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Efforts target underrepresented populations in Parkinson’s disease genetic studies
, attendees at the International Congress of Parkinson’s Disease and Movement Disorders were told.
“Through the years, as we’ve increased the number of individuals that we’ve included in our genetic studies, the number of risk factors that we’ve been able to identify has increased exponentially,” said Ignacio F. Mata, PhD, a neurogeneticist and principal investigator with the Genomic Medicine Institute of the Cleveland Clinic Lerner Research Institute. “This is all due to collaborations.”
Dr. Mata reviewed no fewer than seven initiatives that are gathering genetic data from people with Parkinson’s disease in Central and South America, India, China, Africa, Oceania, the Middle East, and Central Asia, along with efforts to target diverse populations in London and African Americans in the United States.
“One of the problems that we’ve had in the past is that most of the studies have been done just with individuals that are of European ancestry, so there’s a big gap of other populations that we haven’t been able to study,” Dr. Mata said. “And this is true for all of the current studies that are ongoing here in the United States.” That includes the Parkinson’s Progression Markers Initiative, he said, in which fewer than 6% of participants are non-European. Dr. Mata is also the lead in the Global Parkinson’s Genetics Program (GP2) for underrepresented populations.
Lack of diversity in genetic studies isn’t an issue in Parkinson’s studies alone, Dr. Mata said. “This is a generalized problem across all genetic studies,” he said, citing a 2016 analysis that found the proportion of participants in genome-wide studies was 96% European descent in 2009, shifting to 80% by 2016. “There’s still a big gap because most of the non-European populations came mostly from Asia,” Dr. Mata said, with Latinos and people of African descent representing less than 1% of the study populations.
In an interview, Dr. Mata noted there are a multitude of reasons for enrolling more diverse populations. “We’re going to be able to use genetics to create new treatments and do risk prediction – the so-called precision or personalized medicine,” he said. “We’re leaving a big chunk of the population behind if we don’t include those individuals.”
Scientific basis for diversity
There are a multitude of scientific reasons for doing so, too, said Dr. Mata. “In the whole genome we try to find gene variants that modify the risk for certain disease,” he said. “These regions can be quite large, so increasing the number of individuals that come from different genetic backgrounds can actually help us reduce the number of regions that need to be studied to find the causal variants.”
Andrew Singleton, PhD, director of the Center for Alzheimer’s and Related Dementias at the National Institute of Aging in Bethesda, Md., concurred that enrolling more diverse populations can speed up research for targeting genetic variants.
“We can use the differences in genetics to narrow down our search for variants, reduce the places where we’re looking for risk variants, and reduce the number of genes we’re looking at,” he said in an interview.
Roy Alcalay, MD, professor of neurology at Columbia University Irving Medical Center in New York, offered two more scientific reasons for more diverse study populations “in addition to being more ethically appropriate,” he said. “One is, you may identify new genes that you wouldn’t have identified otherwise; and also in the genes that already exist, you may recognize that some of the pathogenic variants may be more prevalent in populations that were unknown.”
One of the challenges in casting a wider net is that much of the research funding has been concentrated in the United States and Europe, Dr. Mata said. And even in the United States, with large, diverse populations, minority groups are underrepresented in these studies, he said, but a potential solution is emerging. “This is something that we’re learning now with COVID,” he said. “We can do a lot remotely. This should help bring some of those barriers down.”
Cultural barriers are also foreboding. “Individuals may not feel comfortable participating in research,” he said in the interview. “I see this especially in the Hispanic community; many don’t understand what they can do with genetic material, or they’re afraid it will be shared with police, and if they’re here in nonofficial immigration status, they’re afraid they could be deported. There are a lot of misconceptions about genetic research.”
An initiative of the Parkinson’s Foundation PD GENEration Study is to provide free genetic tests and give the patient a report on genetic counseling “to empower patients,” Dr. Mata said.
Solutions for targeting underrepresented groups are emerging, Dr. Singleton said. “Actually there’s a really elegant solution, which is that in the populations that we go into and work with, we make sure the ownership of those cohorts, the ownership of the science and the analysis belongs to those populations,” he said.
“Part of that is creating infrastructure on site,” Dr. Singleton added. “Another part is providing training and outreach so we can help to train a whole new generation of scientists and researchers who can work in those populations embedded within those populations. They’re really the champion of moving that research forward.”
Dr. Alcalay credited Dr. Mata for his work with cohorts in Central and South America and in reaching out to other countries to recruit more diverse populations for genetic Parkinson’s studies. “And it’s not just because it’s the politically correct thing to do, about inclusivity and diversity,” Dr. Alcalay said. “It’s because it’s really meaningful. In addition to being ethically more appropriate, it will advance the entire field.
