio, 1.72; P = .008).
At every time point through the study, the proportion of patients experiencing remission was significantly greater with esketamine than with quetiapine. The absolute rate of remission at week 32 was 55.0%, versus 37.0% (P < .001).
Dr. Reif noted that the definition of remission used in the study was a MADRS score of less than or equal to 10, but if the “more lenient” definition of less than or equal to 12, which has been used previously, were to be applied, the absolute remission rates would rise to 65.1%, versus 46.7%.
Dr. Reif also presented results on functional remission rates beyond 32 weeks – data that were not included in the study as published in NEJM.
While remission rates increased over time in both study arms, the functional remission rate at week 32 was, again, significantly higher with esketamine than with quetiapine (38.1% vs. 25.0%; OR, 1.88; P < .001).
The safety data revealed no new signals, Dr. Reif said. Use of esketamine was associated with a lower rate of treatment-emergent adverse events that led to treatment discontinuation, at 4.2% vs. 11.0% with quetiapine.
Among patients given the ketamine-derived drug, there were lower rates of nervous system disorders, and there were no incidences of weight gain, fatigue, or hangover.
Dr. Reif said the results show that esketamine nasal spray was superior to quetiapine in achieving remission over time and that it “greatly improves patients’ functional impairment” while achieving “generally lower” adverse event rates.
He added that they are currently running a significant number of secondary analyses “to give us a better grasp of which patient benefits most” from esketamine therapy over quetiapine. The results may potentially be used to guide patient selection.
‘Tremendous advance’
Session co-chair Mark Weiser, MD, chairman at the department of psychiatry, Tel Aviv (Israel) University, said in an interview that the results are “very exciting” and offer “further proof of a tremendous advance in our field.”
Dr. Weiser, who was not involved in the study, added that demonstrating functional improvement with esketamine was key.
“It’s great to improve symptoms,” he said, “but to have patients show an improvement in their functionality is really the bottom line of this. Not only do you feel better, but you function better, and that’s of extreme importance and makes us feel very optimistic about the future.”
Josep Antoni Ramos-Quiroga, MD, PhD, head of psychiatry, Vall Hebron University Hospital and Autonomous University of Barcelona, welcomed the findings.
“The results of this study show the superior response and safety of esketamine nasal spray when compared with quetiapine,” he said in a release. “This gives people with treatment-resistant depression more safe treatment options.”
The study was funded by Janssen EMEA. Dr. Reif has relationships with Boehringer Ingelheim, COMPASS, Janssen Pharmaceuticals, LivaNova USA, Medice, Saga Therapeutics, and Shire. Other authors have disclosed numerous relationships with industry.
A version of this article first appeared on Medscape.com.
BARCELONA – (TRD), results of a large, multicenter, head-to-head phase 3 trial show.
Results from the ESCAPE-TRD study, which included 675 participants with TRD, show that esketamine was associated with significantly increased rates of both depression and functional remission, compared with quetiapine.
More than 675 patients were randomly assigned to receive one of the two drugs along with ongoing treatment with an SSRI or a serotonin-norepinephrine reuptake inhibitor (SNRI).
Esketamine increased remission rates at 2 and 8 months over quetiapine by 72% and raised functional remission rates at 8 months by 88% while decreasing adverse event rates.
The findings were presented at the annual meeting of the European College of Neuropsychopharmacology and were published online in the New England Journal of Medicine.
New hope
The results provide “some hope for our patients suffering from TRD, which, given the data, is somewhat of a misnomer,” said study investigator Andreas Reif, MD, professor of psychiatry, psychosomatic medicine, and psychotherapy, University Hospital Frankfurt–Goethe University, Frankfurt am Main, Germany, and president-elect of the ECNP.
“These patients are not resistant, they just have resistance to monoaminergic drugs,” he added. Esketamine, he said, is a “new weapon in our armamentarium.”
Dr. Reif said TRD is a serious condition that affects approximately 20%-30% of those with major depressive disorder and has “substantial impact” on patients’ lives, including quality of life and level of functioning.
“We know that esketamine nasal spray is effective in TRD. However, up to now, there were only placebo-controlled trials in addition to ongoing antidepressant treatment,” Dr. Reif noted. Consequently, he added, a head-to-head comparison with an active agent with proven efficacy was “urgently needed.”
For the trial, patients from 171 sites in 24 countries with TRD, defined as a less than 25% improvement in symptoms with two or more consecutive treatments of adequate dosage and duration, were randomly assigned to receive esketamine nasal spray (n = 336) or quetiapine (n = 340) extended release together with ongoing SSRI or SNRI therapy.
Both esketamine and quetiapine were flexibly dosed. The primary endpoint was rates of remission at week 8 on the Montgomery-Åsberg Depression Rating Scale (MADRS). After week 8, patients entered a maintenance phase that lasted to week 32.
Dr. Reif said the study population was representative of a typical TRD population.
The average duration of the current depression episode was more than 5 years, and the average MADRS score was above 30.
Key findings
Results showed that those who received esketamine in combination with an SSRI or SNRI experienced a significantly higher rate of remission at week 8, compared with those treated with quetiapine (27.1% vs. 17.6%; P = .003). This equated to an adjusted odds ratio for remission of 1.74 (P = .003).
Use of esketamine was also associated with a higher rate of remission at week 8, and patients remained relapse free at week 32 (21.7% vs. 14.1% with quetiapine; odds ratio, 1.72; P = .008).
At every time point through the study, the proportion of patients experiencing remission was significantly greater with esketamine than with quetiapine. The absolute rate of remission at week 32 was 55.0%, versus 37.0% (P < .001).
Dr. Reif noted that the definition of remission used in the study was a MADRS score of less than or equal to 10, but if the “more lenient” definition of less than or equal to 12, which has been used previously, were to be applied, the absolute remission rates would rise to 65.1%, versus 46.7%.
Dr. Reif also presented results on functional remission rates beyond 32 weeks – data that were not included in the study as published in NEJM.
While remission rates increased over time in both study arms, the functional remission rate at week 32 was, again, significantly higher with esketamine than with quetiapine (38.1% vs. 25.0%; OR, 1.88; P < .001).
The safety data revealed no new signals, Dr. Reif said. Use of esketamine was associated with a lower rate of treatment-emergent adverse events that led to treatment discontinuation, at 4.2% vs. 11.0% with quetiapine.
Among patients given the ketamine-derived drug, there were lower rates of nervous system disorders, and there were no incidences of weight gain, fatigue, or hangover.
Dr. Reif said the results show that esketamine nasal spray was superior to quetiapine in achieving remission over time and that it “greatly improves patients’ functional impairment” while achieving “generally lower” adverse event rates.
He added that they are currently running a significant number of secondary analyses “to give us a better grasp of which patient benefits most” from esketamine therapy over quetiapine. The results may potentially be used to guide patient selection.
‘Tremendous advance’
Session co-chair Mark Weiser, MD, chairman at the department of psychiatry, Tel Aviv (Israel) University, said in an interview that the results are “very exciting” and offer “further proof of a tremendous advance in our field.”
Dr. Weiser, who was not involved in the study, added that demonstrating functional improvement with esketamine was key.
“It’s great to improve symptoms,” he said, “but to have patients show an improvement in their functionality is really the bottom line of this. Not only do you feel better, but you function better, and that’s of extreme importance and makes us feel very optimistic about the future.”
Josep Antoni Ramos-Quiroga, MD, PhD, head of psychiatry, Vall Hebron University Hospital and Autonomous University of Barcelona, welcomed the findings.
“The results of this study show the superior response and safety of esketamine nasal spray when compared with quetiapine,” he said in a release. “This gives people with treatment-resistant depression more safe treatment options.”
The study was funded by Janssen EMEA. Dr. Reif has relationships with Boehringer Ingelheim, COMPASS, Janssen Pharmaceuticals, LivaNova USA, Medice, Saga Therapeutics, and Shire. Other authors have disclosed numerous relationships with industry.
A version of this article first appeared on Medscape.com.
BARCELONA – (TRD), results of a large, multicenter, head-to-head phase 3 trial show.
Results from the ESCAPE-TRD study, which included 675 participants with TRD, show that esketamine was associated with significantly increased rates of both depression and functional remission, compared with quetiapine.
More than 675 patients were randomly assigned to receive one of the two drugs along with ongoing treatment with an SSRI or a serotonin-norepinephrine reuptake inhibitor (SNRI).
Esketamine increased remission rates at 2 and 8 months over quetiapine by 72% and raised functional remission rates at 8 months by 88% while decreasing adverse event rates.
The findings were presented at the annual meeting of the European College of Neuropsychopharmacology and were published online in the New England Journal of Medicine.
New hope
The results provide “some hope for our patients suffering from TRD, which, given the data, is somewhat of a misnomer,” said study investigator Andreas Reif, MD, professor of psychiatry, psychosomatic medicine, and psychotherapy, University Hospital Frankfurt–Goethe University, Frankfurt am Main, Germany, and president-elect of the ECNP.
“These patients are not resistant, they just have resistance to monoaminergic drugs,” he added. Esketamine, he said, is a “new weapon in our armamentarium.”
Dr. Reif said TRD is a serious condition that affects approximately 20%-30% of those with major depressive disorder and has “substantial impact” on patients’ lives, including quality of life and level of functioning.
“We know that esketamine nasal spray is effective in TRD. However, up to now, there were only placebo-controlled trials in addition to ongoing antidepressant treatment,” Dr. Reif noted. Consequently, he added, a head-to-head comparison with an active agent with proven efficacy was “urgently needed.”
For the trial, patients from 171 sites in 24 countries with TRD, defined as a less than 25% improvement in symptoms with two or more consecutive treatments of adequate dosage and duration, were randomly assigned to receive esketamine nasal spray (n = 336) or quetiapine (n = 340) extended release together with ongoing SSRI or SNRI therapy.
Both esketamine and quetiapine were flexibly dosed. The primary endpoint was rates of remission at week 8 on the Montgomery-Åsberg Depression Rating Scale (MADRS). After week 8, patients entered a maintenance phase that lasted to week 32.
Dr. Reif said the study population was representative of a typical TRD population.
The average duration of the current depression episode was more than 5 years, and the average MADRS score was above 30.
Key findings
Results showed that those who received esketamine in combination with an SSRI or SNRI experienced a significantly higher rate of remission at week 8, compared with those treated with quetiapine (27.1% vs. 17.6%; P = .003). This equated to an adjusted odds ratio for remission of 1.74 (P = .003).
Use of esketamine was also associated with a higher rate of remission at week 8, and patients remained relapse free at week 32 (21.7% vs. 14.1% with quetiapine; odds ratio, 1.72; P = .008).
At every time point through the study, the proportion of patients experiencing remission was significantly greater with esketamine than with quetiapine. The absolute rate of remission at week 32 was 55.0%, versus 37.0% (P < .001).
Dr. Reif noted that the definition of remission used in the study was a MADRS score of less than or equal to 10, but if the “more lenient” definition of less than or equal to 12, which has been used previously, were to be applied, the absolute remission rates would rise to 65.1%, versus 46.7%.
Dr. Reif also presented results on functional remission rates beyond 32 weeks – data that were not included in the study as published in NEJM.
While remission rates increased over time in both study arms, the functional remission rate at week 32 was, again, significantly higher with esketamine than with quetiapine (38.1% vs. 25.0%; OR, 1.88; P < .001).
The safety data revealed no new signals, Dr. Reif said. Use of esketamine was associated with a lower rate of treatment-emergent adverse events that led to treatment discontinuation, at 4.2% vs. 11.0% with quetiapine.
Among patients given the ketamine-derived drug, there were lower rates of nervous system disorders, and there were no incidences of weight gain, fatigue, or hangover.
Dr. Reif said the results show that esketamine nasal spray was superior to quetiapine in achieving remission over time and that it “greatly improves patients’ functional impairment” while achieving “generally lower” adverse event rates.
He added that they are currently running a significant number of secondary analyses “to give us a better grasp of which patient benefits most” from esketamine therapy over quetiapine. The results may potentially be used to guide patient selection.
‘Tremendous advance’
Session co-chair Mark Weiser, MD, chairman at the department of psychiatry, Tel Aviv (Israel) University, said in an interview that the results are “very exciting” and offer “further proof of a tremendous advance in our field.”
Dr. Weiser, who was not involved in the study, added that demonstrating functional improvement with esketamine was key.
“It’s great to improve symptoms,” he said, “but to have patients show an improvement in their functionality is really the bottom line of this. Not only do you feel better, but you function better, and that’s of extreme importance and makes us feel very optimistic about the future.”
Josep Antoni Ramos-Quiroga, MD, PhD, head of psychiatry, Vall Hebron University Hospital and Autonomous University of Barcelona, welcomed the findings.
“The results of this study show the superior response and safety of esketamine nasal spray when compared with quetiapine,” he said in a release. “This gives people with treatment-resistant depression more safe treatment options.”
The study was funded by Janssen EMEA. Dr. Reif has relationships with Boehringer Ingelheim, COMPASS, Janssen Pharmaceuticals, LivaNova USA, Medice, Saga Therapeutics, and Shire. Other authors have disclosed numerous relationships with industry.
A version of this article first appeared on Medscape.com.
AT ECNP 2023
Running vs. meds for depression: Is there a clear winner?
BARCELONA – However, running provides greater physical health benefits while adherence is greater with drug treatment.
“Both interventions helped with the depression to around the same extent,” study presenter Brenda W.J.H. Penninx, PhD, professor of psychiatric epidemiology at the VU University Medical Center in Amsterdam said in a release.
