Jim Kling

AUSTIN, TEX. – Self-treatment of migraines using cannabis can be effective but comes at risk of significant side effects, according to results from a randomized, controlled trial of cannabis products in migraine. The study also suggests that typical recreational doses may be higher than needed, and that products with a mixture of THC and CBD might limit adverse effects, according to lead author Nathaniel Schuster, MD.

“Patients are using cannabis on their own, treating themselves without us having known whether this is effective in a placebo-controlled study. Knowing that there’s a lot of interest in THC and CBD, [it would be useful to know] whether one or both might be effective, as well as a mix,” said Dr. Schuster in an interview. He presented the results at the annual meeting of the American Headache Society.

Dr. Schuster and colleagues tested a cannabis product with 6% THC based on prior studies showing efficacy of that concentration for other pain conditions, according to Dr. Schuster, who is an associate professor and associate clinical director at the University of California, San Diego, center for pain medicine. He added that the study is the first randomized, controlled trial of cannabis in migraine patients that he is aware of. “It’s just hard to do this research. It’s very regulated. We had to go through a lot of government approvals to do this,” he said.

The study produced a key message. “I think one of the really important things for patients to take from this is that recreational doses are probably not necessary. The doses that we studied are lower than people use recreationally. Patients who are self-treating on their own right now are probably using higher doses than they need for the purpose of treating migraine,” said Dr. Schuster.

He also pointed out that the results offer potential insight into reducing side effects. “If [patients] are using THC only, they can hopefully have less of the side effects and tolerate it better by using a THC-CBD mix,” said Dr. Schuster.
 

Four therapies tested

Participants in the study could self-treat up to four migraine attacks. They were instructed to treat each migraine with one of four therapies, which were provided in a randomized, double-blind order: These included a 6% THC formulation; a mix of THC (6%) and CBD (11%); a CBD 11% formulation; and placebo cannabis with THC and CBD removed by alcohol extraction. Participants filled out a questionnaire 2 hours after treatment, and were then allowed to use rescue treatments if needed, but not additional cannabis. The age range was from 21 to 65, and inclusion criteria included 2-23 migraine days per month. Exclusion criteria included a positive urine test for THC, barbiturates, opioids, oxycodone, or methadone prior to enrollment.

The study included 73 patients who treated a migraine during the study period. There were 247 migraine attacks treated. Among participants, the median age was 41, 82.6% were female and 17.4% were male, and the median body mass index was 26.0 kg/m². Participants experienced a median of 15 headache days per month and 6 migraine days per month, and 27.2% had chronic migraine.

At 2 hours, pain relief occurred in 48.3% of placebo treatments, 54.4% of the CBD treatments, 70.5% of the THC treatments (P = .007 versus placebo), and 69.0% of the THC/CBD treatments (P = .014 versus placebo). At 2 hours, pain freedom occurred in 15.5% of the placebo treatments, 24.6% of the CBD treatments, 29.5% of the THC treatments, and 36.2% of the THC/CBD treatments (P = .010 versus placebo). At 2 hours, freedom from most bothersome symptoms (MBS) occurred in 36.2% of the placebo treatments, 43.9% of the CBD treatments, 49.2% of the THC treatments, and 62.1% of the THC/CBD treatments (P = .004 versus placebo).

To achieve at least a 20% improvement in pain relief, compared with placebo, the number needed to treat (NNT) with THC/CBD was five. For at least a 20% improvement in pain freedom, the NNT was five, and for a 20% improvement in freedom from most bothersome symptoms, the NNT was four.

Treatment with THC was associated with the highest frequency of any adverse event (31.0%), followed by CBD and THC/CBD (19.6% each), and placebo (5.0%). At 2 hours, 18.0% of the THC treatments had an adverse event, compared with 7.0% of the CBD treatments, 6.9% of the THC/CBD treatments, and 5.2% of placebo treatments.

The number needed to treat of five for pain relief was encouraging, according to Dr. Schuster. “It’s better than some other things, but at the expense of side effects. The side effects that we see are certainly higher with cannabis than it is with other migraine treatments that patients certainly should be using beforehand. There’s also a risk of addiction, which is a concern,” said Dr. Schuster.
 

Useful data but questions remain

Having a clinical trial will be useful for physicians, said Ali Ezzati, MD, who attended the session. “I think it was an impressive study. Obviously, there are some challenges with cannabis studies in the medical world because of the stigma that comes with it and also the possibility of inducing addiction [and] promoting that to patients. But at the end of the day, it’s very, very common for our patients to ask us about cannabinoid use, and we really don’t have data on it. I’m glad that there are people who are running these studies so we will be able at least to answer our patients,” said Dr. Ezzati, who is an associate professor of neurology at University of California, Irvine.

Dr. Ezzati also noted that clinical trials have investigated cannabinoid use for other types of pain, such as arthritic or generalized pain. Although he said that there are some clinical similarities between other types of pain and migraine, the pathophysiology appears to be unique, which means that more work needs to be done. “It will probably take 5 or 10 years to have sufficient data to give patients a direct path for using (cannabinoids),” said Dr. Ezzati.

The study was funded by the Migraine Research Foundation. Dr. Schuster has consulted with Schedule 1 Therapeutics and Vectura Fertin. Dr. Ezzati has no relevant financial disclosures.

AUSTIN, TEX. – Self-treatment of migraines using cannabis can be effective but comes at risk of significant side effects, according to results from a randomized, controlled trial of cannabis products in migraine. The study also suggests that typical recreational doses may be higher than needed, and that products with a mixture of THC and CBD might limit adverse effects, according to lead author Nathaniel Schuster, MD.

“Patients are using cannabis on their own, treating themselves without us having known whether this is effective in a placebo-controlled study. Knowing that there’s a lot of interest in THC and CBD, [it would be useful to know] whether one or both might be effective, as well as a mix,” said Dr. Schuster in an interview. He presented the results at the annual meeting of the American Headache Society.

Dr. Schuster and colleagues tested a cannabis product with 6% THC based on prior studies showing efficacy of that concentration for other pain conditions, according to Dr. Schuster, who is an associate professor and associate clinical director at the University of California, San Diego, center for pain medicine. He added that the study is the first randomized, controlled trial of cannabis in migraine patients that he is aware of. “It’s just hard to do this research. It’s very regulated. We had to go through a lot of government approvals to do this,” he said.

The study produced a key message. “I think one of the really important things for patients to take from this is that recreational doses are probably not necessary. The doses that we studied are lower than people use recreationally. Patients who are self-treating on their own right now are probably using higher doses than they need for the purpose of treating migraine,” said Dr. Schuster.

He also pointed out that the results offer potential insight into reducing side effects. “If [patients] are using THC only, they can hopefully have less of the side effects and tolerate it better by using a THC-CBD mix,” said Dr. Schuster.
 

Four therapies tested

Participants in the study could self-treat up to four migraine attacks. They were instructed to treat each migraine with one of four therapies, which were provided in a randomized, double-blind order: These included a 6% THC formulation; a mix of THC (6%) and CBD (11%); a CBD 11% formulation; and placebo cannabis with THC and CBD removed by alcohol extraction. Participants filled out a questionnaire 2 hours after treatment, and were then allowed to use rescue treatments if needed, but not additional cannabis. The age range was from 21 to 65, and inclusion criteria included 2-23 migraine days per month. Exclusion criteria included a positive urine test for THC, barbiturates, opioids, oxycodone, or methadone prior to enrollment.

The study included 73 patients who treated a migraine during the study period. There were 247 migraine attacks treated. Among participants, the median age was 41, 82.6% were female and 17.4% were male, and the median body mass index was 26.0 kg/m². Participants experienced a median of 15 headache days per month and 6 migraine days per month, and 27.2% had chronic migraine.

At 2 hours, pain relief occurred in 48.3% of placebo treatments, 54.4% of the CBD treatments, 70.5% of the THC treatments (P = .007 versus placebo), and 69.0% of the THC/CBD treatments (P = .014 versus placebo). At 2 hours, pain freedom occurred in 15.5% of the placebo treatments, 24.6% of the CBD treatments, 29.5% of the THC treatments, and 36.2% of the THC/CBD treatments (P = .010 versus placebo). At 2 hours, freedom from most bothersome symptoms (MBS) occurred in 36.2% of the placebo treatments, 43.9% of the CBD treatments, 49.2% of the THC treatments, and 62.1% of the THC/CBD treatments (P = .004 versus placebo).

To achieve at least a 20% improvement in pain relief, compared with placebo, the number needed to treat (NNT) with THC/CBD was five. For at least a 20% improvement in pain freedom, the NNT was five, and for a 20% improvement in freedom from most bothersome symptoms, the NNT was four.

Treatment with THC was associated with the highest frequency of any adverse event (31.0%), followed by CBD and THC/CBD (19.6% each), and placebo (5.0%). At 2 hours, 18.0% of the THC treatments had an adverse event, compared with 7.0% of the CBD treatments, 6.9% of the THC/CBD treatments, and 5.2% of placebo treatments.

The number needed to treat of five for pain relief was encouraging, according to Dr. Schuster. “It’s better than some other things, but at the expense of side effects. The side effects that we see are certainly higher with cannabis than it is with other migraine treatments that patients certainly should be using beforehand. There’s also a risk of addiction, which is a concern,” said Dr. Schuster.
 

Useful data but questions remain

Having a clinical trial will be useful for physicians, said Ali Ezzati, MD, who attended the session. “I think it was an impressive study. Obviously, there are some challenges with cannabis studies in the medical world because of the stigma that comes with it and also the possibility of inducing addiction [and] promoting that to patients. But at the end of the day, it’s very, very common for our patients to ask us about cannabinoid use, and we really don’t have data on it. I’m glad that there are people who are running these studies so we will be able at least to answer our patients,” said Dr. Ezzati, who is an associate professor of neurology at University of California, Irvine.

Dr. Ezzati also noted that clinical trials have investigated cannabinoid use for other types of pain, such as arthritic or generalized pain. Although he said that there are some clinical similarities between other types of pain and migraine, the pathophysiology appears to be unique, which means that more work needs to be done. “It will probably take 5 or 10 years to have sufficient data to give patients a direct path for using (cannabinoids),” said Dr. Ezzati.

The study was funded by the Migraine Research Foundation. Dr. Schuster has consulted with Schedule 1 Therapeutics and Vectura Fertin. Dr. Ezzati has no relevant financial disclosures.

AUSTIN, TEX. – Self-treatment of migraines using cannabis can be effective but comes at risk of significant side effects, according to results from a randomized, controlled trial of cannabis products in migraine. The study also suggests that typical recreational doses may be higher than needed, and that products with a mixture of THC and CBD might limit adverse effects, according to lead author Nathaniel Schuster, MD.

“Patients are using cannabis on their own, treating themselves without us having known whether this is effective in a placebo-controlled study. Knowing that there’s a lot of interest in THC and CBD, [it would be useful to know] whether one or both might be effective, as well as a mix,” said Dr. Schuster in an interview. He presented the results at the annual meeting of the American Headache Society.

Dr. Schuster and colleagues tested a cannabis product with 6% THC based on prior studies showing efficacy of that concentration for other pain conditions, according to Dr. Schuster, who is an associate professor and associate clinical director at the University of California, San Diego, center for pain medicine. He added that the study is the first randomized, controlled trial of cannabis in migraine patients that he is aware of. “It’s just hard to do this research. It’s very regulated. We had to go through a lot of government approvals to do this,” he said.

The study produced a key message. “I think one of the really important things for patients to take from this is that recreational doses are probably not necessary. The doses that we studied are lower than people use recreationally. Patients who are self-treating on their own right now are probably using higher doses than they need for the purpose of treating migraine,” said Dr. Schuster.

He also pointed out that the results offer potential insight into reducing side effects. “If [patients] are using THC only, they can hopefully have less of the side effects and tolerate it better by using a THC-CBD mix,” said Dr. Schuster.
 

Four therapies tested

Participants in the study could self-treat up to four migraine attacks. They were instructed to treat each migraine with one of four therapies, which were provided in a randomized, double-blind order: These included a 6% THC formulation; a mix of THC (6%) and CBD (11%); a CBD 11% formulation; and placebo cannabis with THC and CBD removed by alcohol extraction. Participants filled out a questionnaire 2 hours after treatment, and were then allowed to use rescue treatments if needed, but not additional cannabis. The age range was from 21 to 65, and inclusion criteria included 2-23 migraine days per month. Exclusion criteria included a positive urine test for THC, barbiturates, opioids, oxycodone, or methadone prior to enrollment.

The study included 73 patients who treated a migraine during the study period. There were 247 migraine attacks treated. Among participants, the median age was 41, 82.6% were female and 17.4% were male, and the median body mass index was 26.0 kg/m². Participants experienced a median of 15 headache days per month and 6 migraine days per month, and 27.2% had chronic migraine.

At 2 hours, pain relief occurred in 48.3% of placebo treatments, 54.4% of the CBD treatments, 70.5% of the THC treatments (P = .007 versus placebo), and 69.0% of the THC/CBD treatments (P = .014 versus placebo). At 2 hours, pain freedom occurred in 15.5% of the placebo treatments, 24.6% of the CBD treatments, 29.5% of the THC treatments, and 36.2% of the THC/CBD treatments (P = .010 versus placebo). At 2 hours, freedom from most bothersome symptoms (MBS) occurred in 36.2% of the placebo treatments, 43.9% of the CBD treatments, 49.2% of the THC treatments, and 62.1% of the THC/CBD treatments (P = .004 versus placebo).

To achieve at least a 20% improvement in pain relief, compared with placebo, the number needed to treat (NNT) with THC/CBD was five. For at least a 20% improvement in pain freedom, the NNT was five, and for a 20% improvement in freedom from most bothersome symptoms, the NNT was four.

Treatment with THC was associated with the highest frequency of any adverse event (31.0%), followed by CBD and THC/CBD (19.6% each), and placebo (5.0%). At 2 hours, 18.0% of the THC treatments had an adverse event, compared with 7.0% of the CBD treatments, 6.9% of the THC/CBD treatments, and 5.2% of placebo treatments.

The number needed to treat of five for pain relief was encouraging, according to Dr. Schuster. “It’s better than some other things, but at the expense of side effects. The side effects that we see are certainly higher with cannabis than it is with other migraine treatments that patients certainly should be using beforehand. There’s also a risk of addiction, which is a concern,” said Dr. Schuster.
 

Useful data but questions remain

Having a clinical trial will be useful for physicians, said Ali Ezzati, MD, who attended the session. “I think it was an impressive study. Obviously, there are some challenges with cannabis studies in the medical world because of the stigma that comes with it and also the possibility of inducing addiction [and] promoting that to patients. But at the end of the day, it’s very, very common for our patients to ask us about cannabinoid use, and we really don’t have data on it. I’m glad that there are people who are running these studies so we will be able at least to answer our patients,” said Dr. Ezzati, who is an associate professor of neurology at University of California, Irvine.

Dr. Ezzati also noted that clinical trials have investigated cannabinoid use for other types of pain, such as arthritic or generalized pain. Although he said that there are some clinical similarities between other types of pain and migraine, the pathophysiology appears to be unique, which means that more work needs to be done. “It will probably take 5 or 10 years to have sufficient data to give patients a direct path for using (cannabinoids),” said Dr. Ezzati.

The study was funded by the Migraine Research Foundation. Dr. Schuster has consulted with Schedule 1 Therapeutics and Vectura Fertin. Dr. Ezzati has no relevant financial disclosures.

AUSTIN, TEX. – A new machine-learning analysis of a large group of migraine patients has identified subgroups that share both clinical and therapeutic response traits. The findings could point to new therapeutic strategies, according to study author Ali Ezzati, MD.

“A lot of diagnostic criteria that we have in the migraine world come from consensus groups of experts, and based on their experience and available data. They classify different types of headache and then on top of that different types of migraine. Unfortunately, this type of classification does not necessarily lead to having very homogeneous groups,” said Dr. Ezzati, who presented the study at the annual meeting of the American Headache Society.

Migraines are generally categorized as episodic (0-14 headache days per month) or chronic (15 or more per month), or as with or without aura. But these broad categories fail to capture the true diversity of migraine, according to Dr. Ezzati, and this may contribute to the fact that response to migraine therapy hovers around 60%. “We feel that the key to improving therapeutic efficacy is to identify individuals who are more homogeneous, more similar to each other, so that when we give a treatment, it is specifically targeting the underlying pathophysiology that those people have,” said Dr. Ezzati, who is an associate professor of neurology and director of the neuroinformatics program at University of California, Irvine.

The analysis revealed some clinically interesting results, said Dr. Ezzati. “For example, allodynia is a symptom that is not particularly used for classification of different types of migraine. There was a specific group that was very high in allodynia, and they were not very responsive to treatments, so that might be a [group] that people have to focus on. Also, we talk a lot about comorbidities in migraine, but we don’t talk about how these comorbidities affect the therapeutic strategies and treatment response to specific medications. We showed that people who have depression are actually less responsive than other groups to treatments, especially prescription medications,” he said.
 

Machine learning reveals clusters

The researchers analyzed data from 4,423 patients drawn from the American Migraine Prevalence and Prevention Study, which was conducted every year between 2005 and 2009. They included adult patients who filled out surveys in both 2006 and 2007. The study population was 83.7% female and had a mean age of 46.8 years, and 6.4% had chronic migraine. The researchers then used a machine-learning based self-organizing map to group patients into similar clusters.

The algorithm produced five such groups: Cluster 1 had the lowest symptom severity, and 0.6% had chronic migraine. Cluster 2 had mild symptom severity with no chronic migraine. Cluster 3 had moderate symptom severity and a high prevalence of allodynia (88.5%, vs. 63.4% overall, P < .001) and no chronic migraine. Cluster 4 had a high frequency of depressive symptoms (63.1% vs. 19.8% overall, P < .001) and 5.2% had chronic migraine. Cluster 5 had frequent and severe migraines, and most (83.0%) had chronic migraine (P < .001).

There were some other broader trends. Triptans were more commonly used in clusters 2 (25.6%), 3 (27.9%), and 5 (28.0%), but less so in cluster 4 (17.1%; P < .001). Pain freedom at 2 hours was most common in cluster 1 (53.1%), followed by cluster 2 (46.4%), but was significantly less frequent in clusters 3 (32.2%), 4 (32.2%), and 5 (34.7%; P < .001).
 

Therapeutic implications

Dr. Ezzati believes that machine learning and data analysis could point the way to a future of more tailored migraine therapies. “I think we have to in general go down the path of using more evidence and more data to inform us about individualized planning for patients. For that we need larger clinical studies and larger epidemiological studies to help us identify more homogeneous subtypes of patients that we can eventually target in clinical trials,” he said.

Catherine Chong, MD, who chaired the session where the research was presented, praised the study in an interview. “Episodic migraine and chronic migraine have been developed [as categories] by headache frequency per month, and it was basically based on consensus in committee. They made basically a determination that 15 and under migraine days would be episodic migraine and over would be chronic migraine. So they dichotomized migraine, in a way, based on what people thought in the field. Looking at the data freely, and letting the algorithm determine the different subtypes, and putting everybody with migraine in it, and having these groups naturally appear from the data, I think is fascinating,” Dr. Chong said.