“I also really think it’s a no-brainer,” Dr. Alcalay said. “It’s something that needs to happen.”
Dr. Mata receives grant funding from the National Institutes of Health. Dr. Singleton and Dr. Alcalay have no relevant disclosures.
, attendees at the International Congress of Parkinson’s Disease and Movement Disorders were told.
“Through the years, as we’ve increased the number of individuals that we’ve included in our genetic studies, the number of risk factors that we’ve been able to identify has increased exponentially,” said Ignacio F. Mata, PhD, a neurogeneticist and principal investigator with the Genomic Medicine Institute of the Cleveland Clinic Lerner Research Institute. “This is all due to collaborations.”
Dr. Mata reviewed no fewer than seven initiatives that are gathering genetic data from people with Parkinson’s disease in Central and South America, India, China, Africa, Oceania, the Middle East, and Central Asia, along with efforts to target diverse populations in London and African Americans in the United States.
“One of the problems that we’ve had in the past is that most of the studies have been done just with individuals that are of European ancestry, so there’s a big gap of other populations that we haven’t been able to study,” Dr. Mata said. “And this is true for all of the current studies that are ongoing here in the United States.” That includes the Parkinson’s Progression Markers Initiative, he said, in which fewer than 6% of participants are non-European. Dr. Mata is also the lead in the Global Parkinson’s Genetics Program (GP2) for underrepresented populations.
Lack of diversity in genetic studies isn’t an issue in Parkinson’s studies alone, Dr. Mata said. “This is a generalized problem across all genetic studies,” he said, citing a 2016 analysis that found the proportion of participants in genome-wide studies was 96% European descent in 2009, shifting to 80% by 2016. “There’s still a big gap because most of the non-European populations came mostly from Asia,” Dr. Mata said, with Latinos and people of African descent representing less than 1% of the study populations.
In an interview, Dr. Mata noted there are a multitude of reasons for enrolling more diverse populations. “We’re going to be able to use genetics to create new treatments and do risk prediction – the so-called precision or personalized medicine,” he said. “We’re leaving a big chunk of the population behind if we don’t include those individuals.”
Scientific basis for diversity
There are a multitude of scientific reasons for doing so, too, said Dr. Mata. “In the whole genome we try to find gene variants that modify the risk for certain disease,” he said. “These regions can be quite large, so increasing the number of individuals that come from different genetic backgrounds can actually help us reduce the number of regions that need to be studied to find the causal variants.”
Andrew Singleton, PhD, director of the Center for Alzheimer’s and Related Dementias at the National Institute of Aging in Bethesda, Md., concurred that enrolling more diverse populations can speed up research for targeting genetic variants.
“We can use the differences in genetics to narrow down our search for variants, reduce the places where we’re looking for risk variants, and reduce the number of genes we’re looking at,” he said in an interview.
Roy Alcalay, MD, professor of neurology at Columbia University Irving Medical Center in New York, offered two more scientific reasons for more diverse study populations “in addition to being more ethically appropriate,” he said. “One is, you may identify new genes that you wouldn’t have identified otherwise; and also in the genes that already exist, you may recognize that some of the pathogenic variants may be more prevalent in populations that were unknown.”
One of the challenges in casting a wider net is that much of the research funding has been concentrated in the United States and Europe, Dr. Mata said. And even in the United States, with large, diverse populations, minority groups are underrepresented in these studies, he said, but a potential solution is emerging. “This is something that we’re learning now with COVID,” he said. “We can do a lot remotely. This should help bring some of those barriers down.”
Cultural barriers are also foreboding. “Individuals may not feel comfortable participating in research,” he said in the interview. “I see this especially in the Hispanic community; many don’t understand what they can do with genetic material, or they’re afraid it will be shared with police, and if they’re here in nonofficial immigration status, they’re afraid they could be deported. There are a lot of misconceptions about genetic research.”
An initiative of the Parkinson’s Foundation PD GENEration Study is to provide free genetic tests and give the patient a report on genetic counseling “to empower patients,” Dr. Mata said.
Solutions for targeting underrepresented groups are emerging, Dr. Singleton said. “Actually there’s a really elegant solution, which is that in the populations that we go into and work with, we make sure the ownership of those cohorts, the ownership of the science and the analysis belongs to those populations,” he said.
“Part of that is creating infrastructure on site,” Dr. Singleton added. “Another part is providing training and outreach so we can help to train a whole new generation of scientists and researchers who can work in those populations embedded within those populations. They’re really the champion of moving that research forward.”