However, medication “generally had worse impact on body weight, heart rate variability, and blood pressure, whereas running therapy led to improved effect on general fitness and heart rate,” Dr. Penninx added.
The findings were presented at the annual congress of the European College of Neuropsychopharmacology and recently published in the Journal of Affective Disorders.
Research gap
Previous research suggests exercise interventions can have a therapeutic effect equivalent to antidepressants, but their impact on physical health has been “poorly examined in a psychiatric population, the investigators note.
The authors note that depressive and anxiety disorders “cause immense suffering by compromising both mental and physical health,” and the need for effective treatments is “pressing.”
Although antidepressant medication is considered a “standard first-line treatment” alongside psychotherapy, the drugs are “not effective for all and [are] often associated with side effects.”
The Mood Treatment with Antidepressant or Running (MOTAR) study was a partially randomized pragmatic trial in adults with depression and/or anxiety disorder, as determined using the DSM-IV algorithms with the Composite International Diagnostic Interview (CIDI).
The 16-week intervention study included 141 patients with depression and/or anxiety. The mean age was 38.2 years and 58% were women. Participants were offered a choice of treatment: 16 weeks of treatment with the selective serotonin reuptake inhibitor (SSRI) escitalopram (Lexapro) or a 16-week group-based running therapy.
Patients without a strong preference for treatment allocation were randomly assigned to either antidepressant medication or running therapy, while those unwilling to be randomized were allocated to their preferred intervention.
A total of 22 patients were randomly assigned to receive antidepressant treatment and 13 to running therapy. A total of 36 participants chose antidepressant treatment, while 83 chose the running therapy.
Running therapy involved 16 weeks of supervised 45-minute outdoor running sessions to a target of two to three sessions per week, in line with U.S. Centers for Disease Control and Prevention/American College of Sports Medicine recommendations.
Physical health benefits
Treatment adherence in the antidepressant group, defined as still using treatment at the posttreatment assessment, was 82.2% vs. 52.1% among running therapy participants, where adherence was specified as completing more than 22 sessions.
Remission was defined as no longer meeting the criteria of a current depressive or anxiety disorder via CIDI at week 16.
On intention-to-treat analysis, this requirement was met by 44.8% of patients taking antidepressants and 43.3% of those in the running therapy group (P = .88).
However, running therapy patients showed significant improvements in weight (P = .001), waist circumference (P = .011), systolic and diastolic blood pressure (P = .011 and P = .002, respectively), heart rate (P = .033), and heart rate variability (P = .006).
The investigators note the more favorable physical health changes in the running therapy group were attributable to “larger improvements in the running therapy group but also due to larger deterioration in the antidepressant group.”
Antidepressants are generally safe and effective and work for most people, said Dr. Penninx. She also noted that untreated depression leads to worse outcomes, so “antidepressants are generally a good choice.”
Nevertheless, she said, “we need to extend our treatment arsenal as not all patients respond to antidepressants or are willing to take them.”
The study’s results, she added, suggest that “implementing exercise therapy is something we should take much more seriously, as it could be a good, and maybe even better, choice for some of our patients.”
Francesca Cirulli, PhD, senior researcher and group leader at the National Institute of Health, Rome, said in an interview that the study is notable because it is one of the first to prospectively measure the effects of antidepressants and running on physical health.
Dr. Cirulli suggested that running therapy could be tried ahead of treatment with antidepressants if patients prefer physical exercise and can adhere to it. However, she said, the findings also suggest that an increase in physical activity should accompany treatment with antidepressant medications.
Overall, Dr. Cirulli said “the message should not be that everyone can be helped by running and antidepressants are bad,” but rather “these are both helpful, but not excellent, interventions against depression.”
‘Important limitations’
In a comment, Eduard Vieta, MD, PhD, chair of the department of psychiatry and psychology at the University of Barcelona Hospital Clinic, noted the study has “very important limitations.”
Among the limitations: the inclusion of nonrandomized patients who received the treatment of their choice, causing obvious bias and the “lack of binding and power issues” over the number of patients enrolled.
Dr. Vieta also said that the results “seem obvious, because it is known that exercise improves physical health.”
The trial therefore shows, “if you can find people who are able to do exercise while depressed and adhere to it, those would benefit from that practice,” he noted.
Also commenting on the research, Eric Ruhe, MD, PhD, Radboud University Medical Center, Nijmegen, the Netherlands, said the results are confirmatory and “again show physical health can influence mental health.”
However, Dr. Ruhe underlined, while it is “common practice” to allow patients to follow their treatment preference and is “understandable from a pragmatic point of view,” the group comparison may be “biased,” compared with a “truly randomized study.”
“For example, patients in the antidepressant group were more depressed, which might be associated with less chance of persisting engagement in the exercises,” he said. “So, we have to be careful not to overinterpret the comparisons between groups, which the authors acknowledge properly.”
Turning to the difference in adherence between the two interventions, Dr. Ruhe said the results show adopting, and adhering to, a lifestyle habit is more difficult than taking a pill.
“This is not exclusively found in psychiatry, indicating that we also have to focus on how to improve compliance to healthy behavior. This could have tremendous impact on health care more generally, but also on psychiatric diseases,” Dr. Ruhe said.
The MOTAR study was funded by a NWO-VICI grant. Funding for the inflammatory markers was provided by ZonMw: The Netherlands Organization for Health Research and Development. The study authors and clinicians interviewed for this story declared no relevant financial relationships.
A version of this article first appeared on Medscape.com.
BARCELONA – However, running provides greater physical health benefits while adherence is greater with drug treatment.
“Both interventions helped with the depression to around the same extent,” study presenter Brenda W.J.H. Penninx, PhD, professor of psychiatric epidemiology at the VU University Medical Center in Amsterdam said in a release.
However, medication “generally had worse impact on body weight, heart rate variability, and blood pressure, whereas running therapy led to improved effect on general fitness and heart rate,” Dr. Penninx added.
The findings were presented at the annual congress of the European College of Neuropsychopharmacology and recently published in the Journal of Affective Disorders.
Research gap
Previous research suggests exercise interventions can have a therapeutic effect equivalent to antidepressants, but their impact on physical health has been “poorly examined in a psychiatric population, the investigators note.
The authors note that depressive and anxiety disorders “cause immense suffering by compromising both mental and physical health,” and the need for effective treatments is “pressing.”
Although antidepressant medication is considered a “standard first-line treatment” alongside psychotherapy, the drugs are “not effective for all and [are] often associated with side effects.”
The Mood Treatment with Antidepressant or Running (MOTAR) study was a partially randomized pragmatic trial in adults with depression and/or anxiety disorder, as determined using the DSM-IV algorithms with the Composite International Diagnostic Interview (CIDI).
The 16-week intervention study included 141 patients with depression and/or anxiety. The mean age was 38.2 years and 58% were women. Participants were offered a choice of treatment: 16 weeks of treatment with the selective serotonin reuptake inhibitor (SSRI) escitalopram (Lexapro) or a 16-week group-based running therapy.
Patients without a strong preference for treatment allocation were randomly assigned to either antidepressant medication or running therapy, while those unwilling to be randomized were allocated to their preferred intervention.
A total of 22 patients were randomly assigned to receive antidepressant treatment and 13 to running therapy. A total of 36 participants chose antidepressant treatment, while 83 chose the running therapy.
Running therapy involved 16 weeks of supervised 45-minute outdoor running sessions to a target of two to three sessions per week, in line with U.S. Centers for Disease Control and Prevention/American College of Sports Medicine recommendations.
Physical health benefits
Treatment adherence in the antidepressant group, defined as still using treatment at the posttreatment assessment, was 82.2% vs. 52.1% among running therapy participants, where adherence was specified as completing more than 22 sessions.
Remission was defined as no longer meeting the criteria of a current depressive or anxiety disorder via CIDI at week 16.
On intention-to-treat analysis, this requirement was met by 44.8% of patients taking antidepressants and 43.3% of those in the running therapy group (P = .88).
However, running therapy patients showed significant improvements in weight (P = .001), waist circumference (P = .011), systolic and diastolic blood pressure (P = .011 and P = .002, respectively), heart rate (P = .033), and heart rate variability (P = .006).
The investigators note the more favorable physical health changes in the running therapy group were attributable to “larger improvements in the running therapy group but also due to larger deterioration in the antidepressant group.”
Antidepressants are generally safe and effective and work for most people, said Dr. Penninx. She also noted that untreated depression leads to worse outcomes, so “antidepressants are generally a good choice.”
Nevertheless, she said, “we need to extend our treatment arsenal as not all patients respond to antidepressants or are willing to take them.”
The study’s results, she added, suggest that “implementing exercise therapy is something we should take much more seriously, as it could be a good, and maybe even better, choice for some of our patients.”
Francesca Cirulli, PhD, senior researcher and group leader at the National Institute of Health, Rome, said in an interview that the study is notable because it is one of the first to prospectively measure the effects of antidepressants and running on physical health.
Dr. Cirulli suggested that running therapy could be tried ahead of treatment with antidepressants if patients prefer physical exercise and can adhere to it. However, she said, the findings also suggest that an increase in physical activity should accompany treatment with antidepressant medications.
Overall, Dr. Cirulli said “the message should not be that everyone can be helped by running and antidepressants are bad,” but rather “these are both helpful, but not excellent, interventions against depression.”
‘Important limitations’
In a comment, Eduard Vieta, MD, PhD, chair of the department of psychiatry and psychology at the University of Barcelona Hospital Clinic, noted the study has “very important limitations.”
Among the limitations: the inclusion of nonrandomized patients who received the treatment of their choice, causing obvious bias and the “lack of binding and power issues” over the number of patients enrolled.
Dr. Vieta also said that the results “seem obvious, because it is known that exercise improves physical health.”
The trial therefore shows, “if you can find people who are able to do exercise while depressed and adhere to it, those would benefit from that practice,” he noted.
Also commenting on the research, Eric Ruhe, MD, PhD, Radboud University Medical Center, Nijmegen, the Netherlands, said the results are confirmatory and “again show physical health can influence mental health.”
However, Dr. Ruhe underlined, while it is “common practice” to allow patients to follow their treatment preference and is “understandable from a pragmatic point of view,” the group comparison may be “biased,” compared with a “truly randomized study.”
“For example, patients in the antidepressant group were more depressed, which might be associated with less chance of persisting engagement in the exercises,” he said. “So, we have to be careful not to overinterpret the comparisons between groups, which the authors acknowledge properly.”
Turning to the difference in adherence between the two interventions, Dr. Ruhe said the results show adopting, and adhering to, a lifestyle habit is more difficult than taking a pill.
“This is not exclusively found in psychiatry, indicating that we also have to focus on how to improve compliance to healthy behavior. This could have tremendous impact on health care more generally, but also on psychiatric diseases,” Dr. Ruhe said.
The MOTAR study was funded by a NWO-VICI grant. Funding for the inflammatory markers was provided by ZonMw: The Netherlands Organization for Health Research and Development. The study authors and clinicians interviewed for this story declared no relevant financial relationships.
A version of this article first appeared on Medscape.com.
BARCELONA – However, running provides greater physical health benefits while adherence is greater with drug treatment.
“Both interventions helped with the depression to around the same extent,” study presenter Brenda W.J.H. Penninx, PhD, professor of psychiatric epidemiology at the VU University Medical Center in Amsterdam said in a release.
However, medication “generally had worse impact on body weight, heart rate variability, and blood pressure, whereas running therapy led to improved effect on general fitness and heart rate,” Dr. Penninx added.
The findings were presented at the annual congress of the European College of Neuropsychopharmacology and recently published in the Journal of Affective Disorders.
Research gap
Previous research suggests exercise interventions can have a therapeutic effect equivalent to antidepressants, but their impact on physical health has been “poorly examined in a psychiatric population, the investigators note.
The authors note that depressive and anxiety disorders “cause immense suffering by compromising both mental and physical health,” and the need for effective treatments is “pressing.”
Although antidepressant medication is considered a “standard first-line treatment” alongside psychotherapy, the drugs are “not effective for all and [are] often associated with side effects.”
The Mood Treatment with Antidepressant or Running (MOTAR) study was a partially randomized pragmatic trial in adults with depression and/or anxiety disorder, as determined using the DSM-IV algorithms with the Composite International Diagnostic Interview (CIDI).
The 16-week intervention study included 141 patients with depression and/or anxiety. The mean age was 38.2 years and 58% were women. Participants were offered a choice of treatment: 16 weeks of treatment with the selective serotonin reuptake inhibitor (SSRI) escitalopram (Lexapro) or a 16-week group-based running therapy.
Patients without a strong preference for treatment allocation were randomly assigned to either antidepressant medication or running therapy, while those unwilling to be randomized were allocated to their preferred intervention.
A total of 22 patients were randomly assigned to receive antidepressant treatment and 13 to running therapy. A total of 36 participants chose antidepressant treatment, while 83 chose the running therapy.
Running therapy involved 16 weeks of supervised 45-minute outdoor running sessions to a target of two to three sessions per week, in line with U.S. Centers for Disease Control and Prevention/American College of Sports Medicine recommendations.
Physical health benefits
Treatment adherence in the antidepressant group, defined as still using treatment at the posttreatment assessment, was 82.2% vs. 52.1% among running therapy participants, where adherence was specified as completing more than 22 sessions.
Remission was defined as no longer meeting the criteria of a current depressive or anxiety disorder via CIDI at week 16.
On intention-to-treat analysis, this requirement was met by 44.8% of patients taking antidepressants and 43.3% of those in the running therapy group (P = .88).