She echoed Dr. Ezzati’s call for further research that could create even more subgroups. “Is it really truly the case that somebody with less than 15 migraine days [per month], that 14 migraines days would be so different than somebody with 15 or over, or 8? I think we need to look at it further to see whether there are additional subgroups within that data. I think there are probably more [groups identifiable] from different data that we have out there,” said Dr. Chong.

Dr. Ezzati has consulted for or been a reviewer or advisory board member for Corium, Eisai, GlaxoSmithKline, Mint Research, and Health Care Horizon Scanning System. He has received research funding from Amgen. Dr. Chong has no relevant financial disclosures.
 

AUSTIN, TEX. – A new machine-learning analysis of a large group of migraine patients has identified subgroups that share both clinical and therapeutic response traits. The findings could point to new therapeutic strategies, according to study author Ali Ezzati, MD.

“A lot of diagnostic criteria that we have in the migraine world come from consensus groups of experts, and based on their experience and available data. They classify different types of headache and then on top of that different types of migraine. Unfortunately, this type of classification does not necessarily lead to having very homogeneous groups,” said Dr. Ezzati, who presented the study at the annual meeting of the American Headache Society.

Migraines are generally categorized as episodic (0-14 headache days per month) or chronic (15 or more per month), or as with or without aura. But these broad categories fail to capture the true diversity of migraine, according to Dr. Ezzati, and this may contribute to the fact that response to migraine therapy hovers around 60%. “We feel that the key to improving therapeutic efficacy is to identify individuals who are more homogeneous, more similar to each other, so that when we give a treatment, it is specifically targeting the underlying pathophysiology that those people have,” said Dr. Ezzati, who is an associate professor of neurology and director of the neuroinformatics program at University of California, Irvine.

The analysis revealed some clinically interesting results, said Dr. Ezzati. “For example, allodynia is a symptom that is not particularly used for classification of different types of migraine. There was a specific group that was very high in allodynia, and they were not very responsive to treatments, so that might be a [group] that people have to focus on. Also, we talk a lot about comorbidities in migraine, but we don’t talk about how these comorbidities affect the therapeutic strategies and treatment response to specific medications. We showed that people who have depression are actually less responsive than other groups to treatments, especially prescription medications,” he said.
 

Machine learning reveals clusters

The researchers analyzed data from 4,423 patients drawn from the American Migraine Prevalence and Prevention Study, which was conducted every year between 2005 and 2009. They included adult patients who filled out surveys in both 2006 and 2007. The study population was 83.7% female and had a mean age of 46.8 years, and 6.4% had chronic migraine. The researchers then used a machine-learning based self-organizing map to group patients into similar clusters.

The algorithm produced five such groups: Cluster 1 had the lowest symptom severity, and 0.6% had chronic migraine. Cluster 2 had mild symptom severity with no chronic migraine. Cluster 3 had moderate symptom severity and a high prevalence of allodynia (88.5%, vs. 63.4% overall, P < .001) and no chronic migraine. Cluster 4 had a high frequency of depressive symptoms (63.1% vs. 19.8% overall, P < .001) and 5.2% had chronic migraine. Cluster 5 had frequent and severe migraines, and most (83.0%) had chronic migraine (P < .001).

There were some other broader trends. Triptans were more commonly used in clusters 2 (25.6%), 3 (27.9%), and 5 (28.0%), but less so in cluster 4 (17.1%; P < .001). Pain freedom at 2 hours was most common in cluster 1 (53.1%), followed by cluster 2 (46.4%), but was significantly less frequent in clusters 3 (32.2%), 4 (32.2%), and 5 (34.7%; P < .001).
 

Therapeutic implications

Dr. Ezzati believes that machine learning and data analysis could point the way to a future of more tailored migraine therapies. “I think we have to in general go down the path of using more evidence and more data to inform us about individualized planning for patients. For that we need larger clinical studies and larger epidemiological studies to help us identify more homogeneous subtypes of patients that we can eventually target in clinical trials,” he said.

Catherine Chong, MD, who chaired the session where the research was presented, praised the study in an interview. “Episodic migraine and chronic migraine have been developed [as categories] by headache frequency per month, and it was basically based on consensus in committee. They made basically a determination that 15 and under migraine days would be episodic migraine and over would be chronic migraine. So they dichotomized migraine, in a way, based on what people thought in the field. Looking at the data freely, and letting the algorithm determine the different subtypes, and putting everybody with migraine in it, and having these groups naturally appear from the data, I think is fascinating,” Dr. Chong said.

She echoed Dr. Ezzati’s call for further research that could create even more subgroups. “Is it really truly the case that somebody with less than 15 migraine days [per month], that 14 migraines days would be so different than somebody with 15 or over, or 8? I think we need to look at it further to see whether there are additional subgroups within that data. I think there are probably more [groups identifiable] from different data that we have out there,” said Dr. Chong.

Dr. Ezzati has consulted for or been a reviewer or advisory board member for Corium, Eisai, GlaxoSmithKline, Mint Research, and Health Care Horizon Scanning System. He has received research funding from Amgen. Dr. Chong has no relevant financial disclosures.
 

AUSTIN, TEX. – A new machine-learning analysis of a large group of migraine patients has identified subgroups that share both clinical and therapeutic response traits. The findings could point to new therapeutic strategies, according to study author Ali Ezzati, MD.

“A lot of diagnostic criteria that we have in the migraine world come from consensus groups of experts, and based on their experience and available data. They classify different types of headache and then on top of that different types of migraine. Unfortunately, this type of classification does not necessarily lead to having very homogeneous groups,” said Dr. Ezzati, who presented the study at the annual meeting of the American Headache Society.

Migraines are generally categorized as episodic (0-14 headache days per month) or chronic (15 or more per month), or as with or without aura. But these broad categories fail to capture the true diversity of migraine, according to Dr. Ezzati, and this may contribute to the fact that response to migraine therapy hovers around 60%. “We feel that the key to improving therapeutic efficacy is to identify individuals who are more homogeneous, more similar to each other, so that when we give a treatment, it is specifically targeting the underlying pathophysiology that those people have,” said Dr. Ezzati, who is an associate professor of neurology and director of the neuroinformatics program at University of California, Irvine.

The analysis revealed some clinically interesting results, said Dr. Ezzati. “For example, allodynia is a symptom that is not particularly used for classification of different types of migraine. There was a specific group that was very high in allodynia, and they were not very responsive to treatments, so that might be a [group] that people have to focus on. Also, we talk a lot about comorbidities in migraine, but we don’t talk about how these comorbidities affect the therapeutic strategies and treatment response to specific medications. We showed that people who have depression are actually less responsive than other groups to treatments, especially prescription medications,” he said.
 

Machine learning reveals clusters

The researchers analyzed data from 4,423 patients drawn from the American Migraine Prevalence and Prevention Study, which was conducted every year between 2005 and 2009. They included adult patients who filled out surveys in both 2006 and 2007. The study population was 83.7% female and had a mean age of 46.8 years, and 6.4% had chronic migraine. The researchers then used a machine-learning based self-organizing map to group patients into similar clusters.

The algorithm produced five such groups: Cluster 1 had the lowest symptom severity, and 0.6% had chronic migraine. Cluster 2 had mild symptom severity with no chronic migraine. Cluster 3 had moderate symptom severity and a high prevalence of allodynia (88.5%, vs. 63.4% overall, P < .001) and no chronic migraine. Cluster 4 had a high frequency of depressive symptoms (63.1% vs. 19.8% overall, P < .001) and 5.2% had chronic migraine. Cluster 5 had frequent and severe migraines, and most (83.0%) had chronic migraine (P < .001).

There were some other broader trends. Triptans were more commonly used in clusters 2 (25.6%), 3 (27.9%), and 5 (28.0%), but less so in cluster 4 (17.1%; P < .001). Pain freedom at 2 hours was most common in cluster 1 (53.1%), followed by cluster 2 (46.4%), but was significantly less frequent in clusters 3 (32.2%), 4 (32.2%), and 5 (34.7%; P < .001).
 

Therapeutic implications

Dr. Ezzati believes that machine learning and data analysis could point the way to a future of more tailored migraine therapies. “I think we have to in general go down the path of using more evidence and more data to inform us about individualized planning for patients. For that we need larger clinical studies and larger epidemiological studies to help us identify more homogeneous subtypes of patients that we can eventually target in clinical trials,” he said.

Catherine Chong, MD, who chaired the session where the research was presented, praised the study in an interview. “Episodic migraine and chronic migraine have been developed [as categories] by headache frequency per month, and it was basically based on consensus in committee. They made basically a determination that 15 and under migraine days would be episodic migraine and over would be chronic migraine. So they dichotomized migraine, in a way, based on what people thought in the field. Looking at the data freely, and letting the algorithm determine the different subtypes, and putting everybody with migraine in it, and having these groups naturally appear from the data, I think is fascinating,” Dr. Chong said.

She echoed Dr. Ezzati’s call for further research that could create even more subgroups. “Is it really truly the case that somebody with less than 15 migraine days [per month], that 14 migraines days would be so different than somebody with 15 or over, or 8? I think we need to look at it further to see whether there are additional subgroups within that data. I think there are probably more [groups identifiable] from different data that we have out there,” said Dr. Chong.

Dr. Ezzati has consulted for or been a reviewer or advisory board member for Corium, Eisai, GlaxoSmithKline, Mint Research, and Health Care Horizon Scanning System. He has received research funding from Amgen. Dr. Chong has no relevant financial disclosures.
 

In metastatic breast cancer, a fixed dose of capecitabine given on a 7-day-on, 7-day-off schedule had similar efficacy and reduced adverse events compared with the standard 14-day-on, 7-day-off schedule, in a new study.

Both progression-free survival (PFS) and overall survival (OS) were similar between the two groups, but patients on the alternative schedule experienced fewer cases of hand-foot syndrome (HFS), diarrhea, and stomatitis, and also had fewer discontinuations and dose modifications.

The Food and Drug Administration–approved dose of capecitabine is 1,250 mg/m², but 14 days of treatment can lead to significant toxicity, said Qamar Khan, MD, during a presentation of the study at the annual meeting of the American Society of Clinical Oncology. “Mathematical models applied to xenograft [animal model] data suggest that the maximum cytotoxic effect of capecitabine occurs after about 7 days of treatment, beyond which time only toxicity increases,” Dr. Khan said during his talk on the randomized control trial.

The researchers randomized 153 patients to receive a fixed 1,500-mg capecitabine dose twice per day on a 7-day-on, 7-day-off schedule (7/7), or the 1,250–mg/m² dose twice per day for 14 days followed by 7 days off (14/7). The median age was 60 years, and 85.6% were White, 8.5% were African American, 3.3% were Hispanic, 0.7% were American Indian or Alaskan Native, and 2.0% were other. With respect to disease characteristics, 44% had visceral metastasis, 78% were hormone receptor positive/HER2 negative, and 11% had triple-negative breast cancer. About two-thirds (65%) had received no prior chemotherapy.

Restricted mean survival time (RMST) at 36 months for PFS was 13.9 months in the 7/7 group and 14.6 months in the 14/7 group (difference, 0.7 months; 95.5% CI, –3.14 to 4.57 months). The objective response rate was 8.9% in the 7/7 group and 19.6% in the 14/7 group (P = .11). Median OS was 19.8 months in the 7/7 group and 17.5 months in the 14/7 group (hazard ratio, 0.76; P = .17). The RMST at 47 months for OS was 24.5 months in the 7/7 group and 20.9 months in the 14/7 group (difference, –3.6 months; 95% CI, –8.89 to 1.54 months).

The researchers found no differences in subgroup analyses by visceral metastasis, breast cancer subtype, or number of lines of previous therapy.

The toxicity profile of 7/7 was better with respect to grade 2-4 diarrhea (2.5% vs. 20.5%, P = .0008), grade 2-4 HFS (3.8% vs. 15.1%; P = .0019), and grade 2-4 mucositis (0% vs. 5.5%; P =.0001).
 

Findings back up clinical practice

“The fixed-dose capecitabine dosing is something that’s been done a lot in practice, because a lot of practitioners recognize that giving the drug for two weeks in a row with a week break is overly toxic, so it’s something we’ve been doing in the community for quite a while,” said Michael Danso, MD, who comoderated the session.

Still, the safety and efficacy data back up that general clinical practice. “There was a randomized trial and colon cancer that didn’t show [equivalent outcomes with the alternate dosing schedule]. So to see that it’s safe and effective in breast cancer is an important [finding],” said Dr. Danso, who is the Research Director at Virginia Oncology Associates, Norfolk.

During the question-and-answer following the talk, Jeffrey Kirshner, MD, a medical oncologist at Hematology-Oncology Associates of Central New York, East Syracuse, noted that his practice has used a similar schedule for years. “I really commend you for doing that study. It really supports what many of us in the real world have been doing for many years. We figured this out empirically, both upfront and when patients can’t tolerate [the 14/7 schedule].”
 

Fixed dose versus body surface area

Dr. Kirshner also said his practice uses a dose of 1 g/m² of body surface area on a 7/7 schedule rather than a fixed dose as was done in Dr. Khan’s study. “If you use the higher dose, you might have seen a higher response rate because many of our patients, as you know, have a body surface [BSA] area much greater than 1.5 g/m².”

Dr. Khan responded that there is little data available on BSA dosing. “We selected 1,500 mg because a lot of people are practicing that, and for convenience, and that most patients who started at a higher dose eventually wound up on a dose of 1,500 mg twice daily.”

Dr. Kirshner also pointed out that the study was conducted in a population with metastatic disease. “I think we need to emphasize that we do not use the 7/7 regimen in a potentially curative setting, such as the CREATE-X regimen for triple-negative [breast cancer].”

Dr. Khan agreed. “I would use the same dose as the CREATE-X trial in the adjuvant setting,” he responded.

Dr. Danso has received honoraria from Amgen and has consulted or advised Immunomedics, Novartis, Pfizer, and Seagen. Dr. Khan and Dr. Kirshner have no relevant financial disclosures.

In metastatic breast cancer, a fixed dose of capecitabine given on a 7-day-on, 7-day-off schedule had similar efficacy and reduced adverse events compared with the standard 14-day-on, 7-day-off schedule, in a new study.

Both progression-free survival (PFS) and overall survival (OS) were similar between the two groups, but patients on the alternative schedule experienced fewer cases of hand-foot syndrome (HFS), diarrhea, and stomatitis, and also had fewer discontinuations and dose modifications.

The Food and Drug Administration–approved dose of capecitabine is 1,250 mg/m², but 14 days of treatment can lead to significant toxicity, said Qamar Khan, MD, during a presentation of the study at the annual meeting of the American Society of Clinical Oncology. “Mathematical models applied to xenograft [animal model] data suggest that the maximum cytotoxic effect of capecitabine occurs after about 7 days of treatment, beyond which time only toxicity increases,” Dr. Khan said during his talk on the randomized control trial.

The researchers randomized 153 patients to receive a fixed 1,500-mg capecitabine dose twice per day on a 7-day-on, 7-day-off schedule (7/7), or the 1,250–mg/m² dose twice per day for 14 days followed by 7 days off (14/7). The median age was 60 years, and 85.6% were White, 8.5% were African American, 3.3% were Hispanic, 0.7% were American Indian or Alaskan Native, and 2.0% were other. With respect to disease characteristics, 44% had visceral metastasis, 78% were hormone receptor positive/HER2 negative, and 11% had triple-negative breast cancer. About two-thirds (65%) had received no prior chemotherapy.

Restricted mean survival time (RMST) at 36 months for PFS was 13.9 months in the 7/7 group and 14.6 months in the 14/7 group (difference, 0.7 months; 95.5% CI, –3.14 to 4.57 months). The objective response rate was 8.9% in the 7/7 group and 19.6% in the 14/7 group (P = .11). Median OS was 19.8 months in the 7/7 group and 17.5 months in the 14/7 group (hazard ratio, 0.76; P = .17). The RMST at 47 months for OS was 24.5 months in the 7/7 group and 20.9 months in the 14/7 group (difference, –3.6 months; 95% CI, –8.89 to 1.54 months).

The researchers found no differences in subgroup analyses by visceral metastasis, breast cancer subtype, or number of lines of previous therapy.

The toxicity profile of 7/7 was better with respect to grade 2-4 diarrhea (2.5% vs. 20.5%, P = .0008), grade 2-4 HFS (3.8% vs. 15.1%; P = .0019), and grade 2-4 mucositis (0% vs. 5.5%; P =.0001).
 

Findings back up clinical practice

“The fixed-dose capecitabine dosing is something that’s been done a lot in practice, because a lot of practitioners recognize that giving the drug for two weeks in a row with a week break is overly toxic, so it’s something we’ve been doing in the community for quite a while,” said Michael Danso, MD, who comoderated the session.

Still, the safety and efficacy data back up that general clinical practice. “There was a randomized trial and colon cancer that didn’t show [equivalent outcomes with the alternate dosing schedule]. So to see that it’s safe and effective in breast cancer is an important [finding],” said Dr. Danso, who is the Research Director at Virginia Oncology Associates, Norfolk.

During the question-and-answer following the talk, Jeffrey Kirshner, MD, a medical oncologist at Hematology-Oncology Associates of Central New York, East Syracuse, noted that his practice has used a similar schedule for years. “I really commend you for doing that study. It really supports what many of us in the real world have been doing for many years. We figured this out empirically, both upfront and when patients can’t tolerate [the 14/7 schedule].”
 

Fixed dose versus body surface area

Dr. Kirshner also said his practice uses a dose of 1 g/m² of body surface area on a 7/7 schedule rather than a fixed dose as was done in Dr. Khan’s study. “If you use the higher dose, you might have seen a higher response rate because many of our patients, as you know, have a body surface [BSA] area much greater than 1.5 g/m².”

Dr. Khan responded that there is little data available on BSA dosing. “We selected 1,500 mg because a lot of people are practicing that, and for convenience, and that most patients who started at a higher dose eventually wound up on a dose of 1,500 mg twice daily.”

Dr. Kirshner also pointed out that the study was conducted in a population with metastatic disease. “I think we need to emphasize that we do not use the 7/7 regimen in a potentially curative setting, such as the CREATE-X regimen for triple-negative [breast cancer].”

Dr. Khan agreed. “I would use the same dose as the CREATE-X trial in the adjuvant setting,” he responded.

Dr. Danso has received honoraria from Amgen and has consulted or advised Immunomedics, Novartis, Pfizer, and Seagen. Dr. Khan and Dr. Kirshner have no relevant financial disclosures.

In metastatic breast cancer, a fixed dose of capecitabine given on a 7-day-on, 7-day-off schedule had similar efficacy and reduced adverse events compared with the standard 14-day-on, 7-day-off schedule, in a new study.

Both progression-free survival (PFS) and overall survival (OS) were similar between the two groups, but patients on the alternative schedule experienced fewer cases of hand-foot syndrome (HFS), diarrhea, and stomatitis, and also had fewer discontinuations and dose modifications.