Dr. Alcalay credited Dr. Mata for his work with cohorts in Central and South America and in reaching out to other countries to recruit more diverse populations for genetic Parkinson’s studies. “And it’s not just because it’s the politically correct thing to do, about inclusivity and diversity,” Dr. Alcalay said. “It’s because it’s really meaningful. In addition to being ethically more appropriate, it will advance the entire field.
“I also really think it’s a no-brainer,” Dr. Alcalay said. “It’s something that needs to happen.”
Dr. Mata receives grant funding from the National Institutes of Health. Dr. Singleton and Dr. Alcalay have no relevant disclosures.
, attendees at the International Congress of Parkinson’s Disease and Movement Disorders were told.
“Through the years, as we’ve increased the number of individuals that we’ve included in our genetic studies, the number of risk factors that we’ve been able to identify has increased exponentially,” said Ignacio F. Mata, PhD, a neurogeneticist and principal investigator with the Genomic Medicine Institute of the Cleveland Clinic Lerner Research Institute. “This is all due to collaborations.”
Dr. Mata reviewed no fewer than seven initiatives that are gathering genetic data from people with Parkinson’s disease in Central and South America, India, China, Africa, Oceania, the Middle East, and Central Asia, along with efforts to target diverse populations in London and African Americans in the United States.
“One of the problems that we’ve had in the past is that most of the studies have been done just with individuals that are of European ancestry, so there’s a big gap of other populations that we haven’t been able to study,” Dr. Mata said. “And this is true for all of the current studies that are ongoing here in the United States.” That includes the Parkinson’s Progression Markers Initiative, he said, in which fewer than 6% of participants are non-European. Dr. Mata is also the lead in the Global Parkinson’s Genetics Program (GP2) for underrepresented populations.
Lack of diversity in genetic studies isn’t an issue in Parkinson’s studies alone, Dr. Mata said. “This is a generalized problem across all genetic studies,” he said, citing a 2016 analysis that found the proportion of participants in genome-wide studies was 96% European descent in 2009, shifting to 80% by 2016. “There’s still a big gap because most of the non-European populations came mostly from Asia,” Dr. Mata said, with Latinos and people of African descent representing less than 1% of the study populations.
In an interview, Dr. Mata noted there are a multitude of reasons for enrolling more diverse populations. “We’re going to be able to use genetics to create new treatments and do risk prediction – the so-called precision or personalized medicine,” he said. “We’re leaving a big chunk of the population behind if we don’t include those individuals.”
Scientific basis for diversity
There are a multitude of scientific reasons for doing so, too, said Dr. Mata. “In the whole genome we try to find gene variants that modify the risk for certain disease,” he said. “These regions can be quite large, so increasing the number of individuals that come from different genetic backgrounds can actually help us reduce the number of regions that need to be studied to find the causal variants.”
Andrew Singleton, PhD, director of the Center for Alzheimer’s and Related Dementias at the National Institute of Aging in Bethesda, Md., concurred that enrolling more diverse populations can speed up research for targeting genetic variants.
“We can use the differences in genetics to narrow down our search for variants, reduce the places where we’re looking for risk variants, and reduce the number of genes we’re looking at,” he said in an interview.
Roy Alcalay, MD, professor of neurology at Columbia University Irving Medical Center in New York, offered two more scientific reasons for more diverse study populations “in addition to being more ethically appropriate,” he said. “One is, you may identify new genes that you wouldn’t have identified otherwise; and also in the genes that already exist, you may recognize that some of the pathogenic variants may be more prevalent in populations that were unknown.”
One of the challenges in casting a wider net is that much of the research funding has been concentrated in the United States and Europe, Dr. Mata said. And even in the United States, with large, diverse populations, minority groups are underrepresented in these studies, he said, but a potential solution is emerging. “This is something that we’re learning now with COVID,” he said. “We can do a lot remotely. This should help bring some of those barriers down.”
Cultural barriers are also foreboding. “Individuals may not feel comfortable participating in research,” he said in the interview. “I see this especially in the Hispanic community; many don’t understand what they can do with genetic material, or they’re afraid it will be shared with police, and if they’re here in nonofficial immigration status, they’re afraid they could be deported. There are a lot of misconceptions about genetic research.”
An initiative of the Parkinson’s Foundation PD GENEration Study is to provide free genetic tests and give the patient a report on genetic counseling “to empower patients,” Dr. Mata said.