However, running therapy patients showed significant improvements in weight (P = .001), waist circumference (P = .011), systolic and diastolic blood pressure (P = .011 and P = .002, respectively), heart rate (P = .033), and heart rate variability (P = .006).
The investigators note the more favorable physical health changes in the running therapy group were attributable to “larger improvements in the running therapy group but also due to larger deterioration in the antidepressant group.”
Antidepressants are generally safe and effective and work for most people, said Dr. Penninx. She also noted that untreated depression leads to worse outcomes, so “antidepressants are generally a good choice.”
Nevertheless, she said, “we need to extend our treatment arsenal as not all patients respond to antidepressants or are willing to take them.”
The study’s results, she added, suggest that “implementing exercise therapy is something we should take much more seriously, as it could be a good, and maybe even better, choice for some of our patients.”
Francesca Cirulli, PhD, senior researcher and group leader at the National Institute of Health, Rome, said in an interview that the study is notable because it is one of the first to prospectively measure the effects of antidepressants and running on physical health.
Dr. Cirulli suggested that running therapy could be tried ahead of treatment with antidepressants if patients prefer physical exercise and can adhere to it. However, she said, the findings also suggest that an increase in physical activity should accompany treatment with antidepressant medications.
Overall, Dr. Cirulli said “the message should not be that everyone can be helped by running and antidepressants are bad,” but rather “these are both helpful, but not excellent, interventions against depression.”
‘Important limitations’
In a comment, Eduard Vieta, MD, PhD, chair of the department of psychiatry and psychology at the University of Barcelona Hospital Clinic, noted the study has “very important limitations.”
Among the limitations: the inclusion of nonrandomized patients who received the treatment of their choice, causing obvious bias and the “lack of binding and power issues” over the number of patients enrolled.
Dr. Vieta also said that the results “seem obvious, because it is known that exercise improves physical health.”
The trial therefore shows, “if you can find people who are able to do exercise while depressed and adhere to it, those would benefit from that practice,” he noted.
Also commenting on the research, Eric Ruhe, MD, PhD, Radboud University Medical Center, Nijmegen, the Netherlands, said the results are confirmatory and “again show physical health can influence mental health.”
However, Dr. Ruhe underlined, while it is “common practice” to allow patients to follow their treatment preference and is “understandable from a pragmatic point of view,” the group comparison may be “biased,” compared with a “truly randomized study.”
“For example, patients in the antidepressant group were more depressed, which might be associated with less chance of persisting engagement in the exercises,” he said. “So, we have to be careful not to overinterpret the comparisons between groups, which the authors acknowledge properly.”
Turning to the difference in adherence between the two interventions, Dr. Ruhe said the results show adopting, and adhering to, a lifestyle habit is more difficult than taking a pill.
“This is not exclusively found in psychiatry, indicating that we also have to focus on how to improve compliance to healthy behavior. This could have tremendous impact on health care more generally, but also on psychiatric diseases,” Dr. Ruhe said.
The MOTAR study was funded by a NWO-VICI grant. Funding for the inflammatory markers was provided by ZonMw: The Netherlands Organization for Health Research and Development. The study authors and clinicians interviewed for this story declared no relevant financial relationships.
A version of this article first appeared on Medscape.com.
AT ECNP 2023
Exercise timing may dictate obesity, type 2 diabetes risk
Tongyu Ma, PhD, research assistant professor with the Health Sciences Department, Franklin Pierce University, Rindge, N.H., and colleagues studied data on almost 5,300 individuals, finding a strong association between moderate to vigorous physical activity (MVPA) and obesity.
The research, published in Obesity, showed that people who exercised in the morning had a lower body mass index than that of those who exercised at other times, even though they were more sedentary.
For the second study, Chirag J. Patel, PhD, associate professor of biomedical informatics at Harvard Medical School, Boston, and colleagues examined more than 93,000 individuals and found that morning and afternoon, but not evening, exercise reduced the risk for type 2 diabetes.
However, the results, published in Diabetologia, also indicated that people who undertook at least MVPA were protected against developing type 2 diabetes no matter what time of day they exercised.
Along with considering the timing of exercise, the authors suggest that it is “helpful to include some higher intensity activity to help reduce the risk of developing diabetes and other cardiovascular disease.”
Morning exercisers perform less physical activity
Dr. Ma and colleagues noted that “although a beneficial association among the levels of physical activity with obesity has been frequently reported, the optimal timing of physical activity for decreasing obesity remains controversial.”
The researchers analyzed data from the National Health and Nutrition Examination Survey for the 2003-2004 and 2005-2006 cycles, because accelerometry was implemented in those periods.
They included 5,285 individuals aged ≥ 20 years who had physical activity measured via an accelerometer worn on the right hip during waking hours for 7 consecutive days.
The diurnal pattern of MVPA was classified into three clusters by the established technique of K-means clustering analysis: morning (n = 642), midday (n = 2,456), and evening (n = 2,187).
The association between MVPA, diurnal pattern, and obesity was then assessed in linear regression models taking into account a range of potential confounding factors.
Overall, participants in the morning cluster were older and more likely to be female than those in the other clusters (P < .001 for both). They were also more likely to be nonsmokers (P = .007) and to have less than high school education (P = .0041).
Morning cluster individuals performed less physical activity and were more sedentary than those in the midday and evening groups (P < .001 for both), although they were more likely to be healthy eaters (P = .004), with a lower calorie intake (P < .001).
Individuals in the morning cluster had, on average, a lower body mass index than those in other clusters, at 27.4 vs. 28.4 in the midday cluster and 28.2 in the evening cluster (P for interaction = .02).
Morning cluster participants also had a lower waist circumference than participants in the midday or evening cluster: 95.9 cm, 97.9 cm, and 97.3 cm, respectively (P for interaction = .06).
The team reported that there was a strong linear association between MVPA and obesity in the morning cluster, whereas there was a weaker curvilinear association in the midday and evening clusters.
“This is exciting new research that is consistent with a common tip for meeting exercise goals – that is, schedule exercise in the morning before emails, phone calls, or meetings that might distract you,” Rebecca Krukowski, PhD, professor, public health sciences, University of Virginia, Charlottesville, said in a release.
However, she noted that the cross-sectional nature of the study means that it is “not known whether people who exercise consistently in the morning may be systematically different from those who exercise at other times, in ways that were not measured in this study.
“For example, people who exercise regularly in the morning could have more predictable schedules, such as being less likely to be shift workers or less likely to have caregiving responsibilities that impede morning exercise,” said Dr. Krukowski, who was not involved in the study.
No association between evening activity and type 2 diabetes risk
In the second study, the team studied 93,095 persons in the UK Biobank, with a mean age of 62 years and no history of type 2 diabetes, who wore a wrist accelerometer for 1 week.
The movement data were used to estimate the metabolic equivalent of task, which was then summed into the total physical activity completed in the morning, afternoon, and evening and linked to the development of incident type 2 diabetes.
After adjustment for potential confounding factors, both morning and afternoon physical activity were associated with a reduced risk of developing type 2 diabetes, at hazard ratios of 0.90 (P = 7 × 10-8) and 0.91 (P = 1 × 10-5), respectively.
However, there was no association between evening activity and the risk for type 2 diabetes, at a hazard ratio of 0.95 (P = .07).
The team found, however, that MVPA and vigorous physical activity were associated with a reduced risk for type 2 diabetes at all times of day.
Dr. Patel’s study was supported in part by National Institutes of Health grants. No other funding was declared. No relevant financial relationships were declared.
A version of this article appeared on Medscape.com.
Tongyu Ma, PhD, research assistant professor with the Health Sciences Department, Franklin Pierce University, Rindge, N.H., and colleagues studied data on almost 5,300 individuals, finding a strong association between moderate to vigorous physical activity (MVPA) and obesity.
The research, published in Obesity, showed that people who exercised in the morning had a lower body mass index than that of those who exercised at other times, even though they were more sedentary.
For the second study, Chirag J. Patel, PhD, associate professor of biomedical informatics at Harvard Medical School, Boston, and colleagues examined more than 93,000 individuals and found that morning and afternoon, but not evening, exercise reduced the risk for type 2 diabetes.
However, the results, published in Diabetologia, also indicated that people who undertook at least MVPA were protected against developing type 2 diabetes no matter what time of day they exercised.
Along with considering the timing of exercise, the authors suggest that it is “helpful to include some higher intensity activity to help reduce the risk of developing diabetes and other cardiovascular disease.”
Morning exercisers perform less physical activity
Dr. Ma and colleagues noted that “although a beneficial association among the levels of physical activity with obesity has been frequently reported, the optimal timing of physical activity for decreasing obesity remains controversial.”
The researchers analyzed data from the National Health and Nutrition Examination Survey for the 2003-2004 and 2005-2006 cycles, because accelerometry was implemented in those periods.
They included 5,285 individuals aged ≥ 20 years who had physical activity measured via an accelerometer worn on the right hip during waking hours for 7 consecutive days.
The diurnal pattern of MVPA was classified into three clusters by the established technique of K-means clustering analysis: morning (n = 642), midday (n = 2,456), and evening (n = 2,187).
The association between MVPA, diurnal pattern, and obesity was then assessed in linear regression models taking into account a range of potential confounding factors.
Overall, participants in the morning cluster were older and more likely to be female than those in the other clusters (P < .001 for both). They were also more likely to be nonsmokers (P = .007) and to have less than high school education (P = .0041).
Morning cluster individuals performed less physical activity and were more sedentary than those in the midday and evening groups (P < .001 for both), although they were more likely to be healthy eaters (P = .004), with a lower calorie intake (P < .001).
Individuals in the morning cluster had, on average, a lower body mass index than those in other clusters, at 27.4 vs. 28.4 in the midday cluster and 28.2 in the evening cluster (P for interaction = .02).
Morning cluster participants also had a lower waist circumference than participants in the midday or evening cluster: 95.9 cm, 97.9 cm, and 97.3 cm, respectively (P for interaction = .06).
The team reported that there was a strong linear association between MVPA and obesity in the morning cluster, whereas there was a weaker curvilinear association in the midday and evening clusters.
“This is exciting new research that is consistent with a common tip for meeting exercise goals – that is, schedule exercise in the morning before emails, phone calls, or meetings that might distract you,” Rebecca Krukowski, PhD, professor, public health sciences, University of Virginia, Charlottesville, said in a release.
However, she noted that the cross-sectional nature of the study means that it is “not known whether people who exercise consistently in the morning may be systematically different from those who exercise at other times, in ways that were not measured in this study.
“For example, people who exercise regularly in the morning could have more predictable schedules, such as being less likely to be shift workers or less likely to have caregiving responsibilities that impede morning exercise,” said Dr. Krukowski, who was not involved in the study.
No association between evening activity and type 2 diabetes risk
In the second study, the team studied 93,095 persons in the UK Biobank, with a mean age of 62 years and no history of type 2 diabetes, who wore a wrist accelerometer for 1 week.
The movement data were used to estimate the metabolic equivalent of task, which was then summed into the total physical activity completed in the morning, afternoon, and evening and linked to the development of incident type 2 diabetes.
After adjustment for potential confounding factors, both morning and afternoon physical activity were associated with a reduced risk of developing type 2 diabetes, at hazard ratios of 0.90 (P = 7 × 10-8) and 0.91 (P = 1 × 10-5), respectively.
However, there was no association between evening activity and the risk for type 2 diabetes, at a hazard ratio of 0.95 (P = .07).
The team found, however, that MVPA and vigorous physical activity were associated with a reduced risk for type 2 diabetes at all times of day.
Dr. Patel’s study was supported in part by National Institutes of Health grants. No other funding was declared. No relevant financial relationships were declared.
A version of this article appeared on Medscape.com.
Tongyu Ma, PhD, research assistant professor with the Health Sciences Department, Franklin Pierce University, Rindge, N.H., and colleagues studied data on almost 5,300 individuals, finding a strong association between moderate to vigorous physical activity (MVPA) and obesity.
The research, published in Obesity, showed that people who exercised in the morning had a lower body mass index than that of those who exercised at other times, even though they were more sedentary.
For the second study, Chirag J. Patel, PhD, associate professor of biomedical informatics at Harvard Medical School, Boston, and colleagues examined more than 93,000 individuals and found that morning and afternoon, but not evening, exercise reduced the risk for type 2 diabetes.
However, the results, published in Diabetologia, also indicated that people who undertook at least MVPA were protected against developing type 2 diabetes no matter what time of day they exercised.
Along with considering the timing of exercise, the authors suggest that it is “helpful to include some higher intensity activity to help reduce the risk of developing diabetes and other cardiovascular disease.”
Morning exercisers perform less physical activity
Dr. Ma and colleagues noted that “although a beneficial association among the levels of physical activity with obesity has been frequently reported, the optimal timing of physical activity for decreasing obesity remains controversial.”
The researchers analyzed data from the National Health and Nutrition Examination Survey for the 2003-2004 and 2005-2006 cycles, because accelerometry was implemented in those periods.
They included 5,285 individuals aged ≥ 20 years who had physical activity measured via an accelerometer worn on the right hip during waking hours for 7 consecutive days.
The diurnal pattern of MVPA was classified into three clusters by the established technique of K-means clustering analysis: morning (n = 642), midday (n = 2,456), and evening (n = 2,187).
The association between MVPA, diurnal pattern, and obesity was then assessed in linear regression models taking into account a range of potential confounding factors.
Overall, participants in the morning cluster were older and more likely to be female than those in the other clusters (P < .001 for both). They were also more likely to be nonsmokers (P = .007) and to have less than high school education (P = .0041).
Morning cluster individuals performed less physical activity and were more sedentary than those in the midday and evening groups (P < .001 for both), although they were more likely to be healthy eaters (P = .004), with a lower calorie intake (P < .001).