The Food and Drug Administration–approved dose of capecitabine is 1,250 mg/m², but 14 days of treatment can lead to significant toxicity, said Qamar Khan, MD, during a presentation of the study at the annual meeting of the American Society of Clinical Oncology. “Mathematical models applied to xenograft [animal model] data suggest that the maximum cytotoxic effect of capecitabine occurs after about 7 days of treatment, beyond which time only toxicity increases,” Dr. Khan said during his talk on the randomized control trial.

The researchers randomized 153 patients to receive a fixed 1,500-mg capecitabine dose twice per day on a 7-day-on, 7-day-off schedule (7/7), or the 1,250–mg/m² dose twice per day for 14 days followed by 7 days off (14/7). The median age was 60 years, and 85.6% were White, 8.5% were African American, 3.3% were Hispanic, 0.7% were American Indian or Alaskan Native, and 2.0% were other. With respect to disease characteristics, 44% had visceral metastasis, 78% were hormone receptor positive/HER2 negative, and 11% had triple-negative breast cancer. About two-thirds (65%) had received no prior chemotherapy.

Restricted mean survival time (RMST) at 36 months for PFS was 13.9 months in the 7/7 group and 14.6 months in the 14/7 group (difference, 0.7 months; 95.5% CI, –3.14 to 4.57 months). The objective response rate was 8.9% in the 7/7 group and 19.6% in the 14/7 group (P = .11). Median OS was 19.8 months in the 7/7 group and 17.5 months in the 14/7 group (hazard ratio, 0.76; P = .17). The RMST at 47 months for OS was 24.5 months in the 7/7 group and 20.9 months in the 14/7 group (difference, –3.6 months; 95% CI, –8.89 to 1.54 months).

The researchers found no differences in subgroup analyses by visceral metastasis, breast cancer subtype, or number of lines of previous therapy.

The toxicity profile of 7/7 was better with respect to grade 2-4 diarrhea (2.5% vs. 20.5%, P = .0008), grade 2-4 HFS (3.8% vs. 15.1%; P = .0019), and grade 2-4 mucositis (0% vs. 5.5%; P =.0001).
 

Findings back up clinical practice

“The fixed-dose capecitabine dosing is something that’s been done a lot in practice, because a lot of practitioners recognize that giving the drug for two weeks in a row with a week break is overly toxic, so it’s something we’ve been doing in the community for quite a while,” said Michael Danso, MD, who comoderated the session.

Still, the safety and efficacy data back up that general clinical practice. “There was a randomized trial and colon cancer that didn’t show [equivalent outcomes with the alternate dosing schedule]. So to see that it’s safe and effective in breast cancer is an important [finding],” said Dr. Danso, who is the Research Director at Virginia Oncology Associates, Norfolk.

During the question-and-answer following the talk, Jeffrey Kirshner, MD, a medical oncologist at Hematology-Oncology Associates of Central New York, East Syracuse, noted that his practice has used a similar schedule for years. “I really commend you for doing that study. It really supports what many of us in the real world have been doing for many years. We figured this out empirically, both upfront and when patients can’t tolerate [the 14/7 schedule].”
 

Fixed dose versus body surface area

Dr. Kirshner also said his practice uses a dose of 1 g/m² of body surface area on a 7/7 schedule rather than a fixed dose as was done in Dr. Khan’s study. “If you use the higher dose, you might have seen a higher response rate because many of our patients, as you know, have a body surface [BSA] area much greater than 1.5 g/m².”

Dr. Khan responded that there is little data available on BSA dosing. “We selected 1,500 mg because a lot of people are practicing that, and for convenience, and that most patients who started at a higher dose eventually wound up on a dose of 1,500 mg twice daily.”

Dr. Kirshner also pointed out that the study was conducted in a population with metastatic disease. “I think we need to emphasize that we do not use the 7/7 regimen in a potentially curative setting, such as the CREATE-X regimen for triple-negative [breast cancer].”

Dr. Khan agreed. “I would use the same dose as the CREATE-X trial in the adjuvant setting,” he responded.

Dr. Danso has received honoraria from Amgen and has consulted or advised Immunomedics, Novartis, Pfizer, and Seagen. Dr. Khan and Dr. Kirshner have no relevant financial disclosures.

Triple-negative breast cancer (TNBC) is characterized by the absence of hormonal receptors and human epidermal growth factor receptor 2 (HER2) expression. Historically, treatments targeting HER2 were found to be ineffective in patients with TNBC and known HER2-zero status. Researchers more recently identified a new type of TNBC involving patients with low expression of HER2. Patients with this type of breast cancer, now referred to as HER2-low, have immunohistochemical (IHC) analysis scores of 1+ or 2+ and negative in situ hybridization (ISH) stain.

In a new study, patients with TNBC who initially tested as having HER2-zero status were later found to have HER2-low status following repeated biopsies. These HER2-low results were of great clinical significance for this patient population, said Yael Bar, MD, PhD, during her presentation of the research, at the annual meeting of the American Society of Clinical Oncology (ASCO).

Previously, the DESTINY-Breast04 trial demonstrated that the antibody-drug conjugate (ADC) trastuzumab deruxtecan (T-DXd) improved progression-free survival (PFS) and overall survival (OS) for patients with HER2-low metastatic breast cancer. “As a result [of the DESTINY-Breast04 findings], T-DXd is now approved for HER2-low but not HER2-zero triple-negative metastatic breast cancer."

“While HER2-low is detected in about 30%-50% of patients with triple-negative breast cancer, several studies have shown that HER2 status is heterogeneous and also dynamic over time, said Dr. Bar, who is an international research fellow in the breast cancer group at Mass General Cancer Center, Boston.

In the new study, Dr. Bar and her co-authors retrospectively identified 512 TNBC patients from 2000 to 2022 from an institutional database. They included core, surgical, or metastatic biopsies. Participants had a mean age of 52 years, with 54% over age 50. They were 83% White, 7% African American, 5% Asian, 3% Hispanic, and 2% other. Stage II was most common at diagnosis at 48%, followed by stage 1 (28%), stage 3 (14%), and stage IV (8%).

Most patients had undergone one (38%) or two (45%) biopsies, while 9% underwent three biopsies, 6% underwent four biopsies, and 2% underwent five or more.

Among all 512 patients in the study, 60% had a HER2-low result on their first biopsy. As of the second biopsy, 73% had at least one HER2-low result, with 13% of the first HER2-low results occurring at the second biopsy. As of the third biopsy, 81% had a HER2-low result, with 9% occurring for the first time. At the fourth biopsy, 86% had a positive result, with 8% occurring for the first time. All patients with five or more biopsies had at least one HER2-low result and none were first-time results.

At the second biopsy, a HER2-low result was detected for 32% of patients for the first time. At the third biopsy, a new HER2-low result was detected in 33%, and at the fourth biopsy, a new HER-2 result was detected in 38%.

The researchers matched early and metastatic biopsies in 71 patients, and 44% had changed status: 68% of those with a status change went HER2-low to HER2-zero, 26% from HER2-zero to HER2-low, and 6% from HER2-low to HER2-positive. Among 50 patients with matched metastatic biopsies, 33% had a change in status, with 63% going from HER2-zero to HER2-low, 31% from HER2-low to HER2-zero, and 6% from HER2-low to HER2-positive.

“We showed here that repeat biopsies can identify new HER2-low results for patients who were previously ineligible for T-DXd; and therefore, we think that a repeat biopsy could be considered if feasible and safe. Also, if a repeat biopsy is performed for any reason, but mainly upon metastatic recurrence, receptors should be retested,” said Dr. Bar.

After Dr. Bar’s presentation, Barbara Pistilli, MD served as a discussant. She noted the increased HER2-low results over successive biopsies. “However, here the question is, are these results related to the changes in the analytical methods over the past 20 years or the changes in the guidelines in terms of definition of HER2 status, or are they more related to a true evolution of HER2 status with the evolution of the disease?” she said during her presentation. Dr. Pistilli is chair of the breast disease committee at Gustave Roussy in Villejuif, France.

She also said that HER2 expression can vary even between different parts of the same tumor and called for alternative methods to following HER2 expression. “I don’t think that we can follow our patients with multiple biopsies over the disease evolution, so we have to find other tools, such as target-positive [circulating tumor cells], or antibody-radiolabeled PET scan in order to better follow the intermetastasis target heterogeneity over time, and finally define what is the optimal ADC sequential strategy for each patient,” said Dr. Pistilli.

Comoderator Michael Danso, MD, also weighed in when asked for comment. 

“It was an important trial to show that serial biopsies potentially allow more patients to receive trastuzumab deruxtecan,” said Dr. Danso, who is the research director at Virginia Oncology Associates, Norfolk. However, he pointed out the concerns of a statistician who had spoken up during the question-and-answer session who said that the positive results could simply be the consequence of repeated testing. “If you do a test often enough, statistically you’re going to get a difference in outcome. That was an important point made. Also, if you’re going to get 100% of patients who are eventually going to [develop HER2-low status], the question is, can you just treat everybody with trastuzumab deruxtecan and not do these sequential biopsies? Obviously that is subject to cost; it’s subject to toxicity as well, so you probably want documentation that there is a HER2-low result,” said Dr. Danso.

Dr. Bar has no relevant financial disclosures. Dr. Pistilli has consulted for or advised AstraZeneca, Daiichi Sankyo/UCB Japan, Myriad Genetics, Novartis, PIERRE FABRE, and Puma Biotechnology. She has received research funding through her institution from AstraZeneca, Daiichi Sankyo, Gilead Sciences, Merus, Pfizer, and Puma Biotechnology. She has received travel or accommodation expenses from AstraZeneca, Daiichi Sankyo Europe, MSD Oncology, Novartis, Pfizer, and Pierre Fabre. Dr. Danso has received honoraria from Amgen and has consulted or advised Immunomedics, Novartis, Pfizer, and Seagen.

*This story was updated on 6/13/2023.

Triple-negative breast cancer (TNBC) is characterized by the absence of hormonal receptors and human epidermal growth factor receptor 2 (HER2) expression. Historically, treatments targeting HER2 were found to be ineffective in patients with TNBC and known HER2-zero status. Researchers more recently identified a new type of TNBC involving patients with low expression of HER2. Patients with this type of breast cancer, now referred to as HER2-low, have immunohistochemical (IHC) analysis scores of 1+ or 2+ and negative in situ hybridization (ISH) stain.

In a new study, patients with TNBC who initially tested as having HER2-zero status were later found to have HER2-low status following repeated biopsies. These HER2-low results were of great clinical significance for this patient population, said Yael Bar, MD, PhD, during her presentation of the research, at the annual meeting of the American Society of Clinical Oncology (ASCO).

Previously, the DESTINY-Breast04 trial demonstrated that the antibody-drug conjugate (ADC) trastuzumab deruxtecan (T-DXd) improved progression-free survival (PFS) and overall survival (OS) for patients with HER2-low metastatic breast cancer. “As a result [of the DESTINY-Breast04 findings], T-DXd is now approved for HER2-low but not HER2-zero triple-negative metastatic breast cancer."

“While HER2-low is detected in about 30%-50% of patients with triple-negative breast cancer, several studies have shown that HER2 status is heterogeneous and also dynamic over time, said Dr. Bar, who is an international research fellow in the breast cancer group at Mass General Cancer Center, Boston.

In the new study, Dr. Bar and her co-authors retrospectively identified 512 TNBC patients from 2000 to 2022 from an institutional database. They included core, surgical, or metastatic biopsies. Participants had a mean age of 52 years, with 54% over age 50. They were 83% White, 7% African American, 5% Asian, 3% Hispanic, and 2% other. Stage II was most common at diagnosis at 48%, followed by stage 1 (28%), stage 3 (14%), and stage IV (8%).

Most patients had undergone one (38%) or two (45%) biopsies, while 9% underwent three biopsies, 6% underwent four biopsies, and 2% underwent five or more.

Among all 512 patients in the study, 60% had a HER2-low result on their first biopsy. As of the second biopsy, 73% had at least one HER2-low result, with 13% of the first HER2-low results occurring at the second biopsy. As of the third biopsy, 81% had a HER2-low result, with 9% occurring for the first time. At the fourth biopsy, 86% had a positive result, with 8% occurring for the first time. All patients with five or more biopsies had at least one HER2-low result and none were first-time results.

At the second biopsy, a HER2-low result was detected for 32% of patients for the first time. At the third biopsy, a new HER2-low result was detected in 33%, and at the fourth biopsy, a new HER-2 result was detected in 38%.

The researchers matched early and metastatic biopsies in 71 patients, and 44% had changed status: 68% of those with a status change went HER2-low to HER2-zero, 26% from HER2-zero to HER2-low, and 6% from HER2-low to HER2-positive. Among 50 patients with matched metastatic biopsies, 33% had a change in status, with 63% going from HER2-zero to HER2-low, 31% from HER2-low to HER2-zero, and 6% from HER2-low to HER2-positive.

“We showed here that repeat biopsies can identify new HER2-low results for patients who were previously ineligible for T-DXd; and therefore, we think that a repeat biopsy could be considered if feasible and safe. Also, if a repeat biopsy is performed for any reason, but mainly upon metastatic recurrence, receptors should be retested,” said Dr. Bar.

After Dr. Bar’s presentation, Barbara Pistilli, MD served as a discussant. She noted the increased HER2-low results over successive biopsies. “However, here the question is, are these results related to the changes in the analytical methods over the past 20 years or the changes in the guidelines in terms of definition of HER2 status, or are they more related to a true evolution of HER2 status with the evolution of the disease?” she said during her presentation. Dr. Pistilli is chair of the breast disease committee at Gustave Roussy in Villejuif, France.

She also said that HER2 expression can vary even between different parts of the same tumor and called for alternative methods to following HER2 expression. “I don’t think that we can follow our patients with multiple biopsies over the disease evolution, so we have to find other tools, such as target-positive [circulating tumor cells], or antibody-radiolabeled PET scan in order to better follow the intermetastasis target heterogeneity over time, and finally define what is the optimal ADC sequential strategy for each patient,” said Dr. Pistilli.

Comoderator Michael Danso, MD, also weighed in when asked for comment. 

“It was an important trial to show that serial biopsies potentially allow more patients to receive trastuzumab deruxtecan,” said Dr. Danso, who is the research director at Virginia Oncology Associates, Norfolk. However, he pointed out the concerns of a statistician who had spoken up during the question-and-answer session who said that the positive results could simply be the consequence of repeated testing. “If you do a test often enough, statistically you’re going to get a difference in outcome. That was an important point made. Also, if you’re going to get 100% of patients who are eventually going to [develop HER2-low status], the question is, can you just treat everybody with trastuzumab deruxtecan and not do these sequential biopsies? Obviously that is subject to cost; it’s subject to toxicity as well, so you probably want documentation that there is a HER2-low result,” said Dr. Danso.

Dr. Bar has no relevant financial disclosures. Dr. Pistilli has consulted for or advised AstraZeneca, Daiichi Sankyo/UCB Japan, Myriad Genetics, Novartis, PIERRE FABRE, and Puma Biotechnology. She has received research funding through her institution from AstraZeneca, Daiichi Sankyo, Gilead Sciences, Merus, Pfizer, and Puma Biotechnology. She has received travel or accommodation expenses from AstraZeneca, Daiichi Sankyo Europe, MSD Oncology, Novartis, Pfizer, and Pierre Fabre. Dr. Danso has received honoraria from Amgen and has consulted or advised Immunomedics, Novartis, Pfizer, and Seagen.

*This story was updated on 6/13/2023.

Triple-negative breast cancer (TNBC) is characterized by the absence of hormonal receptors and human epidermal growth factor receptor 2 (HER2) expression. Historically, treatments targeting HER2 were found to be ineffective in patients with TNBC and known HER2-zero status. Researchers more recently identified a new type of TNBC involving patients with low expression of HER2. Patients with this type of breast cancer, now referred to as HER2-low, have immunohistochemical (IHC) analysis scores of 1+ or 2+ and negative in situ hybridization (ISH) stain.

In a new study, patients with TNBC who initially tested as having HER2-zero status were later found to have HER2-low status following repeated biopsies. These HER2-low results were of great clinical significance for this patient population, said Yael Bar, MD, PhD, during her presentation of the research, at the annual meeting of the American Society of Clinical Oncology (ASCO).

Previously, the DESTINY-Breast04 trial demonstrated that the antibody-drug conjugate (ADC) trastuzumab deruxtecan (T-DXd) improved progression-free survival (PFS) and overall survival (OS) for patients with HER2-low metastatic breast cancer. “As a result [of the DESTINY-Breast04 findings], T-DXd is now approved for HER2-low but not HER2-zero triple-negative metastatic breast cancer."

“While HER2-low is detected in about 30%-50% of patients with triple-negative breast cancer, several studies have shown that HER2 status is heterogeneous and also dynamic over time, said Dr. Bar, who is an international research fellow in the breast cancer group at Mass General Cancer Center, Boston.

In the new study, Dr. Bar and her co-authors retrospectively identified 512 TNBC patients from 2000 to 2022 from an institutional database. They included core, surgical, or metastatic biopsies. Participants had a mean age of 52 years, with 54% over age 50. They were 83% White, 7% African American, 5% Asian, 3% Hispanic, and 2% other. Stage II was most common at diagnosis at 48%, followed by stage 1 (28%), stage 3 (14%), and stage IV (8%).

Most patients had undergone one (38%) or two (45%) biopsies, while 9% underwent three biopsies, 6% underwent four biopsies, and 2% underwent five or more.

Among all 512 patients in the study, 60% had a HER2-low result on their first biopsy. As of the second biopsy, 73% had at least one HER2-low result, with 13% of the first HER2-low results occurring at the second biopsy. As of the third biopsy, 81% had a HER2-low result, with 9% occurring for the first time. At the fourth biopsy, 86% had a positive result, with 8% occurring for the first time. All patients with five or more biopsies had at least one HER2-low result and none were first-time results.

At the second biopsy, a HER2-low result was detected for 32% of patients for the first time. At the third biopsy, a new HER2-low result was detected in 33%, and at the fourth biopsy, a new HER-2 result was detected in 38%.

The researchers matched early and metastatic biopsies in 71 patients, and 44% had changed status: 68% of those with a status change went HER2-low to HER2-zero, 26% from HER2-zero to HER2-low, and 6% from HER2-low to HER2-positive. Among 50 patients with matched metastatic biopsies, 33% had a change in status, with 63% going from HER2-zero to HER2-low, 31% from HER2-low to HER2-zero, and 6% from HER2-low to HER2-positive.

“We showed here that repeat biopsies can identify new HER2-low results for patients who were previously ineligible for T-DXd; and therefore, we think that a repeat biopsy could be considered if feasible and safe. Also, if a repeat biopsy is performed for any reason, but mainly upon metastatic recurrence, receptors should be retested,” said Dr. Bar.

After Dr. Bar’s presentation, Barbara Pistilli, MD served as a discussant. She noted the increased HER2-low results over successive biopsies. “However, here the question is, are these results related to the changes in the analytical methods over the past 20 years or the changes in the guidelines in terms of definition of HER2 status, or are they more related to a true evolution of HER2 status with the evolution of the disease?” she said during her presentation. Dr. Pistilli is chair of the breast disease committee at Gustave Roussy in Villejuif, France.