Solutions for targeting underrepresented groups are emerging, Dr. Singleton said. “Actually there’s a really elegant solution, which is that in the populations that we go into and work with, we make sure the ownership of those cohorts, the ownership of the science and the analysis belongs to those populations,” he said.
“Part of that is creating infrastructure on site,” Dr. Singleton added. “Another part is providing training and outreach so we can help to train a whole new generation of scientists and researchers who can work in those populations embedded within those populations. They’re really the champion of moving that research forward.”
Dr. Alcalay credited Dr. Mata for his work with cohorts in Central and South America and in reaching out to other countries to recruit more diverse populations for genetic Parkinson’s studies. “And it’s not just because it’s the politically correct thing to do, about inclusivity and diversity,” Dr. Alcalay said. “It’s because it’s really meaningful. In addition to being ethically more appropriate, it will advance the entire field.
“I also really think it’s a no-brainer,” Dr. Alcalay said. “It’s something that needs to happen.”
Dr. Mata receives grant funding from the National Institutes of Health. Dr. Singleton and Dr. Alcalay have no relevant disclosures.
FROM MDS VIRTUAL CONGRESS 2021
Synthetic triglyceride shows potential in Huntington’s disease
, according to data presented at the International Congress of Parkinson’s Disease and Movement Disorders.
Reporting results of TRIHEP3 and an extension study, Fanny Mochel, MD, PhD, of Sorbonne University in Paris and the Paris Brain Institute, said in an interview that her group is the only one investigating triheptanoin to target caudate atrophy in Huntington’s disease. The Food and Drug Administration last year approved triheptanoin for the treatment of long-chain fatty acid oxidation disorders.
“The main findings are two observations: that patients were clinically stable based on their gradation of total motor score (TMS) on UHDRS (Unified Huntington’s Disease Rating Scale) after 1 year,” Dr. Mochel said in an interview. “The other is that we observed a reduction of the caudate atrophy progression that we usually see over 1 year by about 50%.”
TRIHEP3 randomized 100 patients with early-stage Huntington’s disease to triheptanoin 1g/kg daily and placebo. It followed on previous research in which the group used 31-phosphorus brain MR spectroscopy to demonstrate triheptanoin restored a normal brain energetic profile in patients with Huntington’s disease. TRIHEP3 was a 6-month randomized controlled trial at two centers, followed by a 6-month open-label phase. After that, 42 patients opted to participate in the 1-year extension study.
TRIHEP3 found no difference in caudate boundary shift integral (cBSI) at 6 months – the primary endpoint. But in the extension study, TMS tended to stabilize in patients treated for 1 year (0.6 ± 5.1), compared with those treated for 6 months (2.5 ± 4.5, P = .072).
Using a placebo control group from an external study of patients with Huntington’s disease with what Dr. Mochel described as “identical clinical characteristics,” she said the research confirmed TMS clinical stability in treated patients at 1 year (2.6 ± 4.6 vs. 0.6 ± 5.1, P = .057) and found significantly lower caudate atrophy (–3% vs. –6.7%, compared with baseline, P < .001).
Dr. Mochel also noted that Diffusion Tensor Imaging and Fixed-based analyses (FBA) showed fewer alterations in fiber metrics at 24 months in patients treated from baseline. FBA also showed improved fiber trophicity at 24 months in both groups.
‘The first good news’
Dr. Mochel noted that the Huntington’s disease community had been shaken in the spring by the failure of three trials of gene-targeting therapies for Huntington’s disease. Roche halted a phase 3 study of its antisense oligonucleotide (ASO) tominersen, and Wave Life Sciences scuttled two ASO programs in phase 1/2 trials.
“Triheptanoin is not going to cure Huntington’s disease; it’s a disease with many components, but it does work on the energy aspects and that seems to stabilize patients over the time of observation,” Dr. Mochel said. “That’s the first good news.”
She also noted that side effects were mainly gastrointestinal in nature, and they typically resolved with dietary management.
As a target in Huntington disease, the caudate nucleus is highly desirable, and caudate atrophy has been shown to occur even before the onset of motor symptoms, said N. Ahmad Aziz, MD, PhD, a neurologist and epidemiologist at the German Center for Neurodegenerative Diseases at the University of Bonn (Germany). “In this light, the findings of the trial conducted by Dr. Mochel and colleagues, which suggest that triheptanoin intake may slow down the rate of caudate atrophy in patients with early-stage Huntington’s disease, are highly promising,” Dr. Aziz said in an interview.