Individuals in the morning cluster had, on average, a lower body mass index than those in other clusters, at 27.4 vs. 28.4 in the midday cluster and 28.2 in the evening cluster (P for interaction = .02).
Morning cluster participants also had a lower waist circumference than participants in the midday or evening cluster: 95.9 cm, 97.9 cm, and 97.3 cm, respectively (P for interaction = .06).
The team reported that there was a strong linear association between MVPA and obesity in the morning cluster, whereas there was a weaker curvilinear association in the midday and evening clusters.
“This is exciting new research that is consistent with a common tip for meeting exercise goals – that is, schedule exercise in the morning before emails, phone calls, or meetings that might distract you,” Rebecca Krukowski, PhD, professor, public health sciences, University of Virginia, Charlottesville, said in a release.
However, she noted that the cross-sectional nature of the study means that it is “not known whether people who exercise consistently in the morning may be systematically different from those who exercise at other times, in ways that were not measured in this study.
“For example, people who exercise regularly in the morning could have more predictable schedules, such as being less likely to be shift workers or less likely to have caregiving responsibilities that impede morning exercise,” said Dr. Krukowski, who was not involved in the study.
No association between evening activity and type 2 diabetes risk
In the second study, the team studied 93,095 persons in the UK Biobank, with a mean age of 62 years and no history of type 2 diabetes, who wore a wrist accelerometer for 1 week.
The movement data were used to estimate the metabolic equivalent of task, which was then summed into the total physical activity completed in the morning, afternoon, and evening and linked to the development of incident type 2 diabetes.
After adjustment for potential confounding factors, both morning and afternoon physical activity were associated with a reduced risk of developing type 2 diabetes, at hazard ratios of 0.90 (P = 7 × 10-8) and 0.91 (P = 1 × 10-5), respectively.
However, there was no association between evening activity and the risk for type 2 diabetes, at a hazard ratio of 0.95 (P = .07).
The team found, however, that MVPA and vigorous physical activity were associated with a reduced risk for type 2 diabetes at all times of day.
Dr. Patel’s study was supported in part by National Institutes of Health grants. No other funding was declared. No relevant financial relationships were declared.
A version of this article appeared on Medscape.com.
Many patients with NSCLC receive immunotherapy ‘indefinitely’ – Are they benefiting?
Most patients with non–small cell lung cancer (NSCLC) who are long-term responders to immunotherapy will continue receiving treatment beyond 2 years. However, the best available evidence to date indicates that receiving immunotherapy after this 2-year mark likely offers no survival benefit.
Is it an overabundance of caution? A desire for more definitive data? Or is it simply a judgment call oncologists make on the basis of the individual patient?
Lova Sun, MD, MSCE, of the University of Pennsylvania in Philadelphia, believes the general inconsistency between the data and clinical practice “likely reflects significant hesitation on the part of clinicians, patients, or both to stop a treatment that is still ‘working.’ ”
H. Jack West, MD, agreed, adding that “in an ambiguous situation, a U.S.-based population is going to err on the side of overtreatment.”
Without “incontrovertible evidence” that immunotherapy should stop at 2 years, “many, many, many patients and clinicians are going to favor continuing ‘doing what you’re doing’ in the absence of either prohibitive toxicity or clinically significant disease progression,” said Dr. West of the City of Hope Comprehensive Cancer Center, Duarte, Calif.
One factor adding to this ambiguity: Most pivotal studies that examine first-line immunotherapy in NSCLC limit therapy duration to 2 years.
Another key factor is the absence of prospective data as to when to stop treatment for these patients, according to Martin Reck, MD, PhD, head of thoracic oncology at the Lung Clinic Grosshansdorf (Germany).
“We have never prospectively investigated the correlation of the duration of a checkpoint blockade and the efficacy of treatment,” Dr. Reck said. “And this is a big problem.” It means “we really do not know how long we should treat the patient.”
To make matters muddier, some data do suggest that more therapy may be better. The recent Checkmate 153 trial, for instance, found that patients who had no signs of disease progression and who received 1-year fixed-duration nivolumab had significantly shorter progression-free and overall survival than those who received treatment indefinitely.
However, randomized trials with longer-term follow-up suggest durable responses can be maintained for years after immunotherapy is stopped.
Data from the KEYNOTE-024 trial, for instance, showed that more than 45% of patients with metastatic NSCLC and high tumor PD-L1 expression who received pembrolizumab for 2 years remained alive at 5 years without further treatment or disease progression. Another trial, KEYNOTE-407, demonstrated similar 5-year survival outcomes among patients with advanced squamous NSCLC, regardless of PD-L1 status, who completed 2 years of chemotherapy plus pembrolizumab followed by maintenance pembrolizumab.
With these studies, however, “we can only speculate about whether the proportion of patients alive without progression would be substantially higher if treatment with immunotherapy continued longer,” Dr. West wrote in a recent editorial .
Perhaps the most telling data so far come from a recent retrospective analysis from Dr. Sun and colleagues. The researchers directly compared survival outcomes among patients who continued receiving immunotherapy indefinitely with outcomes among patients for whom immunotherapy was discontinued at 2 years.
The JAMA Oncology study, which focused on 706 patients with NSCLC who completed 2 years of therapy, found that only 16% stopped receiving immune checkpoint inhibitor therapy at 2 years, whereas the remaining 84% continued receiving treatment indefinitely.
Among patients who continued receiving immunotherapy for 2 additional years, overall survival was not better than among those who stopped receiving immunotherapy at the 2-year mark. Even among the 11 patients whose condition progressed when therapy was discontinued, most still did well after treatment was resumed.
However, the retrospective design of the study limits its impact.
Without more definitive “data about when the treatment can be stopped,” many continue “indefinitely as long as the patient is tolerating treatment and the disease is not progressing,” Conor E. Steuer, MD, and Suresh S. Ramalingam, MD, of Winship Cancer Institute at Emory University, Atlanta, wrote in a recent review.
Impact on practice?
Dr. Sun views her team’s findings not as a recommendation to halt immunotherapy for every patient at 2 years but rather as “one piece of data that may provide reassurance to providers and patients who wish to stop at 2 years.”
Ultimately, however, the decision as to when or whether to stop immunotherapy for long-term responders is “an individualized one that requires shared decision-making and consideration of each patient’s clinical history, preferences, and risk tolerance,” Dr. Sun explained.
Dr. Reck agreed, noting that until prospective trials evaluate a fixed approach, the duration of immunotherapy “has to be determined by the treating physician and the individual patient.”
For a patient with metastatic NSCLC who is having an excellent response to checkpoint blockade, “we are somewhat afraid to stop the immunotherapy,” explained Dr. Reck, “because we are afraid the disease might relapse.” However, he noted, for patients who have a stable response to therapy, it may make sense to consider discontinuing checkpoint blockade.
Outside of survival outcomes, oncologists should also consider quality of life. Stopping treatment at 2 years comes with a “lower risk of toxic effects, less time in treatment for patients, and considerably lower costs for our health care system,” said Dr. West.
But for a fixed strategy to become more standard practice, the burden of proof is high, Dr. West said.
Jonathan W. Goldman, MD, says he understands the mentality, “If it’s going well, why would I change?”
In his experience, at 2 years of immunotherapy, most patients “say they’re feeling great” and “don’t mind coming in every 4 or 6 weeks, depending on the drug,” said Dr. Goldman, director of clinical trials in thoracic oncology at UCLA Medical Center in Santa Monica, Calif.
Dr. Goldman noted that in the future, instead of continuing immunotherapy indefinitely, clinicians may aim to maintain the patient “in the best response possible,” adding an intervention, such as stereotactic body radiotherapy or radiologic ablation, when needed.
“It may be that many of these long-term disease control patients are not cured in a traditional sense,” Dr. Goldman said, “but have controlled cancer that could potentially last years or even decades with ongoing care.”
Dr. Sun has relationships with Regeneron, GenMab, Seagen, and Bayer and has received institutional funding from Blueprint Research, Seagen Research, and IO Biotech Research. Dr. West has relationships with AstraZeneca, Genentech/Roche, Merck, and Regeneron outside the submitted work. Dr. Reck has relationships with Amgen, AstraZeneca, BMS, Boehringer-Ingelheim, Daiichi-Sankyo, GSK, Lilly, Merck, MSD, Mirati, Novartis, Roche Regeneron, and Pfizer.
A version of this article appeared on Medscape.com.
Most patients with non–small cell lung cancer (NSCLC) who are long-term responders to immunotherapy will continue receiving treatment beyond 2 years. However, the best available evidence to date indicates that receiving immunotherapy after this 2-year mark likely offers no survival benefit.
Is it an overabundance of caution? A desire for more definitive data? Or is it simply a judgment call oncologists make on the basis of the individual patient?
Lova Sun, MD, MSCE, of the University of Pennsylvania in Philadelphia, believes the general inconsistency between the data and clinical practice “likely reflects significant hesitation on the part of clinicians, patients, or both to stop a treatment that is still ‘working.’ ”
H. Jack West, MD, agreed, adding that “in an ambiguous situation, a U.S.-based population is going to err on the side of overtreatment.”
Without “incontrovertible evidence” that immunotherapy should stop at 2 years, “many, many, many patients and clinicians are going to favor continuing ‘doing what you’re doing’ in the absence of either prohibitive toxicity or clinically significant disease progression,” said Dr. West of the City of Hope Comprehensive Cancer Center, Duarte, Calif.
One factor adding to this ambiguity: Most pivotal studies that examine first-line immunotherapy in NSCLC limit therapy duration to 2 years.
Another key factor is the absence of prospective data as to when to stop treatment for these patients, according to Martin Reck, MD, PhD, head of thoracic oncology at the Lung Clinic Grosshansdorf (Germany).
“We have never prospectively investigated the correlation of the duration of a checkpoint blockade and the efficacy of treatment,” Dr. Reck said. “And this is a big problem.” It means “we really do not know how long we should treat the patient.”
To make matters muddier, some data do suggest that more therapy may be better. The recent Checkmate 153 trial, for instance, found that patients who had no signs of disease progression and who received 1-year fixed-duration nivolumab had significantly shorter progression-free and overall survival than those who received treatment indefinitely.
However, randomized trials with longer-term follow-up suggest durable responses can be maintained for years after immunotherapy is stopped.
Data from the KEYNOTE-024 trial, for instance, showed that more than 45% of patients with metastatic NSCLC and high tumor PD-L1 expression who received pembrolizumab for 2 years remained alive at 5 years without further treatment or disease progression. Another trial, KEYNOTE-407, demonstrated similar 5-year survival outcomes among patients with advanced squamous NSCLC, regardless of PD-L1 status, who completed 2 years of chemotherapy plus pembrolizumab followed by maintenance pembrolizumab.
With these studies, however, “we can only speculate about whether the proportion of patients alive without progression would be substantially higher if treatment with immunotherapy continued longer,” Dr. West wrote in a recent editorial .
Perhaps the most telling data so far come from a recent retrospective analysis from Dr. Sun and colleagues. The researchers directly compared survival outcomes among patients who continued receiving immunotherapy indefinitely with outcomes among patients for whom immunotherapy was discontinued at 2 years.
The JAMA Oncology study, which focused on 706 patients with NSCLC who completed 2 years of therapy, found that only 16% stopped receiving immune checkpoint inhibitor therapy at 2 years, whereas the remaining 84% continued receiving treatment indefinitely.
Among patients who continued receiving immunotherapy for 2 additional years, overall survival was not better than among those who stopped receiving immunotherapy at the 2-year mark. Even among the 11 patients whose condition progressed when therapy was discontinued, most still did well after treatment was resumed.
However, the retrospective design of the study limits its impact.
Without more definitive “data about when the treatment can be stopped,” many continue “indefinitely as long as the patient is tolerating treatment and the disease is not progressing,” Conor E. Steuer, MD, and Suresh S. Ramalingam, MD, of Winship Cancer Institute at Emory University, Atlanta, wrote in a recent review.
Impact on practice?
Dr. Sun views her team’s findings not as a recommendation to halt immunotherapy for every patient at 2 years but rather as “one piece of data that may provide reassurance to providers and patients who wish to stop at 2 years.”
Ultimately, however, the decision as to when or whether to stop immunotherapy for long-term responders is “an individualized one that requires shared decision-making and consideration of each patient’s clinical history, preferences, and risk tolerance,” Dr. Sun explained.
Dr. Reck agreed, noting that until prospective trials evaluate a fixed approach, the duration of immunotherapy “has to be determined by the treating physician and the individual patient.”
For a patient with metastatic NSCLC who is having an excellent response to checkpoint blockade, “we are somewhat afraid to stop the immunotherapy,” explained Dr. Reck, “because we are afraid the disease might relapse.” However, he noted, for patients who have a stable response to therapy, it may make sense to consider discontinuing checkpoint blockade.
Outside of survival outcomes, oncologists should also consider quality of life. Stopping treatment at 2 years comes with a “lower risk of toxic effects, less time in treatment for patients, and considerably lower costs for our health care system,” said Dr. West.
But for a fixed strategy to become more standard practice, the burden of proof is high, Dr. West said.
Jonathan W. Goldman, MD, says he understands the mentality, “If it’s going well, why would I change?”
In his experience, at 2 years of immunotherapy, most patients “say they’re feeling great” and “don’t mind coming in every 4 or 6 weeks, depending on the drug,” said Dr. Goldman, director of clinical trials in thoracic oncology at UCLA Medical Center in Santa Monica, Calif.