She also said that HER2 expression can vary even between different parts of the same tumor and called for alternative methods to following HER2 expression. “I don’t think that we can follow our patients with multiple biopsies over the disease evolution, so we have to find other tools, such as target-positive [circulating tumor cells], or antibody-radiolabeled PET scan in order to better follow the intermetastasis target heterogeneity over time, and finally define what is the optimal ADC sequential strategy for each patient,” said Dr. Pistilli.

Comoderator Michael Danso, MD, also weighed in when asked for comment. 

“It was an important trial to show that serial biopsies potentially allow more patients to receive trastuzumab deruxtecan,” said Dr. Danso, who is the research director at Virginia Oncology Associates, Norfolk. However, he pointed out the concerns of a statistician who had spoken up during the question-and-answer session who said that the positive results could simply be the consequence of repeated testing. “If you do a test often enough, statistically you’re going to get a difference in outcome. That was an important point made. Also, if you’re going to get 100% of patients who are eventually going to [develop HER2-low status], the question is, can you just treat everybody with trastuzumab deruxtecan and not do these sequential biopsies? Obviously that is subject to cost; it’s subject to toxicity as well, so you probably want documentation that there is a HER2-low result,” said Dr. Danso.

Dr. Bar has no relevant financial disclosures. Dr. Pistilli has consulted for or advised AstraZeneca, Daiichi Sankyo/UCB Japan, Myriad Genetics, Novartis, PIERRE FABRE, and Puma Biotechnology. She has received research funding through her institution from AstraZeneca, Daiichi Sankyo, Gilead Sciences, Merus, Pfizer, and Puma Biotechnology. She has received travel or accommodation expenses from AstraZeneca, Daiichi Sankyo Europe, MSD Oncology, Novartis, Pfizer, and Pierre Fabre. Dr. Danso has received honoraria from Amgen and has consulted or advised Immunomedics, Novartis, Pfizer, and Seagen.

*This story was updated on 6/13/2023.

CHICAGO – Patients with advanced estrogen receptor–positive, HER-negative breast cancer receiving first line treatment with CDK4/6 inhibitors (CDK4/6i) experienced no progression-free survival (PFS) or overall survival (OS) advantages over those who received the same therapy as second line treatment.

That was the conclusion of the phase 3 SONIA study, which was presented at the annual meeting of the American Society of Clinical Oncology.

The benefit from first line therapy is not maintained and almost completely disappears when patients in the control arm cross over to receive CDK4/6 inhibition in second line,” said Gabe Sonke, MD, PhD, during his presentation at the meeting.

CDK4/6 inhibitors have shown benefit in both the first-and second-line setting, according to Dr. Sonke, who is a medical oncologist at the Netherlands Cancer Institute, Amsterdam. He added that most guidelines suggest use of CDK4/6 inhibitors in the first line, but there hasn’t been a direct comparison between use in the first and second line.

“Many patients do very well on endocrine therapy alone [in the first line]. Combination treatment leads to a higher risk of the emergence of resistant patterns such as ESR1 mutations, and CDK4/6 inhibitors also come with added costs and toxicities. Given the absence of comparative data between first line and second line, we designed the SONIA trial,” said Dr. Sonke.
 

Study methods and results

The researchers recruited 1,050 pre- and postmenopausal women who were randomized to a nonsteroidal AI in the first line followed by second-line CDK4/6i plus the estrogen receptor antagonist fulvestrant, or a nonsteroidal AI plus a CDK4/6i in the first line and fulvestrant in the second line. The most commonly used CDK4/6i was palbociclib at 91%, followed by ribociclib at 8%, and abemaciclib at 1%.

After a median follow-up of 37.3 months, the median duration of CDK4/6i exposure was 24.6 months in the first-line CDK4/6i group and 8.1 months in the second-line CDK4/6i group.

The median PFS during first-line therapy was 24.7 months in the first-line CDK4/6i group and 16.1 months in the second-line CDK4/6i group (hazard ratio, 0.59; P < .0001), which was consistent with the results seen in CDK4/6i pivotal trials in the first-line setting, according to Dr. Sonke. However, PFS after two lines of therapy was not significantly different between the groups (31.0 months vs. 26.8 months, respectively; HR, 0.87; P =.10).

The safety profile was similar to what had been seen in previous trials with respect to adverse events like bone marrow and liver function abnormalities and fatigue, but there were 42% more grade 3 or higher adverse events in the first-line CDK4/6i group than in the second-line CDK4/6i group. Dr. Sonke estimated that the increase in costs related to adverse events amounted to about $200,000 per patient receiving CDK4/6i as first line.

There were no significant differences between the two groups in quality of life measurement.

Subgroup analyses of patient categories including prior adjuvant or neoadjuvant chemotherapy or endocrine therapy, de novo metastatic disease, visceral disease, bone-only disease, and treatment with palbociclib or ribociclib showed no difference in outcome for first- versus second-line CDK4/6i treatment.
 

Are CDK4/6i costs and side effects worth it?

The findings challenge the need for using CDK4/6 inhibitors as first-line treatment in this population, according to Dr. Sonke, who also raised the following related questions.

“If you were a patient, would you consider a treatment that offers no improvement in quality of life and does not improve overall survival? As a doctor or nurse, would you recommend such a treatment to your patient that nearly doubles the incidence of side effects? And if you were responsible for covering the costs of this treatment, whether as an individual or health care insurance, would you consider it worth $200,000?”

For many patients, particularly in the first line setting where resistance mechanisms are less prevalent, endocrine therapy alone remains an excellent option,” said Dr. Sonke during his presentation.

During the discussion portion of the session, Daniel Stover, MD, who is an associate professor of translational therapeutics at Ohio State University Comprehensive Cancer Center, Columbus, pointed out that the lack of differences in the subanalyses leaves little guidance for physicians.

“We really have a limited signal on who can delay CDK4/6 inhibitors. I think one of the most important outcomes of this study is the focus on the patient, as there were substantially fewer adverse events and of course we need to think about financial toxicity as well,” he said. “I think one of the things that is perhaps most exciting to think about is who are the very good risk patients who can delay CDK4/6 inhibitor [therapy]? I think for the majority of patients, endocrine therapy plus CDK4/6 inhibitor is still the appropriate treatment, but I would argue we need additional biomarkers, be it RNA-based biomarkers, novel PET imaging, or perhaps [circulating tumor] DNA dynamics.”
 

Do cost savings and reduced side effects outweigh first-line PFS benefit?

During the question-and-answer session, William Sikov, MD, spoke up from the audience in support of Dr. Sonke’s conclusions.

“Clearly there are still patients who benefit from that approach, but I think that we have reached an inflection point: I posit that the question has now changed. [We should not ask] why a certain patient should not receive a CDK4/6 inhibitor, but why a certain patient should receive a CDK4/6 inhibitor in the first-line setting,” said Dr. Sikov, who is professor of medicine at Brown University, Providence, R.I.

Dr. Sonke agreed that first-line CDK4/6i is appropriate for some patients, and later echoed the need for biomarkers, but he said that researchers have so far had little luck in identifying any.

“Of course, it’s a shared decision-making between the patient and a doctor, but I think the baseline would be for all of us to consider first line single-agent endocrine therapy,” he said.

Session comoderator Michael Danso, MD, praised the trial but questioned whether the strategy would be adopted in places like the United States, where cost savings is not a major emphasis.

“Progression-free survival is so significant in the first line setting that I can’t imagine that many oncologists in the U.S. will adopt this approach. The other thing is that this was [almost] all palbociclib, so the question remains, would having a different cyclin dependent kinase inhibitor result in the same results? I think the jury’s still out,” said Dr. Danso, who is the research director at Virginia Oncology Associates, Norfolk.

The study was funded by the Dutch government and Dutch Health Insurers. Dr. Sonke has consulted for or advised Biovica, Novartis, and Seagen. He has received research support through his institution from Agendia, AstraZeneca/Merck, Merck Sharp & Dohme, Novartis, Roche, and Seagen. Dr. Sikov has been a speaker for Lilly. Dr. Danso has received honoraria from Amgen and has consulted or advised Immunomedics, Novartis, Pfizer, and Seagen.

CHICAGO – Patients with advanced estrogen receptor–positive, HER-negative breast cancer receiving first line treatment with CDK4/6 inhibitors (CDK4/6i) experienced no progression-free survival (PFS) or overall survival (OS) advantages over those who received the same therapy as second line treatment.

That was the conclusion of the phase 3 SONIA study, which was presented at the annual meeting of the American Society of Clinical Oncology.

The benefit from first line therapy is not maintained and almost completely disappears when patients in the control arm cross over to receive CDK4/6 inhibition in second line,” said Gabe Sonke, MD, PhD, during his presentation at the meeting.

CDK4/6 inhibitors have shown benefit in both the first-and second-line setting, according to Dr. Sonke, who is a medical oncologist at the Netherlands Cancer Institute, Amsterdam. He added that most guidelines suggest use of CDK4/6 inhibitors in the first line, but there hasn’t been a direct comparison between use in the first and second line.

“Many patients do very well on endocrine therapy alone [in the first line]. Combination treatment leads to a higher risk of the emergence of resistant patterns such as ESR1 mutations, and CDK4/6 inhibitors also come with added costs and toxicities. Given the absence of comparative data between first line and second line, we designed the SONIA trial,” said Dr. Sonke.
 

Study methods and results

The researchers recruited 1,050 pre- and postmenopausal women who were randomized to a nonsteroidal AI in the first line followed by second-line CDK4/6i plus the estrogen receptor antagonist fulvestrant, or a nonsteroidal AI plus a CDK4/6i in the first line and fulvestrant in the second line. The most commonly used CDK4/6i was palbociclib at 91%, followed by ribociclib at 8%, and abemaciclib at 1%.

After a median follow-up of 37.3 months, the median duration of CDK4/6i exposure was 24.6 months in the first-line CDK4/6i group and 8.1 months in the second-line CDK4/6i group.

The median PFS during first-line therapy was 24.7 months in the first-line CDK4/6i group and 16.1 months in the second-line CDK4/6i group (hazard ratio, 0.59; P < .0001), which was consistent with the results seen in CDK4/6i pivotal trials in the first-line setting, according to Dr. Sonke. However, PFS after two lines of therapy was not significantly different between the groups (31.0 months vs. 26.8 months, respectively; HR, 0.87; P =.10).

The safety profile was similar to what had been seen in previous trials with respect to adverse events like bone marrow and liver function abnormalities and fatigue, but there were 42% more grade 3 or higher adverse events in the first-line CDK4/6i group than in the second-line CDK4/6i group. Dr. Sonke estimated that the increase in costs related to adverse events amounted to about $200,000 per patient receiving CDK4/6i as first line.

There were no significant differences between the two groups in quality of life measurement.

Subgroup analyses of patient categories including prior adjuvant or neoadjuvant chemotherapy or endocrine therapy, de novo metastatic disease, visceral disease, bone-only disease, and treatment with palbociclib or ribociclib showed no difference in outcome for first- versus second-line CDK4/6i treatment.
 

Are CDK4/6i costs and side effects worth it?

The findings challenge the need for using CDK4/6 inhibitors as first-line treatment in this population, according to Dr. Sonke, who also raised the following related questions.

“If you were a patient, would you consider a treatment that offers no improvement in quality of life and does not improve overall survival? As a doctor or nurse, would you recommend such a treatment to your patient that nearly doubles the incidence of side effects? And if you were responsible for covering the costs of this treatment, whether as an individual or health care insurance, would you consider it worth $200,000?”

For many patients, particularly in the first line setting where resistance mechanisms are less prevalent, endocrine therapy alone remains an excellent option,” said Dr. Sonke during his presentation.

During the discussion portion of the session, Daniel Stover, MD, who is an associate professor of translational therapeutics at Ohio State University Comprehensive Cancer Center, Columbus, pointed out that the lack of differences in the subanalyses leaves little guidance for physicians.

“We really have a limited signal on who can delay CDK4/6 inhibitors. I think one of the most important outcomes of this study is the focus on the patient, as there were substantially fewer adverse events and of course we need to think about financial toxicity as well,” he said. “I think one of the things that is perhaps most exciting to think about is who are the very good risk patients who can delay CDK4/6 inhibitor [therapy]? I think for the majority of patients, endocrine therapy plus CDK4/6 inhibitor is still the appropriate treatment, but I would argue we need additional biomarkers, be it RNA-based biomarkers, novel PET imaging, or perhaps [circulating tumor] DNA dynamics.”
 

Do cost savings and reduced side effects outweigh first-line PFS benefit?

During the question-and-answer session, William Sikov, MD, spoke up from the audience in support of Dr. Sonke’s conclusions.

“Clearly there are still patients who benefit from that approach, but I think that we have reached an inflection point: I posit that the question has now changed. [We should not ask] why a certain patient should not receive a CDK4/6 inhibitor, but why a certain patient should receive a CDK4/6 inhibitor in the first-line setting,” said Dr. Sikov, who is professor of medicine at Brown University, Providence, R.I.

Dr. Sonke agreed that first-line CDK4/6i is appropriate for some patients, and later echoed the need for biomarkers, but he said that researchers have so far had little luck in identifying any.

“Of course, it’s a shared decision-making between the patient and a doctor, but I think the baseline would be for all of us to consider first line single-agent endocrine therapy,” he said.

Session comoderator Michael Danso, MD, praised the trial but questioned whether the strategy would be adopted in places like the United States, where cost savings is not a major emphasis.

“Progression-free survival is so significant in the first line setting that I can’t imagine that many oncologists in the U.S. will adopt this approach. The other thing is that this was [almost] all palbociclib, so the question remains, would having a different cyclin dependent kinase inhibitor result in the same results? I think the jury’s still out,” said Dr. Danso, who is the research director at Virginia Oncology Associates, Norfolk.

The study was funded by the Dutch government and Dutch Health Insurers. Dr. Sonke has consulted for or advised Biovica, Novartis, and Seagen. He has received research support through his institution from Agendia, AstraZeneca/Merck, Merck Sharp & Dohme, Novartis, Roche, and Seagen. Dr. Sikov has been a speaker for Lilly. Dr. Danso has received honoraria from Amgen and has consulted or advised Immunomedics, Novartis, Pfizer, and Seagen.

CHICAGO – Patients with advanced estrogen receptor–positive, HER-negative breast cancer receiving first line treatment with CDK4/6 inhibitors (CDK4/6i) experienced no progression-free survival (PFS) or overall survival (OS) advantages over those who received the same therapy as second line treatment.

That was the conclusion of the phase 3 SONIA study, which was presented at the annual meeting of the American Society of Clinical Oncology.

The benefit from first line therapy is not maintained and almost completely disappears when patients in the control arm cross over to receive CDK4/6 inhibition in second line,” said Gabe Sonke, MD, PhD, during his presentation at the meeting.

CDK4/6 inhibitors have shown benefit in both the first-and second-line setting, according to Dr. Sonke, who is a medical oncologist at the Netherlands Cancer Institute, Amsterdam. He added that most guidelines suggest use of CDK4/6 inhibitors in the first line, but there hasn’t been a direct comparison between use in the first and second line.

“Many patients do very well on endocrine therapy alone [in the first line]. Combination treatment leads to a higher risk of the emergence of resistant patterns such as ESR1 mutations, and CDK4/6 inhibitors also come with added costs and toxicities. Given the absence of comparative data between first line and second line, we designed the SONIA trial,” said Dr. Sonke.
 

Study methods and results

The researchers recruited 1,050 pre- and postmenopausal women who were randomized to a nonsteroidal AI in the first line followed by second-line CDK4/6i plus the estrogen receptor antagonist fulvestrant, or a nonsteroidal AI plus a CDK4/6i in the first line and fulvestrant in the second line. The most commonly used CDK4/6i was palbociclib at 91%, followed by ribociclib at 8%, and abemaciclib at 1%.

After a median follow-up of 37.3 months, the median duration of CDK4/6i exposure was 24.6 months in the first-line CDK4/6i group and 8.1 months in the second-line CDK4/6i group.

The median PFS during first-line therapy was 24.7 months in the first-line CDK4/6i group and 16.1 months in the second-line CDK4/6i group (hazard ratio, 0.59; P < .0001), which was consistent with the results seen in CDK4/6i pivotal trials in the first-line setting, according to Dr. Sonke. However, PFS after two lines of therapy was not significantly different between the groups (31.0 months vs. 26.8 months, respectively; HR, 0.87; P =.10).

The safety profile was similar to what had been seen in previous trials with respect to adverse events like bone marrow and liver function abnormalities and fatigue, but there were 42% more grade 3 or higher adverse events in the first-line CDK4/6i group than in the second-line CDK4/6i group. Dr. Sonke estimated that the increase in costs related to adverse events amounted to about $200,000 per patient receiving CDK4/6i as first line.

There were no significant differences between the two groups in quality of life measurement.

Subgroup analyses of patient categories including prior adjuvant or neoadjuvant chemotherapy or endocrine therapy, de novo metastatic disease, visceral disease, bone-only disease, and treatment with palbociclib or ribociclib showed no difference in outcome for first- versus second-line CDK4/6i treatment.
 

Are CDK4/6i costs and side effects worth it?

The findings challenge the need for using CDK4/6 inhibitors as first-line treatment in this population, according to Dr. Sonke, who also raised the following related questions.

“If you were a patient, would you consider a treatment that offers no improvement in quality of life and does not improve overall survival? As a doctor or nurse, would you recommend such a treatment to your patient that nearly doubles the incidence of side effects? And if you were responsible for covering the costs of this treatment, whether as an individual or health care insurance, would you consider it worth $200,000?”

For many patients, particularly in the first line setting where resistance mechanisms are less prevalent, endocrine therapy alone remains an excellent option,” said Dr. Sonke during his presentation.

During the discussion portion of the session, Daniel Stover, MD, who is an associate professor of translational therapeutics at Ohio State University Comprehensive Cancer Center, Columbus, pointed out that the lack of differences in the subanalyses leaves little guidance for physicians.

“We really have a limited signal on who can delay CDK4/6 inhibitors. I think one of the most important outcomes of this study is the focus on the patient, as there were substantially fewer adverse events and of course we need to think about financial toxicity as well,” he said. “I think one of the things that is perhaps most exciting to think about is who are the very good risk patients who can delay CDK4/6 inhibitor [therapy]? I think for the majority of patients, endocrine therapy plus CDK4/6 inhibitor is still the appropriate treatment, but I would argue we need additional biomarkers, be it RNA-based biomarkers, novel PET imaging, or perhaps [circulating tumor] DNA dynamics.”
 

Do cost savings and reduced side effects outweigh first-line PFS benefit?

During the question-and-answer session, William Sikov, MD, spoke up from the audience in support of Dr. Sonke’s conclusions.

“Clearly there are still patients who benefit from that approach, but I think that we have reached an inflection point: I posit that the question has now changed. [We should not ask] why a certain patient should not receive a CDK4/6 inhibitor, but why a certain patient should receive a CDK4/6 inhibitor in the first-line setting,” said Dr. Sikov, who is professor of medicine at Brown University, Providence, R.I.