However, he noted that the improvement in caudate atrophy was only a secondary endpoint in the extension study. “Nevertheless, given triheptanoin’s biologically plausible mechanism of action – i.e., provision of substrates to the Krebs cycle and at least partial restoration of the well-documented defective mitochondrial function in Huntington’s disease – combined with its apparently relatively mild side-effect profile and good tolerability, I think that the preliminary findings of this trial are very promising and justify a larger phase 3 trial,” Dr. Aziz said.
Dr. Mochel said that the findings are prompting the investigators to consider just that.
Dr. Mochel has received consulting fees from and conducted investigator‐sponsored studies supported by Ultragenyx Pharmaceuticals. Dr. Aziz has no relevant financial relationships to disclose.
, according to data presented at the International Congress of Parkinson’s Disease and Movement Disorders.
Reporting results of TRIHEP3 and an extension study, Fanny Mochel, MD, PhD, of Sorbonne University in Paris and the Paris Brain Institute, said in an interview that her group is the only one investigating triheptanoin to target caudate atrophy in Huntington’s disease. The Food and Drug Administration last year approved triheptanoin for the treatment of long-chain fatty acid oxidation disorders.
“The main findings are two observations: that patients were clinically stable based on their gradation of total motor score (TMS) on UHDRS (Unified Huntington’s Disease Rating Scale) after 1 year,” Dr. Mochel said in an interview. “The other is that we observed a reduction of the caudate atrophy progression that we usually see over 1 year by about 50%.”
TRIHEP3 randomized 100 patients with early-stage Huntington’s disease to triheptanoin 1g/kg daily and placebo. It followed on previous research in which the group used 31-phosphorus brain MR spectroscopy to demonstrate triheptanoin restored a normal brain energetic profile in patients with Huntington’s disease. TRIHEP3 was a 6-month randomized controlled trial at two centers, followed by a 6-month open-label phase. After that, 42 patients opted to participate in the 1-year extension study.
TRIHEP3 found no difference in caudate boundary shift integral (cBSI) at 6 months – the primary endpoint. But in the extension study, TMS tended to stabilize in patients treated for 1 year (0.6 ± 5.1), compared with those treated for 6 months (2.5 ± 4.5, P = .072).
Using a placebo control group from an external study of patients with Huntington’s disease with what Dr. Mochel described as “identical clinical characteristics,” she said the research confirmed TMS clinical stability in treated patients at 1 year (2.6 ± 4.6 vs. 0.6 ± 5.1, P = .057) and found significantly lower caudate atrophy (–3% vs. –6.7%, compared with baseline, P < .001).
Dr. Mochel also noted that Diffusion Tensor Imaging and Fixed-based analyses (FBA) showed fewer alterations in fiber metrics at 24 months in patients treated from baseline. FBA also showed improved fiber trophicity at 24 months in both groups.
‘The first good news’
Dr. Mochel noted that the Huntington’s disease community had been shaken in the spring by the failure of three trials of gene-targeting therapies for Huntington’s disease. Roche halted a phase 3 study of its antisense oligonucleotide (ASO) tominersen, and Wave Life Sciences scuttled two ASO programs in phase 1/2 trials.
“Triheptanoin is not going to cure Huntington’s disease; it’s a disease with many components, but it does work on the energy aspects and that seems to stabilize patients over the time of observation,” Dr. Mochel said. “That’s the first good news.”
She also noted that side effects were mainly gastrointestinal in nature, and they typically resolved with dietary management.
As a target in Huntington disease, the caudate nucleus is highly desirable, and caudate atrophy has been shown to occur even before the onset of motor symptoms, said N. Ahmad Aziz, MD, PhD, a neurologist and epidemiologist at the German Center for Neurodegenerative Diseases at the University of Bonn (Germany). “In this light, the findings of the trial conducted by Dr. Mochel and colleagues, which suggest that triheptanoin intake may slow down the rate of caudate atrophy in patients with early-stage Huntington’s disease, are highly promising,” Dr. Aziz said in an interview.
However, he noted that the improvement in caudate atrophy was only a secondary endpoint in the extension study. “Nevertheless, given triheptanoin’s biologically plausible mechanism of action – i.e., provision of substrates to the Krebs cycle and at least partial restoration of the well-documented defective mitochondrial function in Huntington’s disease – combined with its apparently relatively mild side-effect profile and good tolerability, I think that the preliminary findings of this trial are very promising and justify a larger phase 3 trial,” Dr. Aziz said.
Dr. Mochel said that the findings are prompting the investigators to consider just that.
Dr. Mochel has received consulting fees from and conducted investigator‐sponsored studies supported by Ultragenyx Pharmaceuticals. Dr. Aziz has no relevant financial relationships to disclose.