Dr. Goldman noted that in the future, instead of continuing immunotherapy indefinitely, clinicians may aim to maintain the patient “in the best response possible,” adding an intervention, such as stereotactic body radiotherapy or radiologic ablation, when needed.
“It may be that many of these long-term disease control patients are not cured in a traditional sense,” Dr. Goldman said, “but have controlled cancer that could potentially last years or even decades with ongoing care.”
Dr. Sun has relationships with Regeneron, GenMab, Seagen, and Bayer and has received institutional funding from Blueprint Research, Seagen Research, and IO Biotech Research. Dr. West has relationships with AstraZeneca, Genentech/Roche, Merck, and Regeneron outside the submitted work. Dr. Reck has relationships with Amgen, AstraZeneca, BMS, Boehringer-Ingelheim, Daiichi-Sankyo, GSK, Lilly, Merck, MSD, Mirati, Novartis, Roche Regeneron, and Pfizer.
A version of this article appeared on Medscape.com.
Most patients with non–small cell lung cancer (NSCLC) who are long-term responders to immunotherapy will continue receiving treatment beyond 2 years. However, the best available evidence to date indicates that receiving immunotherapy after this 2-year mark likely offers no survival benefit.
Is it an overabundance of caution? A desire for more definitive data? Or is it simply a judgment call oncologists make on the basis of the individual patient?
Lova Sun, MD, MSCE, of the University of Pennsylvania in Philadelphia, believes the general inconsistency between the data and clinical practice “likely reflects significant hesitation on the part of clinicians, patients, or both to stop a treatment that is still ‘working.’ ”
H. Jack West, MD, agreed, adding that “in an ambiguous situation, a U.S.-based population is going to err on the side of overtreatment.”
Without “incontrovertible evidence” that immunotherapy should stop at 2 years, “many, many, many patients and clinicians are going to favor continuing ‘doing what you’re doing’ in the absence of either prohibitive toxicity or clinically significant disease progression,” said Dr. West of the City of Hope Comprehensive Cancer Center, Duarte, Calif.
One factor adding to this ambiguity: Most pivotal studies that examine first-line immunotherapy in NSCLC limit therapy duration to 2 years.
Another key factor is the absence of prospective data as to when to stop treatment for these patients, according to Martin Reck, MD, PhD, head of thoracic oncology at the Lung Clinic Grosshansdorf (Germany).
“We have never prospectively investigated the correlation of the duration of a checkpoint blockade and the efficacy of treatment,” Dr. Reck said. “And this is a big problem.” It means “we really do not know how long we should treat the patient.”
To make matters muddier, some data do suggest that more therapy may be better. The recent Checkmate 153 trial, for instance, found that patients who had no signs of disease progression and who received 1-year fixed-duration nivolumab had significantly shorter progression-free and overall survival than those who received treatment indefinitely.
However, randomized trials with longer-term follow-up suggest durable responses can be maintained for years after immunotherapy is stopped.
Data from the KEYNOTE-024 trial, for instance, showed that more than 45% of patients with metastatic NSCLC and high tumor PD-L1 expression who received pembrolizumab for 2 years remained alive at 5 years without further treatment or disease progression. Another trial, KEYNOTE-407, demonstrated similar 5-year survival outcomes among patients with advanced squamous NSCLC, regardless of PD-L1 status, who completed 2 years of chemotherapy plus pembrolizumab followed by maintenance pembrolizumab.
With these studies, however, “we can only speculate about whether the proportion of patients alive without progression would be substantially higher if treatment with immunotherapy continued longer,” Dr. West wrote in a recent editorial .
Perhaps the most telling data so far come from a recent retrospective analysis from Dr. Sun and colleagues. The researchers directly compared survival outcomes among patients who continued receiving immunotherapy indefinitely with outcomes among patients for whom immunotherapy was discontinued at 2 years.
The JAMA Oncology study, which focused on 706 patients with NSCLC who completed 2 years of therapy, found that only 16% stopped receiving immune checkpoint inhibitor therapy at 2 years, whereas the remaining 84% continued receiving treatment indefinitely.
Among patients who continued receiving immunotherapy for 2 additional years, overall survival was not better than among those who stopped receiving immunotherapy at the 2-year mark. Even among the 11 patients whose condition progressed when therapy was discontinued, most still did well after treatment was resumed.
However, the retrospective design of the study limits its impact.
Without more definitive “data about when the treatment can be stopped,” many continue “indefinitely as long as the patient is tolerating treatment and the disease is not progressing,” Conor E. Steuer, MD, and Suresh S. Ramalingam, MD, of Winship Cancer Institute at Emory University, Atlanta, wrote in a recent review.
Impact on practice?
Dr. Sun views her team’s findings not as a recommendation to halt immunotherapy for every patient at 2 years but rather as “one piece of data that may provide reassurance to providers and patients who wish to stop at 2 years.”
Ultimately, however, the decision as to when or whether to stop immunotherapy for long-term responders is “an individualized one that requires shared decision-making and consideration of each patient’s clinical history, preferences, and risk tolerance,” Dr. Sun explained.
Dr. Reck agreed, noting that until prospective trials evaluate a fixed approach, the duration of immunotherapy “has to be determined by the treating physician and the individual patient.”
For a patient with metastatic NSCLC who is having an excellent response to checkpoint blockade, “we are somewhat afraid to stop the immunotherapy,” explained Dr. Reck, “because we are afraid the disease might relapse.” However, he noted, for patients who have a stable response to therapy, it may make sense to consider discontinuing checkpoint blockade.
Outside of survival outcomes, oncologists should also consider quality of life. Stopping treatment at 2 years comes with a “lower risk of toxic effects, less time in treatment for patients, and considerably lower costs for our health care system,” said Dr. West.
But for a fixed strategy to become more standard practice, the burden of proof is high, Dr. West said.
Jonathan W. Goldman, MD, says he understands the mentality, “If it’s going well, why would I change?”
In his experience, at 2 years of immunotherapy, most patients “say they’re feeling great” and “don’t mind coming in every 4 or 6 weeks, depending on the drug,” said Dr. Goldman, director of clinical trials in thoracic oncology at UCLA Medical Center in Santa Monica, Calif.
Dr. Goldman noted that in the future, instead of continuing immunotherapy indefinitely, clinicians may aim to maintain the patient “in the best response possible,” adding an intervention, such as stereotactic body radiotherapy or radiologic ablation, when needed.
“It may be that many of these long-term disease control patients are not cured in a traditional sense,” Dr. Goldman said, “but have controlled cancer that could potentially last years or even decades with ongoing care.”
Dr. Sun has relationships with Regeneron, GenMab, Seagen, and Bayer and has received institutional funding from Blueprint Research, Seagen Research, and IO Biotech Research. Dr. West has relationships with AstraZeneca, Genentech/Roche, Merck, and Regeneron outside the submitted work. Dr. Reck has relationships with Amgen, AstraZeneca, BMS, Boehringer-Ingelheim, Daiichi-Sankyo, GSK, Lilly, Merck, MSD, Mirati, Novartis, Roche Regeneron, and Pfizer.
A version of this article appeared on Medscape.com.
Proposed TNM update could shift staging for lung cancers
The updates for the 9th edition of the TNM Classification of Malignant Tumors: Lung Cancer were presented at the annual World Conference on Lung Cancer. The final version will be published Jan. 1, 2024.
The core proposed change, according to Hisao Asamura, MD, chair of the IASLC Staging and Prognostic Factors Committee, is to divide N2 and M1c disease into two subcategories, while leaving the T descriptors unchanged.
This update is based on large survival differences among patients with these tumor characteristics, following an analysis of outcomes in more than 87,000 individuals diagnosed with lung cancer.
Session cochair Ramón Rami-Porta, MD, PhD, explained that previous editions of the classification were based on “pathologic stage, not clinical stage” but ultimately “we could not validate those findings” clinically.
“This is the first time that some sort of very simple quantification” of lung tumors “could be validated at the clinical stage as well,” which means that clinical staging can improve all over the world, said Dr. Rami-Porta, medical oncologist at Hospital Universitari Mútua Terrassa (Spain).
Session cochair Paul Van Schil, MD, PhD, of Antwerp (the Netherlands) University Hospital explained that the proposed changes reflect what clinicians already see in their daily practice.
The latest TNM classification included data submitted on 124,581 patients diagnosed with lung cancer between 2011 and 2019, 56% of whom were from Asia/Australia, 25% from Europe, and 16% from North America.
Overall, 87,339 patients were included in the analysis – 83% with non–small cell lung cancer (NSCLC) and 7% with small cell lung cancer (SCLC). Most (62%) underwent surgery, either alone (47%), alongside chemotherapy (13%), or plus radiotherapy (2%). A minority (13%) received chemotherapy alone, and 13% received all three modalities.
The committee working on the update to the TNM classification had 112 members and comprised 14 subcommittees, which focused on different aspects of diagnosing and assessing the disease.
The committee agreed there should be no changes to the T category in the upcoming 9th Edition.
Evaluating the T category, some members expressed concern that patients with T3 disease embedded in the chest wall have worse survival outcomes than those with other forms of T3 disease. But, Dr. Asamura explained, the pathological versus clinical findings were inconsistent.
On pathological assessment, patients with T3 disease in the chest wall had a worse prognosis but clinical assessment indicated no survival difference. Given the lack of consensus, “we do not recommend any changes” to the current criteria, said Dr. Asamura.
Turning to the N category, Dr. Asamura explained that N2 disease will be divided into two subcategories: N2a, categorized by single N2 station involvement, and N2b, defined as multiple N2 station involvement.
Further analysis indicated that the estimated 5-year survival was significantly worse for patients with N2b disease on clinical assessment (31% vs. 42% with N2a disease; hazard ratio for death, 1.27; P < .0001) and on pathological assessment (HR, 1.46; P < .0001).
The committee also proposed a change to the M category, dividing M1c disease into two subcategories:
- M1c1 – defined as multiple extrathoracic metastases in a single organ system
- M1c2 – defined as multiple extrathoracic metastases in multiple organ systems
This change was driven by estimates of 5-year survival among patients with M1c1 (27%) versus M1c2 disease (19%). Compared with M1b disease, M1c1 was associated with a lower risk for death than M1c2 disease (HR, 1.27 vs. 1.39).
These changes, particularly those for the N category, will have a notable impact on how patients are staged, Dr. Asamura said.
Dividing the N2 category into N2a and N2b disease will push patients with T1, N1 disease from the IIB category (8th edition) to the IIA category (9th edition). The 8th edition categorized all T1, N2 patients as IIIA but the new edition would categorize patients with T1, N2a disease as IIB overall and those with N2b disease as IIIA. And patients with T2, N2a disease will be staged as IIIA — the same category as T2, N2 disease in the 8th edition – while those with N2b disease will be staged as IIIB.
By contrast, the division of M1c into M1c1 and M1c2 disease will not affect a patient’s overall stage, which will be IVB in all cases.
Upal Basu Roy, PhD, MPH, who was not part of the committee, said the TNM classification stage of cancers is “incredibly important in cataloguing the extent of disease” and to “decide the optimal treatment option.”
TNM classification is also “used to describe the burden of disease to be eligible for a clinical trial,” said Dr. Roy, executive director of research, LUNGevity Foundation, Chicago.
The changes in N staging may require sampling more lymph nodes than the current sampling frame of six, Dr. Roy said, adding that “surgeons and pathologists may need to be educated about the need for additional sampling.”
The subcategories for M1c disease will also need to be aligned with definitions of oligometastatic disease. “This is critical,” Dr. Roy said, as this staging may affect treatment choices.
No funding was declared. Dr. Asamura declares relationships with Medtronic, Taiho Pharmaceutical, Johnson & Johnson, Lily, Astellas, and Ono Pharmaceutical. Dr. Roy declared no relevant financial relationships.
A version of this article first appeared on Medscape.com.
The updates for the 9th edition of the TNM Classification of Malignant Tumors: Lung Cancer were presented at the annual World Conference on Lung Cancer. The final version will be published Jan. 1, 2024.
The core proposed change, according to Hisao Asamura, MD, chair of the IASLC Staging and Prognostic Factors Committee, is to divide N2 and M1c disease into two subcategories, while leaving the T descriptors unchanged.
This update is based on large survival differences among patients with these tumor characteristics, following an analysis of outcomes in more than 87,000 individuals diagnosed with lung cancer.
Session cochair Ramón Rami-Porta, MD, PhD, explained that previous editions of the classification were based on “pathologic stage, not clinical stage” but ultimately “we could not validate those findings” clinically.
“This is the first time that some sort of very simple quantification” of lung tumors “could be validated at the clinical stage as well,” which means that clinical staging can improve all over the world, said Dr. Rami-Porta, medical oncologist at Hospital Universitari Mútua Terrassa (Spain).
Session cochair Paul Van Schil, MD, PhD, of Antwerp (the Netherlands) University Hospital explained that the proposed changes reflect what clinicians already see in their daily practice.
The latest TNM classification included data submitted on 124,581 patients diagnosed with lung cancer between 2011 and 2019, 56% of whom were from Asia/Australia, 25% from Europe, and 16% from North America.
Overall, 87,339 patients were included in the analysis – 83% with non–small cell lung cancer (NSCLC) and 7% with small cell lung cancer (SCLC). Most (62%) underwent surgery, either alone (47%), alongside chemotherapy (13%), or plus radiotherapy (2%). A minority (13%) received chemotherapy alone, and 13% received all three modalities.
The committee working on the update to the TNM classification had 112 members and comprised 14 subcommittees, which focused on different aspects of diagnosing and assessing the disease.
The committee agreed there should be no changes to the T category in the upcoming 9th Edition.