Dr. Sonke agreed that first-line CDK4/6i is appropriate for some patients, and later echoed the need for biomarkers, but he said that researchers have so far had little luck in identifying any.

“Of course, it’s a shared decision-making between the patient and a doctor, but I think the baseline would be for all of us to consider first line single-agent endocrine therapy,” he said.

Session comoderator Michael Danso, MD, praised the trial but questioned whether the strategy would be adopted in places like the United States, where cost savings is not a major emphasis.

“Progression-free survival is so significant in the first line setting that I can’t imagine that many oncologists in the U.S. will adopt this approach. The other thing is that this was [almost] all palbociclib, so the question remains, would having a different cyclin dependent kinase inhibitor result in the same results? I think the jury’s still out,” said Dr. Danso, who is the research director at Virginia Oncology Associates, Norfolk.

The study was funded by the Dutch government and Dutch Health Insurers. Dr. Sonke has consulted for or advised Biovica, Novartis, and Seagen. He has received research support through his institution from Agendia, AstraZeneca/Merck, Merck Sharp & Dohme, Novartis, Roche, and Seagen. Dr. Sikov has been a speaker for Lilly. Dr. Danso has received honoraria from Amgen and has consulted or advised Immunomedics, Novartis, Pfizer, and Seagen.

A new review drafted by three Canadian psychiatrists aims to help primary care physicians diagnose and manage depression in adolescents. 

Depression is common among Canadian adolescents and often goes unnoticed. Many family physicians report feeling unprepared to identify and manage depression in these patients.

“Depression is an increasingly common but treatable condition among adolescents,” the authors wrote. “Primary care physicians and pediatricians are well positioned to support the assessment and first-line management of depression in this group, helping patients to regain their health and function.”

The article was published in CMAJ.
 

Distinct presentation

More than 40% of cases of depression begin during childhood. Onset at this life stage is associated with worse severity of depression in adulthood and worse social, occupational, and physical health outcomes.

Depression is influenced by genetic and environmental factors. Family history of depression is associated with a three- to fivefold increased risk of depression among older children. Genetic loci are known to be associated with depression, but exposure to parental depression, adverse childhood experiences, and family conflict are also linked to greater risk. Bullying and stigma are associated with greater risk among lesbian, gay, bisexual, and transgender youth.

Compared with adults, adolescents with depression are more likely to be irritable and to have a labile mood, rather than a low mood. Social withdrawal is also more common among adolescents than among adults. Unusual features, such as hypersomnia and increased appetite, may also be present. Anxiety, somatic symptoms, psychomotor agitation, and hallucinations are more common in adolescents than in younger persons with depression. It is vital to assess risk of suicidality and self-injury as well as support systems, and validated scales such as the Columbia Suicide Severity Rating Scale can be useful.

There is no consensus as to whether universal screening for depression is beneficial among adolescents. “Screening in this age group may be a reasonable approach, however, when implemented together with adequate systems that ensure accurate diagnosis and appropriate follow-up,” wrote the authors.

Management of depression in adolescents should begin with psychoeducation and may include lifestyle modification, psychotherapy, and medication. “Importantly, a suicide risk assessment must be done to ensure appropriateness of an outpatient management plan and facilitate safety planning,” the authors wrote.

Lifestyle interventions may target physical activity, diet, and sleep, since unhealthy patterns in all three are associated with heightened symptoms of depression in this population. Regular moderate to vigorous physical activity, and perhaps physical activity of short duration, can improve mood in adolescents. Reduced consumption of sugar-sweetened drinks, processed foods, and meats, along with greater consumption of fruits and legumes, has been shown to reduce depressive symptoms in randomized, controlled trials with adults.

Among psychotherapeutic approaches, cognitive-behavioral therapy has shown the most evidence of efficacy among adolescents with depression, though it is less effective for those with more severe symptoms, poor coping skills, and nonsuicidal self-injury. Some evidence supports interpersonal therapy, which focuses on relationships and social functioning. The involvement of caregivers may improve the response, compared with psychotherapy that only includes the adolescent.

The authors recommend antidepressant medications in more severe cases or when psychotherapy is ineffective or impossible. Guidelines generally support trials with at least two SSRIs before switching to another drug class, since efficacy data for them are sparser, and other drugs have worse side effect profiles.

About 2% of adolescents with depression experience an increase in suicidal ideation and behavior after exposure to antidepressants, usually within the first weeks of initiation, so this potential risk should be discussed with patients and caregivers.
 

Clinicians feel unprepared

Commenting on the review, Pierre-Paul Tellier, MD, an associate professor of family medicine at McGill University, Montreal, said that clinicians frequently report that they do not feel confident in their ability to manage and diagnose adolescent depression. “We did two systematic reviews to look at the continuing professional development of family physicians in adolescent health, and it turned out that there’s really a very large lack. When we looked at residents and the training that they were getting in adolescent medicine, it was very similar, so they felt unprepared to deal with issues around mental health.”

Medication can be effective, but it can be seen as “an easy way out,” Dr. Tellier added. “It’s not necessarily an ideal plan. What we need to do is to change the person’s way of thinking, the person’s way of responding to a variety of things which will occur throughout their lives. People will have other transition periods in their lives. It’s best if they learn a variety of techniques to deal with depression.”

These techniques include exercise, relaxation methods [which reduce anxiety], and wellness training. Through such techniques, patients “learn a healthier way of living with themselves and who they are, and then this is a lifelong way of learning,” said Dr. Tellier. “If I give you a pill, what I’m teaching is, yes, you can feel better. But you’re not dealing with the problem, you’re just dealing with the symptoms.”

He frequently refers his patients to YouTube videos that outline and explain various strategies. A favorite is a deep breathing exercise presented by Jeremy Howick.

The authors and Dr. Tellier disclosed no relevant financial relationships.

A version of this article first appeared on Medscape.com.

A new review drafted by three Canadian psychiatrists aims to help primary care physicians diagnose and manage depression in adolescents. 

Depression is common among Canadian adolescents and often goes unnoticed. Many family physicians report feeling unprepared to identify and manage depression in these patients.

“Depression is an increasingly common but treatable condition among adolescents,” the authors wrote. “Primary care physicians and pediatricians are well positioned to support the assessment and first-line management of depression in this group, helping patients to regain their health and function.”

The article was published in CMAJ.
 

Distinct presentation

More than 40% of cases of depression begin during childhood. Onset at this life stage is associated with worse severity of depression in adulthood and worse social, occupational, and physical health outcomes.

Depression is influenced by genetic and environmental factors. Family history of depression is associated with a three- to fivefold increased risk of depression among older children. Genetic loci are known to be associated with depression, but exposure to parental depression, adverse childhood experiences, and family conflict are also linked to greater risk. Bullying and stigma are associated with greater risk among lesbian, gay, bisexual, and transgender youth.

Compared with adults, adolescents with depression are more likely to be irritable and to have a labile mood, rather than a low mood. Social withdrawal is also more common among adolescents than among adults. Unusual features, such as hypersomnia and increased appetite, may also be present. Anxiety, somatic symptoms, psychomotor agitation, and hallucinations are more common in adolescents than in younger persons with depression. It is vital to assess risk of suicidality and self-injury as well as support systems, and validated scales such as the Columbia Suicide Severity Rating Scale can be useful.

There is no consensus as to whether universal screening for depression is beneficial among adolescents. “Screening in this age group may be a reasonable approach, however, when implemented together with adequate systems that ensure accurate diagnosis and appropriate follow-up,” wrote the authors.

Management of depression in adolescents should begin with psychoeducation and may include lifestyle modification, psychotherapy, and medication. “Importantly, a suicide risk assessment must be done to ensure appropriateness of an outpatient management plan and facilitate safety planning,” the authors wrote.

Lifestyle interventions may target physical activity, diet, and sleep, since unhealthy patterns in all three are associated with heightened symptoms of depression in this population. Regular moderate to vigorous physical activity, and perhaps physical activity of short duration, can improve mood in adolescents. Reduced consumption of sugar-sweetened drinks, processed foods, and meats, along with greater consumption of fruits and legumes, has been shown to reduce depressive symptoms in randomized, controlled trials with adults.

Among psychotherapeutic approaches, cognitive-behavioral therapy has shown the most evidence of efficacy among adolescents with depression, though it is less effective for those with more severe symptoms, poor coping skills, and nonsuicidal self-injury. Some evidence supports interpersonal therapy, which focuses on relationships and social functioning. The involvement of caregivers may improve the response, compared with psychotherapy that only includes the adolescent.

The authors recommend antidepressant medications in more severe cases or when psychotherapy is ineffective or impossible. Guidelines generally support trials with at least two SSRIs before switching to another drug class, since efficacy data for them are sparser, and other drugs have worse side effect profiles.

About 2% of adolescents with depression experience an increase in suicidal ideation and behavior after exposure to antidepressants, usually within the first weeks of initiation, so this potential risk should be discussed with patients and caregivers.
 

Clinicians feel unprepared

Commenting on the review, Pierre-Paul Tellier, MD, an associate professor of family medicine at McGill University, Montreal, said that clinicians frequently report that they do not feel confident in their ability to manage and diagnose adolescent depression. “We did two systematic reviews to look at the continuing professional development of family physicians in adolescent health, and it turned out that there’s really a very large lack. When we looked at residents and the training that they were getting in adolescent medicine, it was very similar, so they felt unprepared to deal with issues around mental health.”

Medication can be effective, but it can be seen as “an easy way out,” Dr. Tellier added. “It’s not necessarily an ideal plan. What we need to do is to change the person’s way of thinking, the person’s way of responding to a variety of things which will occur throughout their lives. People will have other transition periods in their lives. It’s best if they learn a variety of techniques to deal with depression.”

These techniques include exercise, relaxation methods [which reduce anxiety], and wellness training. Through such techniques, patients “learn a healthier way of living with themselves and who they are, and then this is a lifelong way of learning,” said Dr. Tellier. “If I give you a pill, what I’m teaching is, yes, you can feel better. But you’re not dealing with the problem, you’re just dealing with the symptoms.”

He frequently refers his patients to YouTube videos that outline and explain various strategies. A favorite is a deep breathing exercise presented by Jeremy Howick.

The authors and Dr. Tellier disclosed no relevant financial relationships.

A version of this article first appeared on Medscape.com.

A new review drafted by three Canadian psychiatrists aims to help primary care physicians diagnose and manage depression in adolescents. 

Depression is common among Canadian adolescents and often goes unnoticed. Many family physicians report feeling unprepared to identify and manage depression in these patients.

“Depression is an increasingly common but treatable condition among adolescents,” the authors wrote. “Primary care physicians and pediatricians are well positioned to support the assessment and first-line management of depression in this group, helping patients to regain their health and function.”

The article was published in CMAJ.
 

Distinct presentation

More than 40% of cases of depression begin during childhood. Onset at this life stage is associated with worse severity of depression in adulthood and worse social, occupational, and physical health outcomes.

Depression is influenced by genetic and environmental factors. Family history of depression is associated with a three- to fivefold increased risk of depression among older children. Genetic loci are known to be associated with depression, but exposure to parental depression, adverse childhood experiences, and family conflict are also linked to greater risk. Bullying and stigma are associated with greater risk among lesbian, gay, bisexual, and transgender youth.

Compared with adults, adolescents with depression are more likely to be irritable and to have a labile mood, rather than a low mood. Social withdrawal is also more common among adolescents than among adults. Unusual features, such as hypersomnia and increased appetite, may also be present. Anxiety, somatic symptoms, psychomotor agitation, and hallucinations are more common in adolescents than in younger persons with depression. It is vital to assess risk of suicidality and self-injury as well as support systems, and validated scales such as the Columbia Suicide Severity Rating Scale can be useful.

There is no consensus as to whether universal screening for depression is beneficial among adolescents. “Screening in this age group may be a reasonable approach, however, when implemented together with adequate systems that ensure accurate diagnosis and appropriate follow-up,” wrote the authors.

Management of depression in adolescents should begin with psychoeducation and may include lifestyle modification, psychotherapy, and medication. “Importantly, a suicide risk assessment must be done to ensure appropriateness of an outpatient management plan and facilitate safety planning,” the authors wrote.

Lifestyle interventions may target physical activity, diet, and sleep, since unhealthy patterns in all three are associated with heightened symptoms of depression in this population. Regular moderate to vigorous physical activity, and perhaps physical activity of short duration, can improve mood in adolescents. Reduced consumption of sugar-sweetened drinks, processed foods, and meats, along with greater consumption of fruits and legumes, has been shown to reduce depressive symptoms in randomized, controlled trials with adults.

Among psychotherapeutic approaches, cognitive-behavioral therapy has shown the most evidence of efficacy among adolescents with depression, though it is less effective for those with more severe symptoms, poor coping skills, and nonsuicidal self-injury. Some evidence supports interpersonal therapy, which focuses on relationships and social functioning. The involvement of caregivers may improve the response, compared with psychotherapy that only includes the adolescent.

The authors recommend antidepressant medications in more severe cases or when psychotherapy is ineffective or impossible. Guidelines generally support trials with at least two SSRIs before switching to another drug class, since efficacy data for them are sparser, and other drugs have worse side effect profiles.

About 2% of adolescents with depression experience an increase in suicidal ideation and behavior after exposure to antidepressants, usually within the first weeks of initiation, so this potential risk should be discussed with patients and caregivers.
 

Clinicians feel unprepared

Commenting on the review, Pierre-Paul Tellier, MD, an associate professor of family medicine at McGill University, Montreal, said that clinicians frequently report that they do not feel confident in their ability to manage and diagnose adolescent depression. “We did two systematic reviews to look at the continuing professional development of family physicians in adolescent health, and it turned out that there’s really a very large lack. When we looked at residents and the training that they were getting in adolescent medicine, it was very similar, so they felt unprepared to deal with issues around mental health.”

Medication can be effective, but it can be seen as “an easy way out,” Dr. Tellier added. “It’s not necessarily an ideal plan. What we need to do is to change the person’s way of thinking, the person’s way of responding to a variety of things which will occur throughout their lives. People will have other transition periods in their lives. It’s best if they learn a variety of techniques to deal with depression.”

These techniques include exercise, relaxation methods [which reduce anxiety], and wellness training. Through such techniques, patients “learn a healthier way of living with themselves and who they are, and then this is a lifelong way of learning,” said Dr. Tellier. “If I give you a pill, what I’m teaching is, yes, you can feel better. But you’re not dealing with the problem, you’re just dealing with the symptoms.”

He frequently refers his patients to YouTube videos that outline and explain various strategies. A favorite is a deep breathing exercise presented by Jeremy Howick.

The authors and Dr. Tellier disclosed no relevant financial relationships.

A version of this article first appeared on Medscape.com.

Chicago – In the second-line setting of head and neck cancer, metronomic triple therapy outperformed clinician choice chemotherapy in both progression-free survival (PFS) and overall survival (OS), according to results from a new phase III clinical trial.

The study was conducted in India in a population that had not previously been treated with immunotherapy, but the results are likely applicable even when patients have been exposed to these agents, according to Rushabh Kothari, MD, DM, who presented the study (Abstract LBA6004), at the annual meeting of the American Society of Clinical Oncology (ASCO).

Although immunotherapy is considered the first-line therapy for the disease, it is often unavailable in low- and middle-income countries: In India, about 3% of head and neck cancer patients receive it, Dr. Kothari said during his presentation.

The study offered improved outcomes and greater tolerability in this population, according to Dr. Kothari. “Metronome chemotherapy led to an improvement [in both OS and PFS] of around 2 months compared to physician’s choice of treatment in this difficult-to-treat population, and metronomic chemotherapy had multiple advantages [over other chemotherapies]. It is an oral treatment, there is an ease of administration, and it is very cost effective. It also lowers adverse events as we saw in the data,” said Dr. Kothari, a medical oncologist at Narayana Multispeciality Hospital in India, in an interview.

The improvement is meaningful given the dire circumstances these patients find themselves in, according to Dr. Kothari: “When you see a second-line relapsed metastatic head and neck cancer, their overall survival is dismal: It is less than 7 months with most of the available agents,” he said in the interview.

Metronomic chemotherapy is continuous, low-dose chemotherapy that includes an anti-angiogenic effect, according to Dr. Kothari. In the current study, the researchers employed a triple metronomic chemotherapy (TMC) that included methotrexate (9 mg/m² weekly), erlotinib (150 mg daily), and celecoxib (200 mg twice daily), which was compared to any of eight single-agent physician choice agents, all of which were consistent with National Comprehensive Care Network (NCCN) guidelines (NCCN-PC group).
 

Study methods and results

The study included 55 patients in the TMC arm and 59 in the NCCN-PC arm. Currently, 13 patients in the TMC arm and 6 in the NCCN-PC are still being treated.

More than 94.5% of the TMC arm and 91.5% of the NCCN-PC arm had previously received platinum-based therapy, and 49.1% and 47.5%, respectively, had received taxane.

The median OS was 181 days in the TMC group, versus 123 days in the NCCN-PC group (hazard ratio, 0.5076; 95% confidence interval, 0.325-0.792). The median PFS was 120 days and 70 days, respectively (HR, 0.4941; 95% CI, 0.312-0.738).

Adverse events were less frequent in TMC, including anemia (grade 3-5, 3.7% versus 14.8%; P = .038), neutropenia (0% versus 13.0%; P =.006), thrombocytopenia (0% versus 9.3%; P = .028), serum glutamic-oxaloacetic transaminase/serum glutamic-pyruvic transaminase (SGOT/SGPT) rise (0% versus 9.3%; P = .028), creatinine rise (0% versus 9.3%; P = .028), and diarrhea (1.9% versus 13.0%; P = .006).

“When you give lower doses continuously, the compliance is very good. When tolerance is good and compliance is good, that is the ideal regimen, which patients want,” said Dr. Kothari in the interview.

Dr. Kothari pointed out that the study included primarily patients with oral cavity cancers, including 89.1% of the TMC group and 83.1% of the NCCN-PC group. Oropharyngeal cancers are more common in high-income countries, but his own clinical experience suggests that the combination also performs well in that group, he said.

During a discussion part of the session, Ezra Cohen, MD, said that when pembrolizumab was moved from second-line to first-line therapy, it left an unmet need in second-line recurrent or metastatic disease.

He welcomed the new results.

“[The study shows] a much better toxicity profile with the triple metronomic therapy. In other words, we can deliver these reagents at the doses prescribed, with a toxicity profile I would say that is not only manageable, but that is in fact favorable. In addition to that, in a limited size phase III study, we see an improvement in the primary endpoint here of overall survival. So in a patient population that may not necessarily have access to anti-PD1 antibodies, we can offer a lower cost triple regimen that does appear to improve survival over standard regimens,” said Dr. Cohen, who is chief medical officer of Tempus.

Dr. Kothari has received honoraria from Alkem Laboratories, AstraZeneca, Bard Peripheral Vascular, Bristol Myers Squibb Foundation, Celon Pharma, Cipla, Emcure, Fresenius Kabi, Glenmark, Merck, Novartis, Pfizer, Roche, and Zydus Pharmaceuticals. He has consulted for or advised MSD. He has received research funding through his institution from Axis Clinicals, Lambda Therapeutic Research, Reliance Life Sciences, and Zydus Pharmaceuticals.