, according to data presented at the International Congress of Parkinson’s Disease and Movement Disorders.
Reporting results of TRIHEP3 and an extension study, Fanny Mochel, MD, PhD, of Sorbonne University in Paris and the Paris Brain Institute, said in an interview that her group is the only one investigating triheptanoin to target caudate atrophy in Huntington’s disease. The Food and Drug Administration last year approved triheptanoin for the treatment of long-chain fatty acid oxidation disorders.
“The main findings are two observations: that patients were clinically stable based on their gradation of total motor score (TMS) on UHDRS (Unified Huntington’s Disease Rating Scale) after 1 year,” Dr. Mochel said in an interview. “The other is that we observed a reduction of the caudate atrophy progression that we usually see over 1 year by about 50%.”
TRIHEP3 randomized 100 patients with early-stage Huntington’s disease to triheptanoin 1g/kg daily and placebo. It followed on previous research in which the group used 31-phosphorus brain MR spectroscopy to demonstrate triheptanoin restored a normal brain energetic profile in patients with Huntington’s disease. TRIHEP3 was a 6-month randomized controlled trial at two centers, followed by a 6-month open-label phase. After that, 42 patients opted to participate in the 1-year extension study.
TRIHEP3 found no difference in caudate boundary shift integral (cBSI) at 6 months – the primary endpoint. But in the extension study, TMS tended to stabilize in patients treated for 1 year (0.6 ± 5.1), compared with those treated for 6 months (2.5 ± 4.5, P = .072).
Using a placebo control group from an external study of patients with Huntington’s disease with what Dr. Mochel described as “identical clinical characteristics,” she said the research confirmed TMS clinical stability in treated patients at 1 year (2.6 ± 4.6 vs. 0.6 ± 5.1, P = .057) and found significantly lower caudate atrophy (–3% vs. –6.7%, compared with baseline, P < .001).
Dr. Mochel also noted that Diffusion Tensor Imaging and Fixed-based analyses (FBA) showed fewer alterations in fiber metrics at 24 months in patients treated from baseline. FBA also showed improved fiber trophicity at 24 months in both groups.
‘The first good news’
Dr. Mochel noted that the Huntington’s disease community had been shaken in the spring by the failure of three trials of gene-targeting therapies for Huntington’s disease. Roche halted a phase 3 study of its antisense oligonucleotide (ASO) tominersen, and Wave Life Sciences scuttled two ASO programs in phase 1/2 trials.
“Triheptanoin is not going to cure Huntington’s disease; it’s a disease with many components, but it does work on the energy aspects and that seems to stabilize patients over the time of observation,” Dr. Mochel said. “That’s the first good news.”
She also noted that side effects were mainly gastrointestinal in nature, and they typically resolved with dietary management.
As a target in Huntington disease, the caudate nucleus is highly desirable, and caudate atrophy has been shown to occur even before the onset of motor symptoms, said N. Ahmad Aziz, MD, PhD, a neurologist and epidemiologist at the German Center for Neurodegenerative Diseases at the University of Bonn (Germany). “In this light, the findings of the trial conducted by Dr. Mochel and colleagues, which suggest that triheptanoin intake may slow down the rate of caudate atrophy in patients with early-stage Huntington’s disease, are highly promising,” Dr. Aziz said in an interview.
However, he noted that the improvement in caudate atrophy was only a secondary endpoint in the extension study. “Nevertheless, given triheptanoin’s biologically plausible mechanism of action – i.e., provision of substrates to the Krebs cycle and at least partial restoration of the well-documented defective mitochondrial function in Huntington’s disease – combined with its apparently relatively mild side-effect profile and good tolerability, I think that the preliminary findings of this trial are very promising and justify a larger phase 3 trial,” Dr. Aziz said.
Dr. Mochel said that the findings are prompting the investigators to consider just that.
Dr. Mochel has received consulting fees from and conducted investigator‐sponsored studies supported by Ultragenyx Pharmaceuticals. Dr. Aziz has no relevant financial relationships to disclose.
FROM MDS VIRTUAL CONGRESS 2021
Datopotamab deruxtecan for advanced NSCLC encouraging so far
according to Edward B. Garon, MD, of the University of California, Los Angeles. Prior results from TROPION-PanTumor01, have demonstrated similarly encouraging activity and a manageable safety profile for Dato-DXd, Dr. Garon said in a 2021 European Society for Medical Oncology Congress virtual oral presentation on Sept. 19 (abstract LBA49).