Evaluating the T category, some members expressed concern that patients with T3 disease embedded in the chest wall have worse survival outcomes than those with other forms of T3 disease. But, Dr. Asamura explained, the pathological versus clinical findings were inconsistent.
On pathological assessment, patients with T3 disease in the chest wall had a worse prognosis but clinical assessment indicated no survival difference. Given the lack of consensus, “we do not recommend any changes” to the current criteria, said Dr. Asamura.
Turning to the N category, Dr. Asamura explained that N2 disease will be divided into two subcategories: N2a, categorized by single N2 station involvement, and N2b, defined as multiple N2 station involvement.
Further analysis indicated that the estimated 5-year survival was significantly worse for patients with N2b disease on clinical assessment (31% vs. 42% with N2a disease; hazard ratio for death, 1.27; P < .0001) and on pathological assessment (HR, 1.46; P < .0001).
The committee also proposed a change to the M category, dividing M1c disease into two subcategories:
- M1c1 – defined as multiple extrathoracic metastases in a single organ system
- M1c2 – defined as multiple extrathoracic metastases in multiple organ systems
This change was driven by estimates of 5-year survival among patients with M1c1 (27%) versus M1c2 disease (19%). Compared with M1b disease, M1c1 was associated with a lower risk for death than M1c2 disease (HR, 1.27 vs. 1.39).
These changes, particularly those for the N category, will have a notable impact on how patients are staged, Dr. Asamura said.
Dividing the N2 category into N2a and N2b disease will push patients with T1, N1 disease from the IIB category (8th edition) to the IIA category (9th edition). The 8th edition categorized all T1, N2 patients as IIIA but the new edition would categorize patients with T1, N2a disease as IIB overall and those with N2b disease as IIIA. And patients with T2, N2a disease will be staged as IIIA — the same category as T2, N2 disease in the 8th edition – while those with N2b disease will be staged as IIIB.
By contrast, the division of M1c into M1c1 and M1c2 disease will not affect a patient’s overall stage, which will be IVB in all cases.
Upal Basu Roy, PhD, MPH, who was not part of the committee, said the TNM classification stage of cancers is “incredibly important in cataloguing the extent of disease” and to “decide the optimal treatment option.”
TNM classification is also “used to describe the burden of disease to be eligible for a clinical trial,” said Dr. Roy, executive director of research, LUNGevity Foundation, Chicago.
The changes in N staging may require sampling more lymph nodes than the current sampling frame of six, Dr. Roy said, adding that “surgeons and pathologists may need to be educated about the need for additional sampling.”
The subcategories for M1c disease will also need to be aligned with definitions of oligometastatic disease. “This is critical,” Dr. Roy said, as this staging may affect treatment choices.
No funding was declared. Dr. Asamura declares relationships with Medtronic, Taiho Pharmaceutical, Johnson & Johnson, Lily, Astellas, and Ono Pharmaceutical. Dr. Roy declared no relevant financial relationships.
A version of this article first appeared on Medscape.com.
The updates for the 9th edition of the TNM Classification of Malignant Tumors: Lung Cancer were presented at the annual World Conference on Lung Cancer. The final version will be published Jan. 1, 2024.
The core proposed change, according to Hisao Asamura, MD, chair of the IASLC Staging and Prognostic Factors Committee, is to divide N2 and M1c disease into two subcategories, while leaving the T descriptors unchanged.
This update is based on large survival differences among patients with these tumor characteristics, following an analysis of outcomes in more than 87,000 individuals diagnosed with lung cancer.
Session cochair Ramón Rami-Porta, MD, PhD, explained that previous editions of the classification were based on “pathologic stage, not clinical stage” but ultimately “we could not validate those findings” clinically.
“This is the first time that some sort of very simple quantification” of lung tumors “could be validated at the clinical stage as well,” which means that clinical staging can improve all over the world, said Dr. Rami-Porta, medical oncologist at Hospital Universitari Mútua Terrassa (Spain).
Session cochair Paul Van Schil, MD, PhD, of Antwerp (the Netherlands) University Hospital explained that the proposed changes reflect what clinicians already see in their daily practice.
The latest TNM classification included data submitted on 124,581 patients diagnosed with lung cancer between 2011 and 2019, 56% of whom were from Asia/Australia, 25% from Europe, and 16% from North America.
Overall, 87,339 patients were included in the analysis – 83% with non–small cell lung cancer (NSCLC) and 7% with small cell lung cancer (SCLC). Most (62%) underwent surgery, either alone (47%), alongside chemotherapy (13%), or plus radiotherapy (2%). A minority (13%) received chemotherapy alone, and 13% received all three modalities.
The committee working on the update to the TNM classification had 112 members and comprised 14 subcommittees, which focused on different aspects of diagnosing and assessing the disease.
The committee agreed there should be no changes to the T category in the upcoming 9th Edition.
Evaluating the T category, some members expressed concern that patients with T3 disease embedded in the chest wall have worse survival outcomes than those with other forms of T3 disease. But, Dr. Asamura explained, the pathological versus clinical findings were inconsistent.
On pathological assessment, patients with T3 disease in the chest wall had a worse prognosis but clinical assessment indicated no survival difference. Given the lack of consensus, “we do not recommend any changes” to the current criteria, said Dr. Asamura.
Turning to the N category, Dr. Asamura explained that N2 disease will be divided into two subcategories: N2a, categorized by single N2 station involvement, and N2b, defined as multiple N2 station involvement.
Further analysis indicated that the estimated 5-year survival was significantly worse for patients with N2b disease on clinical assessment (31% vs. 42% with N2a disease; hazard ratio for death, 1.27; P < .0001) and on pathological assessment (HR, 1.46; P < .0001).
The committee also proposed a change to the M category, dividing M1c disease into two subcategories:
- M1c1 – defined as multiple extrathoracic metastases in a single organ system
- M1c2 – defined as multiple extrathoracic metastases in multiple organ systems
This change was driven by estimates of 5-year survival among patients with M1c1 (27%) versus M1c2 disease (19%). Compared with M1b disease, M1c1 was associated with a lower risk for death than M1c2 disease (HR, 1.27 vs. 1.39).
These changes, particularly those for the N category, will have a notable impact on how patients are staged, Dr. Asamura said.
Dividing the N2 category into N2a and N2b disease will push patients with T1, N1 disease from the IIB category (8th edition) to the IIA category (9th edition). The 8th edition categorized all T1, N2 patients as IIIA but the new edition would categorize patients with T1, N2a disease as IIB overall and those with N2b disease as IIIA. And patients with T2, N2a disease will be staged as IIIA — the same category as T2, N2 disease in the 8th edition – while those with N2b disease will be staged as IIIB.
By contrast, the division of M1c into M1c1 and M1c2 disease will not affect a patient’s overall stage, which will be IVB in all cases.
Upal Basu Roy, PhD, MPH, who was not part of the committee, said the TNM classification stage of cancers is “incredibly important in cataloguing the extent of disease” and to “decide the optimal treatment option.”
TNM classification is also “used to describe the burden of disease to be eligible for a clinical trial,” said Dr. Roy, executive director of research, LUNGevity Foundation, Chicago.
The changes in N staging may require sampling more lymph nodes than the current sampling frame of six, Dr. Roy said, adding that “surgeons and pathologists may need to be educated about the need for additional sampling.”
The subcategories for M1c disease will also need to be aligned with definitions of oligometastatic disease. “This is critical,” Dr. Roy said, as this staging may affect treatment choices.
No funding was declared. Dr. Asamura declares relationships with Medtronic, Taiho Pharmaceutical, Johnson & Johnson, Lily, Astellas, and Ono Pharmaceutical. Dr. Roy declared no relevant financial relationships.
A version of this article first appeared on Medscape.com.
FROM WCLC 2023
Osimertinib plus chemo ups PFS, toxicity in first line
(PFS), according to interim results from the FLAURA2 trial.
Combining the third-generation tyrosine kinase inhibitor (TKI) with platinum-based chemotherapy achieved “statistically significant and clinically meaningful improvement in PFS over osimertinib monotherapy,” said Pasi A. Jänne, MD, PhD, professor of medicine at Harvard Medical School and director of the Lowe Center for Thoracic Oncology, Dana-Farber Cancer Institute, both in Boston, who presented the interim findings at the annual World Conference on Lung Cancer.
However, experts raised some questions about whether the combination would also offer improved overall survival and whether the accompanying toxicity would be acceptable to patients.
Yi-Long Wu, MD, PhD, who was not involved in the research, said that although the combination regimen does appear to offer a benefit, it may come at a steep cost.
Patients who received the combination had an almost fourfold greater risk of grade 3 or higher adverse events related to treatment, said Dr. Wu, professor of oncology, Guangdong Lung Cancer Institute, Guangdong Provincial People’s Hospital, Guangzhou, China.
And, notably, because the overall survival data in the interim analysis are immature, it’s unclear whether the combination will offer an overall survival benefit over osimertinib monotherapy, Dr. Wu said.
The 2019 FLAURA trial, which compared TKI monotherapy, demonstrated an overall survival advantage among patients who received osimertinib vs. a first-generation EGFR TKI, such as gefitinib (Iressa) or erlotinib (Tarceva). These data established the third-generation TKI as the preferred first-line treatment for patients with advanced EGFR NSCLC.
But resistance to EGFR TKIs remains a problem, which has led experts to explore combination strategies that might overcome resistance and improve clinical outcomes. Recent data indicate that combining first-generation EGFR TKIs with chemotherapy may have an additive effect and further improve outcomes with the drugs. And a recent study of untreated EGFR-mutated advanced NSCLC found patients receiving osimertinib plus platinum-pemetrexed demonstrated a promising objective response rate; however, Dr. Jänne noted that the combination has not been tested in a randomized trial.
To better understand the potential additive benefit of osimertinib and chemotherapy, the team conduced a global, open-label study in patients with pathologically confirmed nonsquamous NSCLC who had received no prior systemic therapy for advanced NSCLC and had a performance status of 0 or 1.
The team randomly assigned 557 patients to daily osimertinib alone or osimertinib plus chemotherapy with pemetrexed and carboplatin or cisplatin every 3 weeks for four cycles, followed by maintenance osimertinib plus pemetrexed every 3 weeks.
Treatment was continued until radiological disease progression, as defined using the RECIST 1.1 criteria, or other withdrawal criteria were met. The patients were assessed at weeks 6 and 12, and again every 12 weeks.
The median age of the patients was about 61 years, approximately 61% were female, and about 25% were Asian. Around two-thirds were never-smokers, about 60% had either Ex19del or L858R EGFR mutations, and about 40% had central nervous system metastases.
At the data cutoff, the median follow-up was 16.5 months in the osimertinib monotherapy arm and 19.5 months in the combination arm. Overall, 45% of patients on monotherapy and 56% in the combination arm were still on treatment.
Dr. Jänne reported that osimertinib plus chemotherapy was associated with a greater objective response rate than monotherapy – 83.2% vs. 75.5% – and a longer median duration of response – 24 months vs. 15.3 months.
Patients receiving the combination showed significant improvements in PFS – 25.5 months vs. 16.7 months (hazard ratio, 0.62; P < .0001). At 24 months, 57% of the patients in the combination arm were disease-free vs. 41% in the monotherapy group.
The benefit held across all patient subgroups, including age, sex, smoking history, and EGFR mutation type at baseline.
The PFS benefit appeared most pronounced among patients with CNS metastases at baseline – a median of 24.9 months in the combination arm vs. 13.8 months with monotherapy (HR, 0.47). But patients without CNS metastases who received the combination therapy also showed improvements in PFS (HR, 0.75).
Should there be an overall survival improvement, then the regimen used in FLAURA2 could become the “new standard of care in EGFR-mutated NSCLC in the first-line setting,” particularly in patients with CNS metastases and/or an exon21 mutation, Dr. Wu said. If, however, further analysis indicates no overall survival benefit, then patients will have experienced chemotherapy side effects earlier and longer than those receiving monotherapy, with no life gain.
Dr. Wu pointed out that the future role and sequence of the combination will also hinge on understanding how patients become resistant to it as well as whether the toxicity is manageable.
The FLAURA2 safety data indicated that the combination led to higher rates of grade 3 or higher adverse events overall – 64% vs. 27% – and higher rates of grade 3 or higher adverse events possibly related to treatment – 53% vs. 11%.
Experts who commented on the study findings via X (formerly Twitter) echoed Dr. Wu’s sentiments about the study findings and implications.
Mohana Roy, MD, said she did not find the results surprising, given that “many of us are adding chemo on slow progression on osimertinib already,” but noted that “questions of sequencing” remain.
Christian Rolfo, MD, PhD, MBA, commented that questions about the “real benefit” of osimertinib plus chemotherapy in subgroups and degree of resistance remain. Further toxicity and overall survival data “will clarify the future of the combination,” said Dr. Rolfo, of Icahn School of Medicine at Mount Sinai, New York.
The study was funded by AstraZeneca. Dr. Jänne declared relationships with Gatekeeper Pharmaceuticals, Labcorp, Astellas Pharmaceuticals, AstraZeneca, Boehringer Ingelheim, Daiichi Sankyo, Eli Lilly, PUMA, Revolution Medicines, Takeda Oncology, Biocartis, Mirati Therapeutics, Transcenta, ACEA Biosciences, Araxes, Bayer, Chugai Pharmaceuticals, Eisai, Ignyta, Novartis, Nuvalent, Pfizer, Roche/Genentech, Sanofi, SFJ Pharmaceuticals, Silicon Therapeutics, Syndax, and Voronoi.
A version of this article first appeared on Medscape.com.