Dr. Cohen is an employee of Tempus and has held leadership positions at Akamis Bio, Kinnate Biopharma, Kura Oncology, and Pangaea Biotech. He has stock or other ownership interests in Kinnate Biopharma and Primmune Therapeutics. He has consulted for or advised Adagene, Astellas Pharma, Cidara, Eisai, Genmab, Gilboa Therapeutics, ITeos Therapeutics, Lilly, Merck, MSD, Nectin Tx, Novartis, Nykode Therapeutics, Pangea, PCI Biotech, Replimune, Roche, SOTERIA Precision Medicine, and Viracta Therapeutics.
 

Chicago – In the second-line setting of head and neck cancer, metronomic triple therapy outperformed clinician choice chemotherapy in both progression-free survival (PFS) and overall survival (OS), according to results from a new phase III clinical trial.

The study was conducted in India in a population that had not previously been treated with immunotherapy, but the results are likely applicable even when patients have been exposed to these agents, according to Rushabh Kothari, MD, DM, who presented the study (Abstract LBA6004), at the annual meeting of the American Society of Clinical Oncology (ASCO).

Although immunotherapy is considered the first-line therapy for the disease, it is often unavailable in low- and middle-income countries: In India, about 3% of head and neck cancer patients receive it, Dr. Kothari said during his presentation.

The study offered improved outcomes and greater tolerability in this population, according to Dr. Kothari. “Metronome chemotherapy led to an improvement [in both OS and PFS] of around 2 months compared to physician’s choice of treatment in this difficult-to-treat population, and metronomic chemotherapy had multiple advantages [over other chemotherapies]. It is an oral treatment, there is an ease of administration, and it is very cost effective. It also lowers adverse events as we saw in the data,” said Dr. Kothari, a medical oncologist at Narayana Multispeciality Hospital in India, in an interview.

The improvement is meaningful given the dire circumstances these patients find themselves in, according to Dr. Kothari: “When you see a second-line relapsed metastatic head and neck cancer, their overall survival is dismal: It is less than 7 months with most of the available agents,” he said in the interview.

Metronomic chemotherapy is continuous, low-dose chemotherapy that includes an anti-angiogenic effect, according to Dr. Kothari. In the current study, the researchers employed a triple metronomic chemotherapy (TMC) that included methotrexate (9 mg/m² weekly), erlotinib (150 mg daily), and celecoxib (200 mg twice daily), which was compared to any of eight single-agent physician choice agents, all of which were consistent with National Comprehensive Care Network (NCCN) guidelines (NCCN-PC group).
 

Study methods and results

The study included 55 patients in the TMC arm and 59 in the NCCN-PC arm. Currently, 13 patients in the TMC arm and 6 in the NCCN-PC are still being treated.

More than 94.5% of the TMC arm and 91.5% of the NCCN-PC arm had previously received platinum-based therapy, and 49.1% and 47.5%, respectively, had received taxane.

The median OS was 181 days in the TMC group, versus 123 days in the NCCN-PC group (hazard ratio, 0.5076; 95% confidence interval, 0.325-0.792). The median PFS was 120 days and 70 days, respectively (HR, 0.4941; 95% CI, 0.312-0.738).

Adverse events were less frequent in TMC, including anemia (grade 3-5, 3.7% versus 14.8%; P = .038), neutropenia (0% versus 13.0%; P =.006), thrombocytopenia (0% versus 9.3%; P = .028), serum glutamic-oxaloacetic transaminase/serum glutamic-pyruvic transaminase (SGOT/SGPT) rise (0% versus 9.3%; P = .028), creatinine rise (0% versus 9.3%; P = .028), and diarrhea (1.9% versus 13.0%; P = .006).

“When you give lower doses continuously, the compliance is very good. When tolerance is good and compliance is good, that is the ideal regimen, which patients want,” said Dr. Kothari in the interview.

Dr. Kothari pointed out that the study included primarily patients with oral cavity cancers, including 89.1% of the TMC group and 83.1% of the NCCN-PC group. Oropharyngeal cancers are more common in high-income countries, but his own clinical experience suggests that the combination also performs well in that group, he said.

During a discussion part of the session, Ezra Cohen, MD, said that when pembrolizumab was moved from second-line to first-line therapy, it left an unmet need in second-line recurrent or metastatic disease.

He welcomed the new results.

“[The study shows] a much better toxicity profile with the triple metronomic therapy. In other words, we can deliver these reagents at the doses prescribed, with a toxicity profile I would say that is not only manageable, but that is in fact favorable. In addition to that, in a limited size phase III study, we see an improvement in the primary endpoint here of overall survival. So in a patient population that may not necessarily have access to anti-PD1 antibodies, we can offer a lower cost triple regimen that does appear to improve survival over standard regimens,” said Dr. Cohen, who is chief medical officer of Tempus.

Dr. Kothari has received honoraria from Alkem Laboratories, AstraZeneca, Bard Peripheral Vascular, Bristol Myers Squibb Foundation, Celon Pharma, Cipla, Emcure, Fresenius Kabi, Glenmark, Merck, Novartis, Pfizer, Roche, and Zydus Pharmaceuticals. He has consulted for or advised MSD. He has received research funding through his institution from Axis Clinicals, Lambda Therapeutic Research, Reliance Life Sciences, and Zydus Pharmaceuticals.

Dr. Cohen is an employee of Tempus and has held leadership positions at Akamis Bio, Kinnate Biopharma, Kura Oncology, and Pangaea Biotech. He has stock or other ownership interests in Kinnate Biopharma and Primmune Therapeutics. He has consulted for or advised Adagene, Astellas Pharma, Cidara, Eisai, Genmab, Gilboa Therapeutics, ITeos Therapeutics, Lilly, Merck, MSD, Nectin Tx, Novartis, Nykode Therapeutics, Pangea, PCI Biotech, Replimune, Roche, SOTERIA Precision Medicine, and Viracta Therapeutics.
 

Chicago – In the second-line setting of head and neck cancer, metronomic triple therapy outperformed clinician choice chemotherapy in both progression-free survival (PFS) and overall survival (OS), according to results from a new phase III clinical trial.

The study was conducted in India in a population that had not previously been treated with immunotherapy, but the results are likely applicable even when patients have been exposed to these agents, according to Rushabh Kothari, MD, DM, who presented the study (Abstract LBA6004), at the annual meeting of the American Society of Clinical Oncology (ASCO).

Although immunotherapy is considered the first-line therapy for the disease, it is often unavailable in low- and middle-income countries: In India, about 3% of head and neck cancer patients receive it, Dr. Kothari said during his presentation.

The study offered improved outcomes and greater tolerability in this population, according to Dr. Kothari. “Metronome chemotherapy led to an improvement [in both OS and PFS] of around 2 months compared to physician’s choice of treatment in this difficult-to-treat population, and metronomic chemotherapy had multiple advantages [over other chemotherapies]. It is an oral treatment, there is an ease of administration, and it is very cost effective. It also lowers adverse events as we saw in the data,” said Dr. Kothari, a medical oncologist at Narayana Multispeciality Hospital in India, in an interview.

The improvement is meaningful given the dire circumstances these patients find themselves in, according to Dr. Kothari: “When you see a second-line relapsed metastatic head and neck cancer, their overall survival is dismal: It is less than 7 months with most of the available agents,” he said in the interview.

Metronomic chemotherapy is continuous, low-dose chemotherapy that includes an anti-angiogenic effect, according to Dr. Kothari. In the current study, the researchers employed a triple metronomic chemotherapy (TMC) that included methotrexate (9 mg/m² weekly), erlotinib (150 mg daily), and celecoxib (200 mg twice daily), which was compared to any of eight single-agent physician choice agents, all of which were consistent with National Comprehensive Care Network (NCCN) guidelines (NCCN-PC group).
 

Study methods and results

The study included 55 patients in the TMC arm and 59 in the NCCN-PC arm. Currently, 13 patients in the TMC arm and 6 in the NCCN-PC are still being treated.

More than 94.5% of the TMC arm and 91.5% of the NCCN-PC arm had previously received platinum-based therapy, and 49.1% and 47.5%, respectively, had received taxane.

The median OS was 181 days in the TMC group, versus 123 days in the NCCN-PC group (hazard ratio, 0.5076; 95% confidence interval, 0.325-0.792). The median PFS was 120 days and 70 days, respectively (HR, 0.4941; 95% CI, 0.312-0.738).

Adverse events were less frequent in TMC, including anemia (grade 3-5, 3.7% versus 14.8%; P = .038), neutropenia (0% versus 13.0%; P =.006), thrombocytopenia (0% versus 9.3%; P = .028), serum glutamic-oxaloacetic transaminase/serum glutamic-pyruvic transaminase (SGOT/SGPT) rise (0% versus 9.3%; P = .028), creatinine rise (0% versus 9.3%; P = .028), and diarrhea (1.9% versus 13.0%; P = .006).

“When you give lower doses continuously, the compliance is very good. When tolerance is good and compliance is good, that is the ideal regimen, which patients want,” said Dr. Kothari in the interview.

Dr. Kothari pointed out that the study included primarily patients with oral cavity cancers, including 89.1% of the TMC group and 83.1% of the NCCN-PC group. Oropharyngeal cancers are more common in high-income countries, but his own clinical experience suggests that the combination also performs well in that group, he said.

During a discussion part of the session, Ezra Cohen, MD, said that when pembrolizumab was moved from second-line to first-line therapy, it left an unmet need in second-line recurrent or metastatic disease.

He welcomed the new results.

“[The study shows] a much better toxicity profile with the triple metronomic therapy. In other words, we can deliver these reagents at the doses prescribed, with a toxicity profile I would say that is not only manageable, but that is in fact favorable. In addition to that, in a limited size phase III study, we see an improvement in the primary endpoint here of overall survival. So in a patient population that may not necessarily have access to anti-PD1 antibodies, we can offer a lower cost triple regimen that does appear to improve survival over standard regimens,” said Dr. Cohen, who is chief medical officer of Tempus.

Dr. Kothari has received honoraria from Alkem Laboratories, AstraZeneca, Bard Peripheral Vascular, Bristol Myers Squibb Foundation, Celon Pharma, Cipla, Emcure, Fresenius Kabi, Glenmark, Merck, Novartis, Pfizer, Roche, and Zydus Pharmaceuticals. He has consulted for or advised MSD. He has received research funding through his institution from Axis Clinicals, Lambda Therapeutic Research, Reliance Life Sciences, and Zydus Pharmaceuticals.

Dr. Cohen is an employee of Tempus and has held leadership positions at Akamis Bio, Kinnate Biopharma, Kura Oncology, and Pangaea Biotech. He has stock or other ownership interests in Kinnate Biopharma and Primmune Therapeutics. He has consulted for or advised Adagene, Astellas Pharma, Cidara, Eisai, Genmab, Gilboa Therapeutics, ITeos Therapeutics, Lilly, Merck, MSD, Nectin Tx, Novartis, Nykode Therapeutics, Pangea, PCI Biotech, Replimune, Roche, SOTERIA Precision Medicine, and Viracta Therapeutics.
 

CHICAGO – In the phase 3 MIRASOL study, the antibody-drug conjugate (ADC) mirvetuximab soravtansine-gynx (MIRV, Elahere, ImmunoGen) produced an overall survival benefit in women with platinum-resistant ovarian cancer.

The conclusion of this study marks the first time that a novel therapy has demonstrated an overall survival (OS) improvement in any phase 3 trial in this population, according to lead investigator Kathleen Moore, MD.

“We believe these data are practice changing and position mirvetuximab [soravtansine] as the new standard of care for patients with folate receptor–alpha positive, platinum-resistant ovarian cancer,” said Dr. Moore during a presentation of the study at a special session of the annual meeting of the American Society of Clinical Oncology devoted solely to the MIRASOL study.
 

New standard of care

Following Dr. Moore’s presentation, Roisin Eilish O’Cearbhaill, MD, served as a discussant, and she confirmed the trial’s importance.

“It has firmly established the role of mirvetuximab [soravtansine] in folate receptor–alpha high-expression, platinum-resistant ovarian cancer,” said Dr. O’Cearbhaill, who is Research director of the gynecologic medical oncology service and clinical director of the solid tumor, cellular therapy service at Memorial Sloan Kettering Cancer Center, New York.

Mirvetuximab soravtansine received accelerated FDA approval in November based on the results of the single-arm SORAYA trial, which demonstrated a progression-free survival (PFS) benefit in platinum-resistant patients who had been previously treated with one to three treatment regimens, at least one of which having included bevacizumab.

The new study compared MIRV with physician choice chemotherapy and found both a PFS and OS benefit in the MIRV arm. The results garnered significant enthusiasm from the audience, and others reacted positively as well.

“The results that she presented are just astounding, with a significant improvement in both progression-free and overall survival. I think certainly the overall survival needs to be highlighted here, because this is a patient population that’s notoriously difficult to treat,” said Ana Valente, MD, a gynecologic oncologist at the Ochsner Health System in New Orleans. Dr. Valente, who did not attend the presentation but was asked to comment on the study, is also a member of the Society of Gynecological Oncologist communications committee.

Unlike SORAYA, MIRASOL was open to patients who had not received bevacizumab, and Dr. Moore and colleagues found similar survival benefits in patients who had not received bevacizumab as in those who had, said Dr. Moore, who is the associate director of clinical research at Stephenson Cancer Center and director of the Oklahoma TSET Phase 1 Program, both in Oklahoma City. This opens the possibility of using MIRV instead of bevacizumab combined with chemotherapy in platinum-resistant patients.

“I think this data really shows you can move right to mirvetuximab [soravtansine] and feel pretty solid about the decision in a biomarker selected [population],” Dr. Moore said, during an interview.
 

Not just for high expression levels

MIRASOL was restricted to patients with high levels of expression of folate receptor–alpha, which is MIRV’s target on the surface of tumor cells. High expression is defined as at least 75% of viable tumor cells exhibiting a minimum of 2+ level membrane staining intensity by immunohistochemistry. That represents about 35% of patients, according to Dr. Moore, but she said that the drug also shows promise in patients with medium levels of folate receptor–alpha expression.

“I think it’s just going to be now starting to get those label extension studies launched to branch it out. Then you account for 60% of your population which [have] medium to high [expression levels], and that’s really where you see benefit,” said Dr. Moore. Medium expression levels of folate receptor–alpha are defined as 50% to greater than 75% of tumor cells with 2+ level membrane staining intensity.

She also noted that the FORWARD II trial combining mirvetuximab soravtansine with bevacizumab in platinum-resistant ovarian cancer is showing good results.

“We have really beautiful data [from FORWARD II]. If I have a medium expresser, I’m using the doublet [of MIRV and bevacizumab], and it works,” said Dr. Moore, while also pointing out that this remains an off-label use.

It’s possible that the drug could be extended even to low expression levels, defined as 25% to less than 50% of tumor cells with 2+ level membrane staining intensity. “[We are] currently working on that strategy with already available data,” said Dr. Moore.

She speculated that the improved OS may be attributed to the reduced toxicity of MIRV, compared with chemotherapy agents, which leaves patients feeling better and more able to pursue other treatments, which in turn may increase survival odds.

Dr. O’Cearbhaill touted the benefits of ADCs and their ability to target powerful cytotoxic agents while limiting side effects, and she is looking forward to more new therapies on the horizon.

“There are four [ADCs] in late stages of development [for platinum-resistant ovarian cancer], so hopefully there will be other ones coming online as well,” Dr. O’Cearbhaill said in an interview. “Then we’ll have to figure out how to sequence them, which drug will be best in class. Will we be just giving one or will be giving ADC followed by ADC?”
 

Study methods and results

The study enrolled 453 patients and randomized them to treatment with MIRV or investigator’s choice of chemotherapy, which could be paclitaxel, pegylated liposomal doxorubicin, or topotecan. The MIRV dose was 6 mg/kg adjusted ideal body weight every 3 weeks. The median age was 62 in the chemotherapy arm and 63 years in the MIRV arm. About 63% of the chemotherapy arm had prior bevacizumab exposure, as did 61% of the MIRV arm.

Median PFS was 5.62 months in the MIRV arm and 3.98 months in the chemotherapy arm (hazard ratio, 0.65; P less than .0001). The overall response rate was 42% in the MIRV arm and 16% in the chemotherapy arm (P < .0001).

The safety outcomes also favored MIRV: 42% experienced grade 3 or higher treatment-emergent adverse events (TEAEs) versus 54% in the chemotherapy group. Severe adverse events were also lower in MIRV, 24% versus 33%. Just 9% of patients in the MIRV discontinued because of TEAEs, compared with 16% in the chemotherapy arm.

MIRV was associated with blurred vision (41%), keratopathy (32%), and dry eye (28%), but these issues were generally manageable through collaboration with optometrists or ophthalmologists.

Dr. Moore and Dr. O’Cearbhaill reported receiving honoraria, research funding, and travel expenses from numerous pharmaceutical companies. Dr. O’Cearbhaill has consulted for or advised Aptitude Health, Bayer, Carina Biotech, Fresenius Kabi, GlaxoSmithKline, GOG Foundation, Immunogen, R-Pharm, Regeneron, and Seagen.

CHICAGO – In the phase 3 MIRASOL study, the antibody-drug conjugate (ADC) mirvetuximab soravtansine-gynx (MIRV, Elahere, ImmunoGen) produced an overall survival benefit in women with platinum-resistant ovarian cancer.

The conclusion of this study marks the first time that a novel therapy has demonstrated an overall survival (OS) improvement in any phase 3 trial in this population, according to lead investigator Kathleen Moore, MD.

“We believe these data are practice changing and position mirvetuximab [soravtansine] as the new standard of care for patients with folate receptor–alpha positive, platinum-resistant ovarian cancer,” said Dr. Moore during a presentation of the study at a special session of the annual meeting of the American Society of Clinical Oncology devoted solely to the MIRASOL study.
 

New standard of care

Following Dr. Moore’s presentation, Roisin Eilish O’Cearbhaill, MD, served as a discussant, and she confirmed the trial’s importance.

“It has firmly established the role of mirvetuximab [soravtansine] in folate receptor–alpha high-expression, platinum-resistant ovarian cancer,” said Dr. O’Cearbhaill, who is Research director of the gynecologic medical oncology service and clinical director of the solid tumor, cellular therapy service at Memorial Sloan Kettering Cancer Center, New York.

Mirvetuximab soravtansine received accelerated FDA approval in November based on the results of the single-arm SORAYA trial, which demonstrated a progression-free survival (PFS) benefit in platinum-resistant patients who had been previously treated with one to three treatment regimens, at least one of which having included bevacizumab.

The new study compared MIRV with physician choice chemotherapy and found both a PFS and OS benefit in the MIRV arm. The results garnered significant enthusiasm from the audience, and others reacted positively as well.