Limited benefit from existing treatments
Once tyrosine kinase inhibitors and platinum chemotherapy have failed, patients with advanced/metastatic NSCLC with AGAs (e.g., EGFR or ALK mutations) derive limited benefit from existing treatments, Dr. Garon observed. Datopotamab deruxtecan is an antibody-drug conjugate composed of a humanized anti-TROP2 monoclonal antibody conjugated to a potent topoisomerase I inhibitor payload via a stable tetrapeptide-based cleavable linker. TROP2 is highly expressed in NSCLC, regardless of genomic mutation status and has been associated with poor prognosis. Patients in TROPION-PanTumor01 were not selected based on TROP2 expression or AGA status, Dr. Garon noted.
TROPION-PanTumor01 (NCT03401385), an ongoing multicenter, open-label, dose-expansion study evaluating datopotamab deruxtecan in solid tumors, including NSCLC in 210 patients, is assessing safety, pharmacokinetics, antitumor activity, and biomarkers. All included patients (n = 180; median age, 62 years; 56% female) had progressed after standard treatment or had measurable disease and had no standard treatment available. Stable/treated brain metastases were permitted.
Subgroup with AGAs
The current report includes outcomes from the subgroup of 34 patients with AGAs, who were treated with 4 (n = 8), 6 (n = 10), and 8 mg/kg (n = 16) of datopotamab deruxtecan. AGAs were EGFR in 29 patients, ALK in 3, and ROS1 and RET in 1 each. Most patients (82%) had received three or more prior regimens; 85% had prior TKI, and among EGFR mutation patients, 69% had received osimertinib. Prior systemic treatment consisted of immunotherapy in 41%, platinum-based chemotherapy in 91%, and tyrosine kinase inhibitor in 85%. The primary objectives were to establish the maximum tolerated dose, safety, and tolerability. Efficacy was a secondary outcome.
Treatment-emergent adverse events were reported in all patients, with grade 3 or higher events in 53%. Most common were grade 1-2 nausea, stomatitis, fatigue, and alopecia. Drug-attributed events in 88% were grade 3 or higher in 38%. Treatment-emergent adverse events led to discontinuation in 15%, dose interruption in 27% and dose reductions in 15%. One case of grade 5 interstitial lung disease, in the 8-mg group, was adjudicated as drug related. “The safety profile of Dato-DXd was manageable and consistent with that observed in the overall NSCLC population in TROPION-PanTumor01,” Dr. Garon said, “and were primarily nonhematologic.”
The objective response rate was 35%, all partial responses. The stable disease rate was 41%; the progressive disease rate was 6%. Median duration of response was 9.5 months (95% confidence interval, 3.3-NE). Dr. Garon noted that clinical activity was observed in EGFR (Ex 19del, L858R) including after osimertinib and across other AGAs.
Further evaluation ongoing
Further evaluation of datopotamab deruxtecan is ongoing in the TROPION-Lung05 study among NSCLC patients with AGAs after targeted therapy and platinum-based chemotherapy options have been exhausted. Eligible AGAs include EGFR (including exon 20 insertions), ALK, ROS1, RET, BRAF, NTRK and MET exon 14 skipping.
Session moderator David Gandara, MD, University of California Davis Health, questioned the rationale for targeting oncogene driven cancers with this particular drug: “Is this just because this is felt to be an unmet need, or is there higher expression or some other biologic rationale?”
Dr. Garon responded, “Why are we looking at these driver mutation–positive patients? I think it has less to do with mechanism and more to do with the differences in treatment between these driver mutation positive patients and the rest of the population. This is a group of patients which has TROP2, but TROP2 expression is seen really across non–small cell lung cancer. But, in fact, one of the reasons it has been postulated that TROP2 is not a good biomarker for this class of drugs to date, is that its expression is so ubiquitous in the disease.”
The study was funded by Daiichi Sankyo. Dr. Garon disclosed numerous pharmaceutical-related financial interests.
This article was updated Sept. 24, 2021.
according to Edward B. Garon, MD, of the University of California, Los Angeles. Prior results from TROPION-PanTumor01, have demonstrated similarly encouraging activity and a manageable safety profile for Dato-DXd, Dr. Garon said in a 2021 European Society for Medical Oncology Congress virtual oral presentation on Sept. 19 (abstract LBA49).