(PFS), according to interim results from the FLAURA2 trial.
Combining the third-generation tyrosine kinase inhibitor (TKI) with platinum-based chemotherapy achieved “statistically significant and clinically meaningful improvement in PFS over osimertinib monotherapy,” said Pasi A. Jänne, MD, PhD, professor of medicine at Harvard Medical School and director of the Lowe Center for Thoracic Oncology, Dana-Farber Cancer Institute, both in Boston, who presented the interim findings at the annual World Conference on Lung Cancer.
However, experts raised some questions about whether the combination would also offer improved overall survival and whether the accompanying toxicity would be acceptable to patients.
Yi-Long Wu, MD, PhD, who was not involved in the research, said that although the combination regimen does appear to offer a benefit, it may come at a steep cost.
Patients who received the combination had an almost fourfold greater risk of grade 3 or higher adverse events related to treatment, said Dr. Wu, professor of oncology, Guangdong Lung Cancer Institute, Guangdong Provincial People’s Hospital, Guangzhou, China.
And, notably, because the overall survival data in the interim analysis are immature, it’s unclear whether the combination will offer an overall survival benefit over osimertinib monotherapy, Dr. Wu said.
The 2019 FLAURA trial, which compared TKI monotherapy, demonstrated an overall survival advantage among patients who received osimertinib vs. a first-generation EGFR TKI, such as gefitinib (Iressa) or erlotinib (Tarceva). These data established the third-generation TKI as the preferred first-line treatment for patients with advanced EGFR NSCLC.
But resistance to EGFR TKIs remains a problem, which has led experts to explore combination strategies that might overcome resistance and improve clinical outcomes. Recent data indicate that combining first-generation EGFR TKIs with chemotherapy may have an additive effect and further improve outcomes with the drugs. And a recent study of untreated EGFR-mutated advanced NSCLC found patients receiving osimertinib plus platinum-pemetrexed demonstrated a promising objective response rate; however, Dr. Jänne noted that the combination has not been tested in a randomized trial.
To better understand the potential additive benefit of osimertinib and chemotherapy, the team conduced a global, open-label study in patients with pathologically confirmed nonsquamous NSCLC who had received no prior systemic therapy for advanced NSCLC and had a performance status of 0 or 1.
The team randomly assigned 557 patients to daily osimertinib alone or osimertinib plus chemotherapy with pemetrexed and carboplatin or cisplatin every 3 weeks for four cycles, followed by maintenance osimertinib plus pemetrexed every 3 weeks.
Treatment was continued until radiological disease progression, as defined using the RECIST 1.1 criteria, or other withdrawal criteria were met. The patients were assessed at weeks 6 and 12, and again every 12 weeks.
The median age of the patients was about 61 years, approximately 61% were female, and about 25% were Asian. Around two-thirds were never-smokers, about 60% had either Ex19del or L858R EGFR mutations, and about 40% had central nervous system metastases.
At the data cutoff, the median follow-up was 16.5 months in the osimertinib monotherapy arm and 19.5 months in the combination arm. Overall, 45% of patients on monotherapy and 56% in the combination arm were still on treatment.
Dr. Jänne reported that osimertinib plus chemotherapy was associated with a greater objective response rate than monotherapy – 83.2% vs. 75.5% – and a longer median duration of response – 24 months vs. 15.3 months.
Patients receiving the combination showed significant improvements in PFS – 25.5 months vs. 16.7 months (hazard ratio, 0.62; P < .0001). At 24 months, 57% of the patients in the combination arm were disease-free vs. 41% in the monotherapy group.
The benefit held across all patient subgroups, including age, sex, smoking history, and EGFR mutation type at baseline.
The PFS benefit appeared most pronounced among patients with CNS metastases at baseline – a median of 24.9 months in the combination arm vs. 13.8 months with monotherapy (HR, 0.47). But patients without CNS metastases who received the combination therapy also showed improvements in PFS (HR, 0.75).
Should there be an overall survival improvement, then the regimen used in FLAURA2 could become the “new standard of care in EGFR-mutated NSCLC in the first-line setting,” particularly in patients with CNS metastases and/or an exon21 mutation, Dr. Wu said. If, however, further analysis indicates no overall survival benefit, then patients will have experienced chemotherapy side effects earlier and longer than those receiving monotherapy, with no life gain.
Dr. Wu pointed out that the future role and sequence of the combination will also hinge on understanding how patients become resistant to it as well as whether the toxicity is manageable.
The FLAURA2 safety data indicated that the combination led to higher rates of grade 3 or higher adverse events overall – 64% vs. 27% – and higher rates of grade 3 or higher adverse events possibly related to treatment – 53% vs. 11%.
Experts who commented on the study findings via X (formerly Twitter) echoed Dr. Wu’s sentiments about the study findings and implications.
Mohana Roy, MD, said she did not find the results surprising, given that “many of us are adding chemo on slow progression on osimertinib already,” but noted that “questions of sequencing” remain.
Christian Rolfo, MD, PhD, MBA, commented that questions about the “real benefit” of osimertinib plus chemotherapy in subgroups and degree of resistance remain. Further toxicity and overall survival data “will clarify the future of the combination,” said Dr. Rolfo, of Icahn School of Medicine at Mount Sinai, New York.
The study was funded by AstraZeneca. Dr. Jänne declared relationships with Gatekeeper Pharmaceuticals, Labcorp, Astellas Pharmaceuticals, AstraZeneca, Boehringer Ingelheim, Daiichi Sankyo, Eli Lilly, PUMA, Revolution Medicines, Takeda Oncology, Biocartis, Mirati Therapeutics, Transcenta, ACEA Biosciences, Araxes, Bayer, Chugai Pharmaceuticals, Eisai, Ignyta, Novartis, Nuvalent, Pfizer, Roche/Genentech, Sanofi, SFJ Pharmaceuticals, Silicon Therapeutics, Syndax, and Voronoi.
A version of this article first appeared on Medscape.com.
(PFS), according to interim results from the FLAURA2 trial.
Combining the third-generation tyrosine kinase inhibitor (TKI) with platinum-based chemotherapy achieved “statistically significant and clinically meaningful improvement in PFS over osimertinib monotherapy,” said Pasi A. Jänne, MD, PhD, professor of medicine at Harvard Medical School and director of the Lowe Center for Thoracic Oncology, Dana-Farber Cancer Institute, both in Boston, who presented the interim findings at the annual World Conference on Lung Cancer.
However, experts raised some questions about whether the combination would also offer improved overall survival and whether the accompanying toxicity would be acceptable to patients.
Yi-Long Wu, MD, PhD, who was not involved in the research, said that although the combination regimen does appear to offer a benefit, it may come at a steep cost.
Patients who received the combination had an almost fourfold greater risk of grade 3 or higher adverse events related to treatment, said Dr. Wu, professor of oncology, Guangdong Lung Cancer Institute, Guangdong Provincial People’s Hospital, Guangzhou, China.
And, notably, because the overall survival data in the interim analysis are immature, it’s unclear whether the combination will offer an overall survival benefit over osimertinib monotherapy, Dr. Wu said.
The 2019 FLAURA trial, which compared TKI monotherapy, demonstrated an overall survival advantage among patients who received osimertinib vs. a first-generation EGFR TKI, such as gefitinib (Iressa) or erlotinib (Tarceva). These data established the third-generation TKI as the preferred first-line treatment for patients with advanced EGFR NSCLC.
But resistance to EGFR TKIs remains a problem, which has led experts to explore combination strategies that might overcome resistance and improve clinical outcomes. Recent data indicate that combining first-generation EGFR TKIs with chemotherapy may have an additive effect and further improve outcomes with the drugs. And a recent study of untreated EGFR-mutated advanced NSCLC found patients receiving osimertinib plus platinum-pemetrexed demonstrated a promising objective response rate; however, Dr. Jänne noted that the combination has not been tested in a randomized trial.
To better understand the potential additive benefit of osimertinib and chemotherapy, the team conduced a global, open-label study in patients with pathologically confirmed nonsquamous NSCLC who had received no prior systemic therapy for advanced NSCLC and had a performance status of 0 or 1.
The team randomly assigned 557 patients to daily osimertinib alone or osimertinib plus chemotherapy with pemetrexed and carboplatin or cisplatin every 3 weeks for four cycles, followed by maintenance osimertinib plus pemetrexed every 3 weeks.
Treatment was continued until radiological disease progression, as defined using the RECIST 1.1 criteria, or other withdrawal criteria were met. The patients were assessed at weeks 6 and 12, and again every 12 weeks.
The median age of the patients was about 61 years, approximately 61% were female, and about 25% were Asian. Around two-thirds were never-smokers, about 60% had either Ex19del or L858R EGFR mutations, and about 40% had central nervous system metastases.
At the data cutoff, the median follow-up was 16.5 months in the osimertinib monotherapy arm and 19.5 months in the combination arm. Overall, 45% of patients on monotherapy and 56% in the combination arm were still on treatment.
Dr. Jänne reported that osimertinib plus chemotherapy was associated with a greater objective response rate than monotherapy – 83.2% vs. 75.5% – and a longer median duration of response – 24 months vs. 15.3 months.
Patients receiving the combination showed significant improvements in PFS – 25.5 months vs. 16.7 months (hazard ratio, 0.62; P < .0001). At 24 months, 57% of the patients in the combination arm were disease-free vs. 41% in the monotherapy group.
The benefit held across all patient subgroups, including age, sex, smoking history, and EGFR mutation type at baseline.
The PFS benefit appeared most pronounced among patients with CNS metastases at baseline – a median of 24.9 months in the combination arm vs. 13.8 months with monotherapy (HR, 0.47). But patients without CNS metastases who received the combination therapy also showed improvements in PFS (HR, 0.75).
Should there be an overall survival improvement, then the regimen used in FLAURA2 could become the “new standard of care in EGFR-mutated NSCLC in the first-line setting,” particularly in patients with CNS metastases and/or an exon21 mutation, Dr. Wu said. If, however, further analysis indicates no overall survival benefit, then patients will have experienced chemotherapy side effects earlier and longer than those receiving monotherapy, with no life gain.
Dr. Wu pointed out that the future role and sequence of the combination will also hinge on understanding how patients become resistant to it as well as whether the toxicity is manageable.
The FLAURA2 safety data indicated that the combination led to higher rates of grade 3 or higher adverse events overall – 64% vs. 27% – and higher rates of grade 3 or higher adverse events possibly related to treatment – 53% vs. 11%.
Experts who commented on the study findings via X (formerly Twitter) echoed Dr. Wu’s sentiments about the study findings and implications.
Mohana Roy, MD, said she did not find the results surprising, given that “many of us are adding chemo on slow progression on osimertinib already,” but noted that “questions of sequencing” remain.
Christian Rolfo, MD, PhD, MBA, commented that questions about the “real benefit” of osimertinib plus chemotherapy in subgroups and degree of resistance remain. Further toxicity and overall survival data “will clarify the future of the combination,” said Dr. Rolfo, of Icahn School of Medicine at Mount Sinai, New York.
The study was funded by AstraZeneca. Dr. Jänne declared relationships with Gatekeeper Pharmaceuticals, Labcorp, Astellas Pharmaceuticals, AstraZeneca, Boehringer Ingelheim, Daiichi Sankyo, Eli Lilly, PUMA, Revolution Medicines, Takeda Oncology, Biocartis, Mirati Therapeutics, Transcenta, ACEA Biosciences, Araxes, Bayer, Chugai Pharmaceuticals, Eisai, Ignyta, Novartis, Nuvalent, Pfizer, Roche/Genentech, Sanofi, SFJ Pharmaceuticals, Silicon Therapeutics, Syndax, and Voronoi.
A version of this article first appeared on Medscape.com.
FROM WCLC 2023
Novel ADC offers hope in heavily pretreated NSCLC
SINGAPORE – Heavily pretreated patients with EGFR-mutated non–small cell lung cancer (NSCLC) may experience a clinically meaningful benefit with the antibody-drug conjugate (ADC) patritumab deruxtecan (HER3-DXd), new phase 2 trial results suggest.
In the trial, almost 30% of patients receiving HER3-DXd achieved an objective response, and patients’ median overall survival approached 1 year.
HER3-DXd has “emerged as a promising therapy” in this patient population, “for whom available treatment options provide only limited efficacy,” concluded lead study author Helena A. Yu, MD, from Memorial Sloan Kettering Cancer Center, New York City, who presented findings from the HERTHENA-Lung01 trial at the 2023 World Conference on Lung Cancer.
The results were simultaneously published in the Journal of Clinical Oncology.
Acquired resistance to therapy among heavily pretreated patients with EGFR-mutated NSCLC is “universal,” Dr. Yu explained. The mechanisms of resistance to first-line osimertinib are also “diverse” and hard to identify. Salvage therapies after failed EGFR tyrosine kinase inhibitor (TKI) therapy and platinum-based chemotherapy offer “only a limited and transient and clinical benefit,” she said.
And with limited treatment options available to patients resistant to TKIs, there is a “high unmet medical need” for new therapies, said Helena Linardou, MD, PhD, who was not involved in the study.
HER3-DXd consists of a fully human anti-HER3 immunoglobulin G1 monoclonal antibody (patritumab) attached to a topoisomerase I inhibitor payload (DXd) via a tetrapeptide-based cleavable linker.
HER3, Dr. Linardou explained, is a “biologically and clinically important target” in NSCLC. It is highly expressed in NSCLC, upregulated in TKI-resistant EGFR-mutated NSCLC, and is associated with a poor prognosis.