“The results that she presented are just astounding, with a significant improvement in both progression-free and overall survival. I think certainly the overall survival needs to be highlighted here, because this is a patient population that’s notoriously difficult to treat,” said Ana Valente, MD, a gynecologic oncologist at the Ochsner Health System in New Orleans. Dr. Valente, who did not attend the presentation but was asked to comment on the study, is also a member of the Society of Gynecological Oncologist communications committee.

Unlike SORAYA, MIRASOL was open to patients who had not received bevacizumab, and Dr. Moore and colleagues found similar survival benefits in patients who had not received bevacizumab as in those who had, said Dr. Moore, who is the associate director of clinical research at Stephenson Cancer Center and director of the Oklahoma TSET Phase 1 Program, both in Oklahoma City. This opens the possibility of using MIRV instead of bevacizumab combined with chemotherapy in platinum-resistant patients.

“I think this data really shows you can move right to mirvetuximab [soravtansine] and feel pretty solid about the decision in a biomarker selected [population],” Dr. Moore said, during an interview.
 

Not just for high expression levels

MIRASOL was restricted to patients with high levels of expression of folate receptor–alpha, which is MIRV’s target on the surface of tumor cells. High expression is defined as at least 75% of viable tumor cells exhibiting a minimum of 2+ level membrane staining intensity by immunohistochemistry. That represents about 35% of patients, according to Dr. Moore, but she said that the drug also shows promise in patients with medium levels of folate receptor–alpha expression.

“I think it’s just going to be now starting to get those label extension studies launched to branch it out. Then you account for 60% of your population which [have] medium to high [expression levels], and that’s really where you see benefit,” said Dr. Moore. Medium expression levels of folate receptor–alpha are defined as 50% to greater than 75% of tumor cells with 2+ level membrane staining intensity.

She also noted that the FORWARD II trial combining mirvetuximab soravtansine with bevacizumab in platinum-resistant ovarian cancer is showing good results.

“We have really beautiful data [from FORWARD II]. If I have a medium expresser, I’m using the doublet [of MIRV and bevacizumab], and it works,” said Dr. Moore, while also pointing out that this remains an off-label use.

It’s possible that the drug could be extended even to low expression levels, defined as 25% to less than 50% of tumor cells with 2+ level membrane staining intensity. “[We are] currently working on that strategy with already available data,” said Dr. Moore.

She speculated that the improved OS may be attributed to the reduced toxicity of MIRV, compared with chemotherapy agents, which leaves patients feeling better and more able to pursue other treatments, which in turn may increase survival odds.

Dr. O’Cearbhaill touted the benefits of ADCs and their ability to target powerful cytotoxic agents while limiting side effects, and she is looking forward to more new therapies on the horizon.

“There are four [ADCs] in late stages of development [for platinum-resistant ovarian cancer], so hopefully there will be other ones coming online as well,” Dr. O’Cearbhaill said in an interview. “Then we’ll have to figure out how to sequence them, which drug will be best in class. Will we be just giving one or will be giving ADC followed by ADC?”
 

Study methods and results

The study enrolled 453 patients and randomized them to treatment with MIRV or investigator’s choice of chemotherapy, which could be paclitaxel, pegylated liposomal doxorubicin, or topotecan. The MIRV dose was 6 mg/kg adjusted ideal body weight every 3 weeks. The median age was 62 in the chemotherapy arm and 63 years in the MIRV arm. About 63% of the chemotherapy arm had prior bevacizumab exposure, as did 61% of the MIRV arm.

Median PFS was 5.62 months in the MIRV arm and 3.98 months in the chemotherapy arm (hazard ratio, 0.65; P less than .0001). The overall response rate was 42% in the MIRV arm and 16% in the chemotherapy arm (P < .0001).

The safety outcomes also favored MIRV: 42% experienced grade 3 or higher treatment-emergent adverse events (TEAEs) versus 54% in the chemotherapy group. Severe adverse events were also lower in MIRV, 24% versus 33%. Just 9% of patients in the MIRV discontinued because of TEAEs, compared with 16% in the chemotherapy arm.

MIRV was associated with blurred vision (41%), keratopathy (32%), and dry eye (28%), but these issues were generally manageable through collaboration with optometrists or ophthalmologists.

Dr. Moore and Dr. O’Cearbhaill reported receiving honoraria, research funding, and travel expenses from numerous pharmaceutical companies. Dr. O’Cearbhaill has consulted for or advised Aptitude Health, Bayer, Carina Biotech, Fresenius Kabi, GlaxoSmithKline, GOG Foundation, Immunogen, R-Pharm, Regeneron, and Seagen.

CHICAGO – In the phase 3 MIRASOL study, the antibody-drug conjugate (ADC) mirvetuximab soravtansine-gynx (MIRV, Elahere, ImmunoGen) produced an overall survival benefit in women with platinum-resistant ovarian cancer.

The conclusion of this study marks the first time that a novel therapy has demonstrated an overall survival (OS) improvement in any phase 3 trial in this population, according to lead investigator Kathleen Moore, MD.

“We believe these data are practice changing and position mirvetuximab [soravtansine] as the new standard of care for patients with folate receptor–alpha positive, platinum-resistant ovarian cancer,” said Dr. Moore during a presentation of the study at a special session of the annual meeting of the American Society of Clinical Oncology devoted solely to the MIRASOL study.
 

New standard of care

Following Dr. Moore’s presentation, Roisin Eilish O’Cearbhaill, MD, served as a discussant, and she confirmed the trial’s importance.

“It has firmly established the role of mirvetuximab [soravtansine] in folate receptor–alpha high-expression, platinum-resistant ovarian cancer,” said Dr. O’Cearbhaill, who is Research director of the gynecologic medical oncology service and clinical director of the solid tumor, cellular therapy service at Memorial Sloan Kettering Cancer Center, New York.

Mirvetuximab soravtansine received accelerated FDA approval in November based on the results of the single-arm SORAYA trial, which demonstrated a progression-free survival (PFS) benefit in platinum-resistant patients who had been previously treated with one to three treatment regimens, at least one of which having included bevacizumab.

The new study compared MIRV with physician choice chemotherapy and found both a PFS and OS benefit in the MIRV arm. The results garnered significant enthusiasm from the audience, and others reacted positively as well.

“The results that she presented are just astounding, with a significant improvement in both progression-free and overall survival. I think certainly the overall survival needs to be highlighted here, because this is a patient population that’s notoriously difficult to treat,” said Ana Valente, MD, a gynecologic oncologist at the Ochsner Health System in New Orleans. Dr. Valente, who did not attend the presentation but was asked to comment on the study, is also a member of the Society of Gynecological Oncologist communications committee.

Unlike SORAYA, MIRASOL was open to patients who had not received bevacizumab, and Dr. Moore and colleagues found similar survival benefits in patients who had not received bevacizumab as in those who had, said Dr. Moore, who is the associate director of clinical research at Stephenson Cancer Center and director of the Oklahoma TSET Phase 1 Program, both in Oklahoma City. This opens the possibility of using MIRV instead of bevacizumab combined with chemotherapy in platinum-resistant patients.

“I think this data really shows you can move right to mirvetuximab [soravtansine] and feel pretty solid about the decision in a biomarker selected [population],” Dr. Moore said, during an interview.
 

Not just for high expression levels

MIRASOL was restricted to patients with high levels of expression of folate receptor–alpha, which is MIRV’s target on the surface of tumor cells. High expression is defined as at least 75% of viable tumor cells exhibiting a minimum of 2+ level membrane staining intensity by immunohistochemistry. That represents about 35% of patients, according to Dr. Moore, but she said that the drug also shows promise in patients with medium levels of folate receptor–alpha expression.

“I think it’s just going to be now starting to get those label extension studies launched to branch it out. Then you account for 60% of your population which [have] medium to high [expression levels], and that’s really where you see benefit,” said Dr. Moore. Medium expression levels of folate receptor–alpha are defined as 50% to greater than 75% of tumor cells with 2+ level membrane staining intensity.

She also noted that the FORWARD II trial combining mirvetuximab soravtansine with bevacizumab in platinum-resistant ovarian cancer is showing good results.

“We have really beautiful data [from FORWARD II]. If I have a medium expresser, I’m using the doublet [of MIRV and bevacizumab], and it works,” said Dr. Moore, while also pointing out that this remains an off-label use.

It’s possible that the drug could be extended even to low expression levels, defined as 25% to less than 50% of tumor cells with 2+ level membrane staining intensity. “[We are] currently working on that strategy with already available data,” said Dr. Moore.

She speculated that the improved OS may be attributed to the reduced toxicity of MIRV, compared with chemotherapy agents, which leaves patients feeling better and more able to pursue other treatments, which in turn may increase survival odds.

Dr. O’Cearbhaill touted the benefits of ADCs and their ability to target powerful cytotoxic agents while limiting side effects, and she is looking forward to more new therapies on the horizon.

“There are four [ADCs] in late stages of development [for platinum-resistant ovarian cancer], so hopefully there will be other ones coming online as well,” Dr. O’Cearbhaill said in an interview. “Then we’ll have to figure out how to sequence them, which drug will be best in class. Will we be just giving one or will be giving ADC followed by ADC?”
 

Study methods and results

The study enrolled 453 patients and randomized them to treatment with MIRV or investigator’s choice of chemotherapy, which could be paclitaxel, pegylated liposomal doxorubicin, or topotecan. The MIRV dose was 6 mg/kg adjusted ideal body weight every 3 weeks. The median age was 62 in the chemotherapy arm and 63 years in the MIRV arm. About 63% of the chemotherapy arm had prior bevacizumab exposure, as did 61% of the MIRV arm.

Median PFS was 5.62 months in the MIRV arm and 3.98 months in the chemotherapy arm (hazard ratio, 0.65; P less than .0001). The overall response rate was 42% in the MIRV arm and 16% in the chemotherapy arm (P < .0001).

The safety outcomes also favored MIRV: 42% experienced grade 3 or higher treatment-emergent adverse events (TEAEs) versus 54% in the chemotherapy group. Severe adverse events were also lower in MIRV, 24% versus 33%. Just 9% of patients in the MIRV discontinued because of TEAEs, compared with 16% in the chemotherapy arm.

MIRV was associated with blurred vision (41%), keratopathy (32%), and dry eye (28%), but these issues were generally manageable through collaboration with optometrists or ophthalmologists.

Dr. Moore and Dr. O’Cearbhaill reported receiving honoraria, research funding, and travel expenses from numerous pharmaceutical companies. Dr. O’Cearbhaill has consulted for or advised Aptitude Health, Bayer, Carina Biotech, Fresenius Kabi, GlaxoSmithKline, GOG Foundation, Immunogen, R-Pharm, Regeneron, and Seagen.

CHICAGO – In a phase 1 small cell lung cancer (SCLC) trial, a bispecific antibody that targets T cells and the inhibitory notch ligand known as delta-like ligand 3 (DLL3) showed a good safety profile and encouraging signs of efficacy, including one response that lasted more than a year.

The antibody promotes the destruction of tumor cells by T cells by acting as a bridge between T cells and tumors.

SCLC has largely resisted efforts to identify unique surface markers. DLL3 is an exception: It is rarely expressed in normal cells, and it seems to be important to tumor biology, according to Martin Wermke, MD, who presented the study at the annual meeting of the American Society of Clinical Oncology.
 

A rare SCLC biomarker

“The problem, I think, is that small cell [lung cancer] with its high mutational burden is a bunch of many different subentities and you will probably not find a single driver mutation as you do in non–small cell lung cancer. So in that [way] it’s different in its biology,” said Dr. Wermke, professor of experimental tumor therapy at the National Center for Tumor Diseases in Dresden, Germany.

Nevertheless, DLL3 is a sensitive biomarker, with over 90% of SCLC tumors positive for the surface marker, according to Dr. Wermke. “It’s one of the first which proved to be a reliable [SCLC] biomarker for therapeutic approaches,” said Dr. Wermke.

This isn’t the first clinical experience with DLL3. An anti-DLL3 antibody was used as part of an antibody-drug conjugate called Rova-T, which failed a phase 3 trial in SCLC in 2021 and was subsequently canceled by AbbVie, but Dr. Wermke believes that the issue was with the drug and linker (a chemical tag that links the cytotoxic drug to the antibody, which is designed to release the drug in an appropriate environment such as the interior of a tumor cell after an antibody-drug conjugate has been internalized by the tumor cell), not DLL3. DLL3 is also being investigated as a component of chimeric antigen receptor T-cell therapy, though no clinical results have been reported, Dr. Wermke said.
 

Study methods and results

The study included 107 patients. The median age was 60.0 years, and 57% were male. To be included, patients had to have advanced SCLC, large cell neuroendocrine carcinoma, or extrapulmonary neuroendocrine carcinoma, as well as test positive for DLL3 expression.

The drug was well tolerated: 86% of patients experienced at least one treatment-related adverse event: 59% with a grade 1-2 TRAE and 27% with a grade 3-5 TRAE. Cytokine release syndrome (CRS) occurred in 59% of patients, but just 2% were grade 3-5. TRAEs led to discontinuation in 4% of patients. Physicians were able to manage CRS with supportive care, steroids, and anti–interleukin-6 receptor antibodies.

The treatment showed signs of efficacy, with partial responses occurring in 18% of patients, stable disease in 23%, progressive disease in 45%, while 13% were not evaluable.

At doses of 90 mg/kg or above, partial response occurred in 25% of patients, stable disease in 27%, and progressive disease in 31%, while 13% were not evaluable. Similar patterns were seen across three tumor types.

Of 18 responders, 14 continued to be responders at the time of the presentation. The longest response lengths were 13.1 months, 10.7 months, and 9.4 months.

Dr. Wermke said that the responses were encouraging, particularly the duration of some responses.

“Having a small cell [lung cancer] patient responding to something for more than a year is extraordinary. It comes with side effects, which are usually seen during the first [doses]. After that, the drug is pretty well tolerable, and that is also something which distinguishes it from alternative second-line approaches,” he said.
 

Well tolerated, but take efficacy data with a grain of salt

The study was encouraging but should be treated with caution, according to Vamsidhar Velcheti, MD, who moderated the session where the research was presented.

“The toxicity profile is actually very promising and it’s still very early, but there’s certainly a lot of interest in DLL3-targeted [therapies]. We’ve seen some very exciting data with other assets in this category as well,” said Dr. Velcheti, director of thoracic oncology at NYU Langone Health, New York.

Phase 1 efficacy data can be tantalizing but often fails to hold up to further testing, according to Dr. Velcheti. “We’ve seen signals in phase 1 data before, and we’ve been burned. We saw really promising data with Rova-T, and the confirmatory trials were negative, – so we want to be cautiously optimistic,” said Dr. Velcheti.

He also pointed out that patient selection will be important for such studies, considering that SCLC patients often have a lot of comorbidities and the therapy’s potential for causing CRS.

Both Dr. Wermke and Dr. Velcheti have received funding from numerous pharmaceutical companies. Dr. Wermke has consulted with or advised with Amgen, Bayer, Boehringer Ingelheim, Bristol-Myers Squibb, ImCheck Therapeutics, Immatics, ISA Pharmaceuticals, Lilly, and Novartis.

CHICAGO – In a phase 1 small cell lung cancer (SCLC) trial, a bispecific antibody that targets T cells and the inhibitory notch ligand known as delta-like ligand 3 (DLL3) showed a good safety profile and encouraging signs of efficacy, including one response that lasted more than a year.

The antibody promotes the destruction of tumor cells by T cells by acting as a bridge between T cells and tumors.

SCLC has largely resisted efforts to identify unique surface markers. DLL3 is an exception: It is rarely expressed in normal cells, and it seems to be important to tumor biology, according to Martin Wermke, MD, who presented the study at the annual meeting of the American Society of Clinical Oncology.
 

A rare SCLC biomarker

“The problem, I think, is that small cell [lung cancer] with its high mutational burden is a bunch of many different subentities and you will probably not find a single driver mutation as you do in non–small cell lung cancer. So in that [way] it’s different in its biology,” said Dr. Wermke, professor of experimental tumor therapy at the National Center for Tumor Diseases in Dresden, Germany.

Nevertheless, DLL3 is a sensitive biomarker, with over 90% of SCLC tumors positive for the surface marker, according to Dr. Wermke. “It’s one of the first which proved to be a reliable [SCLC] biomarker for therapeutic approaches,” said Dr. Wermke.

This isn’t the first clinical experience with DLL3. An anti-DLL3 antibody was used as part of an antibody-drug conjugate called Rova-T, which failed a phase 3 trial in SCLC in 2021 and was subsequently canceled by AbbVie, but Dr. Wermke believes that the issue was with the drug and linker (a chemical tag that links the cytotoxic drug to the antibody, which is designed to release the drug in an appropriate environment such as the interior of a tumor cell after an antibody-drug conjugate has been internalized by the tumor cell), not DLL3. DLL3 is also being investigated as a component of chimeric antigen receptor T-cell therapy, though no clinical results have been reported, Dr. Wermke said.
 

Study methods and results

The study included 107 patients. The median age was 60.0 years, and 57% were male. To be included, patients had to have advanced SCLC, large cell neuroendocrine carcinoma, or extrapulmonary neuroendocrine carcinoma, as well as test positive for DLL3 expression.

The drug was well tolerated: 86% of patients experienced at least one treatment-related adverse event: 59% with a grade 1-2 TRAE and 27% with a grade 3-5 TRAE. Cytokine release syndrome (CRS) occurred in 59% of patients, but just 2% were grade 3-5. TRAEs led to discontinuation in 4% of patients. Physicians were able to manage CRS with supportive care, steroids, and anti–interleukin-6 receptor antibodies.

The treatment showed signs of efficacy, with partial responses occurring in 18% of patients, stable disease in 23%, progressive disease in 45%, while 13% were not evaluable.

At doses of 90 mg/kg or above, partial response occurred in 25% of patients, stable disease in 27%, and progressive disease in 31%, while 13% were not evaluable. Similar patterns were seen across three tumor types.

Of 18 responders, 14 continued to be responders at the time of the presentation. The longest response lengths were 13.1 months, 10.7 months, and 9.4 months.

Dr. Wermke said that the responses were encouraging, particularly the duration of some responses.

“Having a small cell [lung cancer] patient responding to something for more than a year is extraordinary. It comes with side effects, which are usually seen during the first [doses]. After that, the drug is pretty well tolerable, and that is also something which distinguishes it from alternative second-line approaches,” he said.
 

Well tolerated, but take efficacy data with a grain of salt

The study was encouraging but should be treated with caution, according to Vamsidhar Velcheti, MD, who moderated the session where the research was presented.

“The toxicity profile is actually very promising and it’s still very early, but there’s certainly a lot of interest in DLL3-targeted [therapies]. We’ve seen some very exciting data with other assets in this category as well,” said Dr. Velcheti, director of thoracic oncology at NYU Langone Health, New York.

Phase 1 efficacy data can be tantalizing but often fails to hold up to further testing, according to Dr. Velcheti. “We’ve seen signals in phase 1 data before, and we’ve been burned. We saw really promising data with Rova-T, and the confirmatory trials were negative, – so we want to be cautiously optimistic,” said Dr. Velcheti.

He also pointed out that patient selection will be important for such studies, considering that SCLC patients often have a lot of comorbidities and the therapy’s potential for causing CRS.