After promising phase 1 data, Dr. Yu and colleagues conducted a phase 2 trial in patients with advanced EGFR-mutated NSCLC who had progressed on systematic therapy and had received EGFR TKI and platinum-based chemotherapy. Patients could have active or previously treated asymptomatic brain metastases.
Patients were initially randomized either to a fixed-dose arm of HER3-DXd 5.6 mg/kg once every 3 weeks or an uptitration arm with doses escalating from 3.2 mg/kg to 4.8 mg/kg to 6.4 mg/kg over three cycles. However, Dr. Yu noted, enrollment in the uptitration arm closed early based on a “benefit-risk assessment.”
The current findings focus on the 225 patients in the fixed-dose arm.
About half of patients had a history of central nervous system metastasis, and patients had a median of three prior lines of systemic therapy. Most patients (92.9%) had previously received a third-generation EGFR TKI, about 40% had received immunotherapy, and all had received platinum-based chemotherapy.
After a median follow-up of 18.9 months, the confirmed objective response rate with HER3-DXd across the whole patient population was 29.8%. The median duration of response was 6.4 months, median progression-free survival was 5.5 months, and median overall survival was 11.9 months.
The results were virtually identical when looking only at patients who had received a third-generation EGFR TKI versus any EGFR TKI. Response rates were also similar regardless of the driver of EGFR TKI resistance.
Among the 30 patients with measurable brain metastases at baseline, 33.3% had a confirmed objective response to therapy. In this group, the disease control rate was 76.7% and the intracranial duration of response was 8.4 months.
To identify biomarkers of response to HER3-DXd, the team stratified the patients by baseline tumor HER3 membrane H-scores. Dr. Yu and colleagues found no differences in the likelihood of having a complete or partial response, stable disease, or progressive disease based on HER3 expression at study entry.
Looking at the safety of the ADC, only 7.1% of patients experienced a treatment-emergent adverse event associated with treatment discontinuation, but close to half of patients (45.3%) experienced a grade 3 or higher treatment-emergent adverse event. Interstitial lung disease, for instance, occurred in 5.3% of patients, including one patient who died.
The safety profile of HER3-DXd in this population appeared to be consistent with previous reports, Dr. Yu noted.
Overall, the findings suggest that “HER3-DXd provided clinically meaningful and durable efficacy” in patients with advanced EGFR-mutant NSCLC that has progressed after EGFR TKI and platinum-based chemotherapy, Dr. Yu said.
“Efficacy was observed across diverse mechanisms of resistance and across a broad range of pretreatment tumor HER3 expression” and the ADC demonstrated “clinically meaningful intracranial antitumor activity,” she added.
Dr. Linardou agreed that the current results suggest that HER3-DXd was associated with a “meaningful and durable efficacy,” including in patients with intracranial metastases, and she pointed to its “easy dosing schedule” and activity across patient subgroups.
However, she noted that, despite the researchers’ best efforts with the data available, “we don’t have a biomarker of activity,” which is a “general issue with ADCs.”
Still, Dr. Linardou said, “HER3 is now a clinically actionable therapeutic target, and this is a great bonus.”
The study was sponsored by Daiichi Sankyo. Dr. Yu declared relationships with AstraZeneca, Daiichi Sankyo, Blueprint Medicines, Janssen, C4 Therapeutics, Cullinan Oncology, Black Diamond Therapeutics, Taiho Oncology, and others. Other authors declare numerous relationships.
A version of this article first appeared on Medscape.com.
SINGAPORE – Heavily pretreated patients with EGFR-mutated non–small cell lung cancer (NSCLC) may experience a clinically meaningful benefit with the antibody-drug conjugate (ADC) patritumab deruxtecan (HER3-DXd), new phase 2 trial results suggest.
In the trial, almost 30% of patients receiving HER3-DXd achieved an objective response, and patients’ median overall survival approached 1 year.
HER3-DXd has “emerged as a promising therapy” in this patient population, “for whom available treatment options provide only limited efficacy,” concluded lead study author Helena A. Yu, MD, from Memorial Sloan Kettering Cancer Center, New York City, who presented findings from the HERTHENA-Lung01 trial at the 2023 World Conference on Lung Cancer.
The results were simultaneously published in the Journal of Clinical Oncology.
Acquired resistance to therapy among heavily pretreated patients with EGFR-mutated NSCLC is “universal,” Dr. Yu explained. The mechanisms of resistance to first-line osimertinib are also “diverse” and hard to identify. Salvage therapies after failed EGFR tyrosine kinase inhibitor (TKI) therapy and platinum-based chemotherapy offer “only a limited and transient and clinical benefit,” she said.
And with limited treatment options available to patients resistant to TKIs, there is a “high unmet medical need” for new therapies, said Helena Linardou, MD, PhD, who was not involved in the study.
HER3-DXd consists of a fully human anti-HER3 immunoglobulin G1 monoclonal antibody (patritumab) attached to a topoisomerase I inhibitor payload (DXd) via a tetrapeptide-based cleavable linker.
HER3, Dr. Linardou explained, is a “biologically and clinically important target” in NSCLC. It is highly expressed in NSCLC, upregulated in TKI-resistant EGFR-mutated NSCLC, and is associated with a poor prognosis.
After promising phase 1 data, Dr. Yu and colleagues conducted a phase 2 trial in patients with advanced EGFR-mutated NSCLC who had progressed on systematic therapy and had received EGFR TKI and platinum-based chemotherapy. Patients could have active or previously treated asymptomatic brain metastases.
Patients were initially randomized either to a fixed-dose arm of HER3-DXd 5.6 mg/kg once every 3 weeks or an uptitration arm with doses escalating from 3.2 mg/kg to 4.8 mg/kg to 6.4 mg/kg over three cycles. However, Dr. Yu noted, enrollment in the uptitration arm closed early based on a “benefit-risk assessment.”
The current findings focus on the 225 patients in the fixed-dose arm.
About half of patients had a history of central nervous system metastasis, and patients had a median of three prior lines of systemic therapy. Most patients (92.9%) had previously received a third-generation EGFR TKI, about 40% had received immunotherapy, and all had received platinum-based chemotherapy.
After a median follow-up of 18.9 months, the confirmed objective response rate with HER3-DXd across the whole patient population was 29.8%. The median duration of response was 6.4 months, median progression-free survival was 5.5 months, and median overall survival was 11.9 months.
The results were virtually identical when looking only at patients who had received a third-generation EGFR TKI versus any EGFR TKI. Response rates were also similar regardless of the driver of EGFR TKI resistance.
Among the 30 patients with measurable brain metastases at baseline, 33.3% had a confirmed objective response to therapy. In this group, the disease control rate was 76.7% and the intracranial duration of response was 8.4 months.
To identify biomarkers of response to HER3-DXd, the team stratified the patients by baseline tumor HER3 membrane H-scores. Dr. Yu and colleagues found no differences in the likelihood of having a complete or partial response, stable disease, or progressive disease based on HER3 expression at study entry.
Looking at the safety of the ADC, only 7.1% of patients experienced a treatment-emergent adverse event associated with treatment discontinuation, but close to half of patients (45.3%) experienced a grade 3 or higher treatment-emergent adverse event. Interstitial lung disease, for instance, occurred in 5.3% of patients, including one patient who died.
The safety profile of HER3-DXd in this population appeared to be consistent with previous reports, Dr. Yu noted.
Overall, the findings suggest that “HER3-DXd provided clinically meaningful and durable efficacy” in patients with advanced EGFR-mutant NSCLC that has progressed after EGFR TKI and platinum-based chemotherapy, Dr. Yu said.
“Efficacy was observed across diverse mechanisms of resistance and across a broad range of pretreatment tumor HER3 expression” and the ADC demonstrated “clinically meaningful intracranial antitumor activity,” she added.
Dr. Linardou agreed that the current results suggest that HER3-DXd was associated with a “meaningful and durable efficacy,” including in patients with intracranial metastases, and she pointed to its “easy dosing schedule” and activity across patient subgroups.
However, she noted that, despite the researchers’ best efforts with the data available, “we don’t have a biomarker of activity,” which is a “general issue with ADCs.”
Still, Dr. Linardou said, “HER3 is now a clinically actionable therapeutic target, and this is a great bonus.”
The study was sponsored by Daiichi Sankyo. Dr. Yu declared relationships with AstraZeneca, Daiichi Sankyo, Blueprint Medicines, Janssen, C4 Therapeutics, Cullinan Oncology, Black Diamond Therapeutics, Taiho Oncology, and others. Other authors declare numerous relationships.
A version of this article first appeared on Medscape.com.
SINGAPORE – Heavily pretreated patients with EGFR-mutated non–small cell lung cancer (NSCLC) may experience a clinically meaningful benefit with the antibody-drug conjugate (ADC) patritumab deruxtecan (HER3-DXd), new phase 2 trial results suggest.
In the trial, almost 30% of patients receiving HER3-DXd achieved an objective response, and patients’ median overall survival approached 1 year.
HER3-DXd has “emerged as a promising therapy” in this patient population, “for whom available treatment options provide only limited efficacy,” concluded lead study author Helena A. Yu, MD, from Memorial Sloan Kettering Cancer Center, New York City, who presented findings from the HERTHENA-Lung01 trial at the 2023 World Conference on Lung Cancer.
The results were simultaneously published in the Journal of Clinical Oncology.
Acquired resistance to therapy among heavily pretreated patients with EGFR-mutated NSCLC is “universal,” Dr. Yu explained. The mechanisms of resistance to first-line osimertinib are also “diverse” and hard to identify. Salvage therapies after failed EGFR tyrosine kinase inhibitor (TKI) therapy and platinum-based chemotherapy offer “only a limited and transient and clinical benefit,” she said.
And with limited treatment options available to patients resistant to TKIs, there is a “high unmet medical need” for new therapies, said Helena Linardou, MD, PhD, who was not involved in the study.
HER3-DXd consists of a fully human anti-HER3 immunoglobulin G1 monoclonal antibody (patritumab) attached to a topoisomerase I inhibitor payload (DXd) via a tetrapeptide-based cleavable linker.
HER3, Dr. Linardou explained, is a “biologically and clinically important target” in NSCLC. It is highly expressed in NSCLC, upregulated in TKI-resistant EGFR-mutated NSCLC, and is associated with a poor prognosis.
After promising phase 1 data, Dr. Yu and colleagues conducted a phase 2 trial in patients with advanced EGFR-mutated NSCLC who had progressed on systematic therapy and had received EGFR TKI and platinum-based chemotherapy. Patients could have active or previously treated asymptomatic brain metastases.
Patients were initially randomized either to a fixed-dose arm of HER3-DXd 5.6 mg/kg once every 3 weeks or an uptitration arm with doses escalating from 3.2 mg/kg to 4.8 mg/kg to 6.4 mg/kg over three cycles. However, Dr. Yu noted, enrollment in the uptitration arm closed early based on a “benefit-risk assessment.”
The current findings focus on the 225 patients in the fixed-dose arm.
About half of patients had a history of central nervous system metastasis, and patients had a median of three prior lines of systemic therapy. Most patients (92.9%) had previously received a third-generation EGFR TKI, about 40% had received immunotherapy, and all had received platinum-based chemotherapy.
After a median follow-up of 18.9 months, the confirmed objective response rate with HER3-DXd across the whole patient population was 29.8%. The median duration of response was 6.4 months, median progression-free survival was 5.5 months, and median overall survival was 11.9 months.
The results were virtually identical when looking only at patients who had received a third-generation EGFR TKI versus any EGFR TKI. Response rates were also similar regardless of the driver of EGFR TKI resistance.
Among the 30 patients with measurable brain metastases at baseline, 33.3% had a confirmed objective response to therapy. In this group, the disease control rate was 76.7% and the intracranial duration of response was 8.4 months.
To identify biomarkers of response to HER3-DXd, the team stratified the patients by baseline tumor HER3 membrane H-scores. Dr. Yu and colleagues found no differences in the likelihood of having a complete or partial response, stable disease, or progressive disease based on HER3 expression at study entry.
Looking at the safety of the ADC, only 7.1% of patients experienced a treatment-emergent adverse event associated with treatment discontinuation, but close to half of patients (45.3%) experienced a grade 3 or higher treatment-emergent adverse event. Interstitial lung disease, for instance, occurred in 5.3% of patients, including one patient who died.
The safety profile of HER3-DXd in this population appeared to be consistent with previous reports, Dr. Yu noted.
Overall, the findings suggest that “HER3-DXd provided clinically meaningful and durable efficacy” in patients with advanced EGFR-mutant NSCLC that has progressed after EGFR TKI and platinum-based chemotherapy, Dr. Yu said.
“Efficacy was observed across diverse mechanisms of resistance and across a broad range of pretreatment tumor HER3 expression” and the ADC demonstrated “clinically meaningful intracranial antitumor activity,” she added.
Dr. Linardou agreed that the current results suggest that HER3-DXd was associated with a “meaningful and durable efficacy,” including in patients with intracranial metastases, and she pointed to its “easy dosing schedule” and activity across patient subgroups.
However, she noted that, despite the researchers’ best efforts with the data available, “we don’t have a biomarker of activity,” which is a “general issue with ADCs.”
Still, Dr. Linardou said, “HER3 is now a clinically actionable therapeutic target, and this is a great bonus.”
The study was sponsored by Daiichi Sankyo. Dr. Yu declared relationships with AstraZeneca, Daiichi Sankyo, Blueprint Medicines, Janssen, C4 Therapeutics, Cullinan Oncology, Black Diamond Therapeutics, Taiho Oncology, and others. Other authors declare numerous relationships.
A version of this article first appeared on Medscape.com.
AT IASLC 2023