Both Dr. Wermke and Dr. Velcheti have received funding from numerous pharmaceutical companies. Dr. Wermke has consulted with or advised with Amgen, Bayer, Boehringer Ingelheim, Bristol-Myers Squibb, ImCheck Therapeutics, Immatics, ISA Pharmaceuticals, Lilly, and Novartis.

CHICAGO – In a phase 1 small cell lung cancer (SCLC) trial, a bispecific antibody that targets T cells and the inhibitory notch ligand known as delta-like ligand 3 (DLL3) showed a good safety profile and encouraging signs of efficacy, including one response that lasted more than a year.

The antibody promotes the destruction of tumor cells by T cells by acting as a bridge between T cells and tumors.

SCLC has largely resisted efforts to identify unique surface markers. DLL3 is an exception: It is rarely expressed in normal cells, and it seems to be important to tumor biology, according to Martin Wermke, MD, who presented the study at the annual meeting of the American Society of Clinical Oncology.
 

A rare SCLC biomarker

“The problem, I think, is that small cell [lung cancer] with its high mutational burden is a bunch of many different subentities and you will probably not find a single driver mutation as you do in non–small cell lung cancer. So in that [way] it’s different in its biology,” said Dr. Wermke, professor of experimental tumor therapy at the National Center for Tumor Diseases in Dresden, Germany.

Nevertheless, DLL3 is a sensitive biomarker, with over 90% of SCLC tumors positive for the surface marker, according to Dr. Wermke. “It’s one of the first which proved to be a reliable [SCLC] biomarker for therapeutic approaches,” said Dr. Wermke.

This isn’t the first clinical experience with DLL3. An anti-DLL3 antibody was used as part of an antibody-drug conjugate called Rova-T, which failed a phase 3 trial in SCLC in 2021 and was subsequently canceled by AbbVie, but Dr. Wermke believes that the issue was with the drug and linker (a chemical tag that links the cytotoxic drug to the antibody, which is designed to release the drug in an appropriate environment such as the interior of a tumor cell after an antibody-drug conjugate has been internalized by the tumor cell), not DLL3. DLL3 is also being investigated as a component of chimeric antigen receptor T-cell therapy, though no clinical results have been reported, Dr. Wermke said.
 

Study methods and results

The study included 107 patients. The median age was 60.0 years, and 57% were male. To be included, patients had to have advanced SCLC, large cell neuroendocrine carcinoma, or extrapulmonary neuroendocrine carcinoma, as well as test positive for DLL3 expression.

The drug was well tolerated: 86% of patients experienced at least one treatment-related adverse event: 59% with a grade 1-2 TRAE and 27% with a grade 3-5 TRAE. Cytokine release syndrome (CRS) occurred in 59% of patients, but just 2% were grade 3-5. TRAEs led to discontinuation in 4% of patients. Physicians were able to manage CRS with supportive care, steroids, and anti–interleukin-6 receptor antibodies.

The treatment showed signs of efficacy, with partial responses occurring in 18% of patients, stable disease in 23%, progressive disease in 45%, while 13% were not evaluable.

At doses of 90 mg/kg or above, partial response occurred in 25% of patients, stable disease in 27%, and progressive disease in 31%, while 13% were not evaluable. Similar patterns were seen across three tumor types.

Of 18 responders, 14 continued to be responders at the time of the presentation. The longest response lengths were 13.1 months, 10.7 months, and 9.4 months.

Dr. Wermke said that the responses were encouraging, particularly the duration of some responses.

“Having a small cell [lung cancer] patient responding to something for more than a year is extraordinary. It comes with side effects, which are usually seen during the first [doses]. After that, the drug is pretty well tolerable, and that is also something which distinguishes it from alternative second-line approaches,” he said.
 

Well tolerated, but take efficacy data with a grain of salt

The study was encouraging but should be treated with caution, according to Vamsidhar Velcheti, MD, who moderated the session where the research was presented.

“The toxicity profile is actually very promising and it’s still very early, but there’s certainly a lot of interest in DLL3-targeted [therapies]. We’ve seen some very exciting data with other assets in this category as well,” said Dr. Velcheti, director of thoracic oncology at NYU Langone Health, New York.

Phase 1 efficacy data can be tantalizing but often fails to hold up to further testing, according to Dr. Velcheti. “We’ve seen signals in phase 1 data before, and we’ve been burned. We saw really promising data with Rova-T, and the confirmatory trials were negative, – so we want to be cautiously optimistic,” said Dr. Velcheti.

He also pointed out that patient selection will be important for such studies, considering that SCLC patients often have a lot of comorbidities and the therapy’s potential for causing CRS.

Both Dr. Wermke and Dr. Velcheti have received funding from numerous pharmaceutical companies. Dr. Wermke has consulted with or advised with Amgen, Bayer, Boehringer Ingelheim, Bristol-Myers Squibb, ImCheck Therapeutics, Immatics, ISA Pharmaceuticals, Lilly, and Novartis.

CHICAGO – When it comes to preventing pelvic recurrence in low-risk cervical cancer, simple hysterectomy is not inferior to radical hysterectomy, according to results from a phase 3, randomized, controlled trial.

“Following adequate and rigorous preoperative assessment, and that’s key – very careful [patient selection] – simple hysterectomies can now be considered the new standard of care for patients with low-risk early-stage cervical cancer,” said Marie Plante, MD, during a presentation of the study at the annual meeting of the American Society of Clinical Oncology. A simple hysterectomy removes the uterus and cervix, while a radical hysterectomy also removes the parametrium and upper vagina.

Cervical cancer incidence has gone down over the past 2 decades as a result of improved screening, and patients tend to be lower in age and are more likely to have low-risk, early-stage disease, according to Dr. Plante. “Although radical surgery is highly effective for the treatment of low-risk disease, women are at risk of suffering survivorship issues related to long-term surgical side effects including compromised bladder, bowel, and sexual function,” said Dr. Plante, who is a professor of obstetrics and gynecology at Laval University and head of clinical research at l’Hôtel-Dieu de Québec, both in Quebec City.

Retrospective studies found that infiltration of the parametrium is quite rare in low-risk cases, “suggesting that less radical surgery may be a safe option associated with decreased morbidity – what we call surgical de-escalation,” said Dr. Plante.

To test that idea more rigorously, the researchers designed the SHAPE trial, which randomized 700 women to a simple hysterectomy or radical hysterectomy. Patients were carefully selected to be low risk, having squamous cell, adenocarcinoma, or adenosquamous carcinoma, stage IA2 or IB2 tumors, fewer than 10 mm of stromal invasion on loop electrosurgical excision procedure or cone biopsy, less than 50% stromal invasion seen in MRI, and a maximum tumor dimension of 20 mm or less. Tumors were grade I-III or not assessable.

Over a median follow-up of 4.5 years, pelvic recurrence was 2.52% in the simple hysterectomy group and 2.17% in the radical hysterectomy group. The difference between the recurrence rate between the two groups was 0.35%, with an upper 95% confidence limit of 2.32%, below the threshold of 4% which had been predetermined as a benchmark for similar outcomes between the two groups. “Therefore, noninferiority of simple hysterectomy to radical hysterectomy could be concluded,” said Dr. Plante.

There were no statistically significant differences in intraoperative complications or mortality between the groups.
 

Surgery-related adverse events greater in radical hysterectomy group

There were some differences between the groups with respect to surgery-related adverse events. Within 4 weeks of surgery, there was a greater incidence of any adverse event in the radical hysterectomy group (50.6% vs. 42.6%; P = .04), as well as greater incidences of urinary incontinence (5.5% vs. 2.4%; P = .048) and urinary retention (11.0% vs. 0.6%; P < .0001). In the 4 weeks following surgery, there was a trend toward more surgery-related adverse events in the radical hysterectomy group (60.5% vs. 53.6%; P = .08) and higher incidences of urinary incontinence (11.0% vs. 4.7%; P = .003) and urinary retention (9.9% vs. 0.6%; P < .0001).

“Urinary incontinence and urinary retention are statistically worse in the radical hysterectomy group – both acutely, as well as [during] the following four weeks after surgery, suggesting that the problem persisted over time,” said Dr. Plante.

Dr. Plante also presented the study at a premeeting virtual press conference, during which Kathleen Moore, MD, provided comments on the study. She expressed enthusiasm about the results.

“Amongst those carefully selected tumors, radical hysterectomy can be converted to a simple hysterectomy, including minimally invasive. You still have to do nodes – that’s an important thing to remember – but you can do this without loss of oncologic control. And importantly, with reduction in surgical complications, postop morbidity, specifically neurologic morbidity. The moment this is presented [at the ASCO conference] this will be the new standard of care, and it represents a huge step forward in the care of women with early-stage cervical cancer,” said Dr. Moore, who is a professor of gynecologic oncology at the University of Oklahoma Health Sciences Center, Oklahoma City.

Also in the press conference, Dr. Plante emphasized the importance of a thorough understanding of the tumor, including size, imaging, and pathology. “The more conservative one wants to be, the more meticulous, the more careful one has to be to make sure that we’re truly dealing with low-risk patients.”

During the question-and-answer session following her presentation at the ASCO session, a moderator asked Dr. Plante if the presence of lymph vascular space invasion (LVSI) should prompt a radical hysterectomy.

Dr. Plante noted that about 13% of both radical and simple hysterectomy groups had LVSI present. “I think the key thing is careful selection, but I’m not sure that we should exclude LVSI [from consideration for simple hysterectomy] de facto,” she said.

Dr. Plante has consulted or advised Merck Serono and has received travel, accommodations, or other expenses from AstraZeneca. Dr. Moore has consulted, advised, and received research funding and travel expenses from numerous pharmaceutical companies.

CHICAGO – When it comes to preventing pelvic recurrence in low-risk cervical cancer, simple hysterectomy is not inferior to radical hysterectomy, according to results from a phase 3, randomized, controlled trial.

“Following adequate and rigorous preoperative assessment, and that’s key – very careful [patient selection] – simple hysterectomies can now be considered the new standard of care for patients with low-risk early-stage cervical cancer,” said Marie Plante, MD, during a presentation of the study at the annual meeting of the American Society of Clinical Oncology. A simple hysterectomy removes the uterus and cervix, while a radical hysterectomy also removes the parametrium and upper vagina.

Cervical cancer incidence has gone down over the past 2 decades as a result of improved screening, and patients tend to be lower in age and are more likely to have low-risk, early-stage disease, according to Dr. Plante. “Although radical surgery is highly effective for the treatment of low-risk disease, women are at risk of suffering survivorship issues related to long-term surgical side effects including compromised bladder, bowel, and sexual function,” said Dr. Plante, who is a professor of obstetrics and gynecology at Laval University and head of clinical research at l’Hôtel-Dieu de Québec, both in Quebec City.

Retrospective studies found that infiltration of the parametrium is quite rare in low-risk cases, “suggesting that less radical surgery may be a safe option associated with decreased morbidity – what we call surgical de-escalation,” said Dr. Plante.

To test that idea more rigorously, the researchers designed the SHAPE trial, which randomized 700 women to a simple hysterectomy or radical hysterectomy. Patients were carefully selected to be low risk, having squamous cell, adenocarcinoma, or adenosquamous carcinoma, stage IA2 or IB2 tumors, fewer than 10 mm of stromal invasion on loop electrosurgical excision procedure or cone biopsy, less than 50% stromal invasion seen in MRI, and a maximum tumor dimension of 20 mm or less. Tumors were grade I-III or not assessable.

Over a median follow-up of 4.5 years, pelvic recurrence was 2.52% in the simple hysterectomy group and 2.17% in the radical hysterectomy group. The difference between the recurrence rate between the two groups was 0.35%, with an upper 95% confidence limit of 2.32%, below the threshold of 4% which had been predetermined as a benchmark for similar outcomes between the two groups. “Therefore, noninferiority of simple hysterectomy to radical hysterectomy could be concluded,” said Dr. Plante.

There were no statistically significant differences in intraoperative complications or mortality between the groups.
 

Surgery-related adverse events greater in radical hysterectomy group

There were some differences between the groups with respect to surgery-related adverse events. Within 4 weeks of surgery, there was a greater incidence of any adverse event in the radical hysterectomy group (50.6% vs. 42.6%; P = .04), as well as greater incidences of urinary incontinence (5.5% vs. 2.4%; P = .048) and urinary retention (11.0% vs. 0.6%; P < .0001). In the 4 weeks following surgery, there was a trend toward more surgery-related adverse events in the radical hysterectomy group (60.5% vs. 53.6%; P = .08) and higher incidences of urinary incontinence (11.0% vs. 4.7%; P = .003) and urinary retention (9.9% vs. 0.6%; P < .0001).

“Urinary incontinence and urinary retention are statistically worse in the radical hysterectomy group – both acutely, as well as [during] the following four weeks after surgery, suggesting that the problem persisted over time,” said Dr. Plante.

Dr. Plante also presented the study at a premeeting virtual press conference, during which Kathleen Moore, MD, provided comments on the study. She expressed enthusiasm about the results.

“Amongst those carefully selected tumors, radical hysterectomy can be converted to a simple hysterectomy, including minimally invasive. You still have to do nodes – that’s an important thing to remember – but you can do this without loss of oncologic control. And importantly, with reduction in surgical complications, postop morbidity, specifically neurologic morbidity. The moment this is presented [at the ASCO conference] this will be the new standard of care, and it represents a huge step forward in the care of women with early-stage cervical cancer,” said Dr. Moore, who is a professor of gynecologic oncology at the University of Oklahoma Health Sciences Center, Oklahoma City.

Also in the press conference, Dr. Plante emphasized the importance of a thorough understanding of the tumor, including size, imaging, and pathology. “The more conservative one wants to be, the more meticulous, the more careful one has to be to make sure that we’re truly dealing with low-risk patients.”

During the question-and-answer session following her presentation at the ASCO session, a moderator asked Dr. Plante if the presence of lymph vascular space invasion (LVSI) should prompt a radical hysterectomy.

Dr. Plante noted that about 13% of both radical and simple hysterectomy groups had LVSI present. “I think the key thing is careful selection, but I’m not sure that we should exclude LVSI [from consideration for simple hysterectomy] de facto,” she said.

Dr. Plante has consulted or advised Merck Serono and has received travel, accommodations, or other expenses from AstraZeneca. Dr. Moore has consulted, advised, and received research funding and travel expenses from numerous pharmaceutical companies.

CHICAGO – When it comes to preventing pelvic recurrence in low-risk cervical cancer, simple hysterectomy is not inferior to radical hysterectomy, according to results from a phase 3, randomized, controlled trial.

“Following adequate and rigorous preoperative assessment, and that’s key – very careful [patient selection] – simple hysterectomies can now be considered the new standard of care for patients with low-risk early-stage cervical cancer,” said Marie Plante, MD, during a presentation of the study at the annual meeting of the American Society of Clinical Oncology. A simple hysterectomy removes the uterus and cervix, while a radical hysterectomy also removes the parametrium and upper vagina.

Cervical cancer incidence has gone down over the past 2 decades as a result of improved screening, and patients tend to be lower in age and are more likely to have low-risk, early-stage disease, according to Dr. Plante. “Although radical surgery is highly effective for the treatment of low-risk disease, women are at risk of suffering survivorship issues related to long-term surgical side effects including compromised bladder, bowel, and sexual function,” said Dr. Plante, who is a professor of obstetrics and gynecology at Laval University and head of clinical research at l’Hôtel-Dieu de Québec, both in Quebec City.

Retrospective studies found that infiltration of the parametrium is quite rare in low-risk cases, “suggesting that less radical surgery may be a safe option associated with decreased morbidity – what we call surgical de-escalation,” said Dr. Plante.

To test that idea more rigorously, the researchers designed the SHAPE trial, which randomized 700 women to a simple hysterectomy or radical hysterectomy. Patients were carefully selected to be low risk, having squamous cell, adenocarcinoma, or adenosquamous carcinoma, stage IA2 or IB2 tumors, fewer than 10 mm of stromal invasion on loop electrosurgical excision procedure or cone biopsy, less than 50% stromal invasion seen in MRI, and a maximum tumor dimension of 20 mm or less. Tumors were grade I-III or not assessable.

Over a median follow-up of 4.5 years, pelvic recurrence was 2.52% in the simple hysterectomy group and 2.17% in the radical hysterectomy group. The difference between the recurrence rate between the two groups was 0.35%, with an upper 95% confidence limit of 2.32%, below the threshold of 4% which had been predetermined as a benchmark for similar outcomes between the two groups. “Therefore, noninferiority of simple hysterectomy to radical hysterectomy could be concluded,” said Dr. Plante.

There were no statistically significant differences in intraoperative complications or mortality between the groups.
 

Surgery-related adverse events greater in radical hysterectomy group

There were some differences between the groups with respect to surgery-related adverse events. Within 4 weeks of surgery, there was a greater incidence of any adverse event in the radical hysterectomy group (50.6% vs. 42.6%; P = .04), as well as greater incidences of urinary incontinence (5.5% vs. 2.4%; P = .048) and urinary retention (11.0% vs. 0.6%; P < .0001). In the 4 weeks following surgery, there was a trend toward more surgery-related adverse events in the radical hysterectomy group (60.5% vs. 53.6%; P = .08) and higher incidences of urinary incontinence (11.0% vs. 4.7%; P = .003) and urinary retention (9.9% vs. 0.6%; P < .0001).

“Urinary incontinence and urinary retention are statistically worse in the radical hysterectomy group – both acutely, as well as [during] the following four weeks after surgery, suggesting that the problem persisted over time,” said Dr. Plante.

Dr. Plante also presented the study at a premeeting virtual press conference, during which Kathleen Moore, MD, provided comments on the study. She expressed enthusiasm about the results.

“Amongst those carefully selected tumors, radical hysterectomy can be converted to a simple hysterectomy, including minimally invasive. You still have to do nodes – that’s an important thing to remember – but you can do this without loss of oncologic control. And importantly, with reduction in surgical complications, postop morbidity, specifically neurologic morbidity. The moment this is presented [at the ASCO conference] this will be the new standard of care, and it represents a huge step forward in the care of women with early-stage cervical cancer,” said Dr. Moore, who is a professor of gynecologic oncology at the University of Oklahoma Health Sciences Center, Oklahoma City.

Also in the press conference, Dr. Plante emphasized the importance of a thorough understanding of the tumor, including size, imaging, and pathology. “The more conservative one wants to be, the more meticulous, the more careful one has to be to make sure that we’re truly dealing with low-risk patients.”

During the question-and-answer session following her presentation at the ASCO session, a moderator asked Dr. Plante if the presence of lymph vascular space invasion (LVSI) should prompt a radical hysterectomy.

Dr. Plante noted that about 13% of both radical and simple hysterectomy groups had LVSI present. “I think the key thing is careful selection, but I’m not sure that we should exclude LVSI [from consideration for simple hysterectomy] de facto,” she said.

Dr. Plante has consulted or advised Merck Serono and has received travel, accommodations, or other expenses from AstraZeneca. Dr. Moore has consulted, advised, and received research funding and travel expenses from numerous pharmaceutical companies.