Limited benefit from existing treatments
Once tyrosine kinase inhibitors and platinum chemotherapy have failed, patients with advanced/metastatic NSCLC with AGAs (e.g., EGFR or ALK mutations) derive limited benefit from existing treatments, Dr. Garon observed. Datopotamab deruxtecan is an antibody-drug conjugate composed of a humanized anti-TROP2 monoclonal antibody conjugated to a potent topoisomerase I inhibitor payload via a stable tetrapeptide-based cleavable linker. TROP2 is highly expressed in NSCLC, regardless of genomic mutation status and has been associated with poor prognosis. Patients in TROPION-PanTumor01 were not selected based on TROP2 expression or AGA status, Dr. Garon noted.
TROPION-PanTumor01 (NCT03401385), an ongoing multicenter, open-label, dose-expansion study evaluating datopotamab deruxtecan in solid tumors, including NSCLC in 210 patients, is assessing safety, pharmacokinetics, antitumor activity, and biomarkers. All included patients (n = 180; median age, 62 years; 56% female) had progressed after standard treatment or had measurable disease and had no standard treatment available. Stable/treated brain metastases were permitted.
Subgroup with AGAs
The current report includes outcomes from the subgroup of 34 patients with AGAs, who were treated with 4 (n = 8), 6 (n = 10), and 8 mg/kg (n = 16) of datopotamab deruxtecan. AGAs were EGFR in 29 patients, ALK in 3, and ROS1 and RET in 1 each. Most patients (82%) had received three or more prior regimens; 85% had prior TKI, and among EGFR mutation patients, 69% had received osimertinib. Prior systemic treatment consisted of immunotherapy in 41%, platinum-based chemotherapy in 91%, and tyrosine kinase inhibitor in 85%. The primary objectives were to establish the maximum tolerated dose, safety, and tolerability. Efficacy was a secondary outcome.
Treatment-emergent adverse events were reported in all patients, with grade 3 or higher events in 53%. Most common were grade 1-2 nausea, stomatitis, fatigue, and alopecia. Drug-attributed events in 88% were grade 3 or higher in 38%. Treatment-emergent adverse events led to discontinuation in 15%, dose interruption in 27% and dose reductions in 15%. One case of grade 5 interstitial lung disease, in the 8-mg group, was adjudicated as drug related. “The safety profile of Dato-DXd was manageable and consistent with that observed in the overall NSCLC population in TROPION-PanTumor01,” Dr. Garon said, “and were primarily nonhematologic.”
The objective response rate was 35%, all partial responses. The stable disease rate was 41%; the progressive disease rate was 6%. Median duration of response was 9.5 months (95% confidence interval, 3.3-NE). Dr. Garon noted that clinical activity was observed in EGFR (Ex 19del, L858R) including after osimertinib and across other AGAs.
Further evaluation ongoing
Further evaluation of datopotamab deruxtecan is ongoing in the TROPION-Lung05 study among NSCLC patients with AGAs after targeted therapy and platinum-based chemotherapy options have been exhausted. Eligible AGAs include EGFR (including exon 20 insertions), ALK, ROS1, RET, BRAF, NTRK and MET exon 14 skipping.
Session moderator David Gandara, MD, University of California Davis Health, questioned the rationale for targeting oncogene driven cancers with this particular drug: “Is this just because this is felt to be an unmet need, or is there higher expression or some other biologic rationale?”
Dr. Garon responded, “Why are we looking at these driver mutation–positive patients? I think it has less to do with mechanism and more to do with the differences in treatment between these driver mutation positive patients and the rest of the population. This is a group of patients which has TROP2, but TROP2 expression is seen really across non–small cell lung cancer. But, in fact, one of the reasons it has been postulated that TROP2 is not a good biomarker for this class of drugs to date, is that its expression is so ubiquitous in the disease.”
The study was funded by Daiichi Sankyo. Dr. Garon disclosed numerous pharmaceutical-related financial interests.
This article was updated Sept. 24, 2021.
according to Edward B. Garon, MD, of the University of California, Los Angeles. Prior results from TROPION-PanTumor01, have demonstrated similarly encouraging activity and a manageable safety profile for Dato-DXd, Dr. Garon said in a 2021 European Society for Medical Oncology Congress virtual oral presentation on Sept. 19 (abstract LBA49).
Limited benefit from existing treatments
Once tyrosine kinase inhibitors and platinum chemotherapy have failed, patients with advanced/metastatic NSCLC with AGAs (e.g., EGFR or ALK mutations) derive limited benefit from existing treatments, Dr. Garon observed. Datopotamab deruxtecan is an antibody-drug conjugate composed of a humanized anti-TROP2 monoclonal antibody conjugated to a potent topoisomerase I inhibitor payload via a stable tetrapeptide-based cleavable linker. TROP2 is highly expressed in NSCLC, regardless of genomic mutation status and has been associated with poor prognosis. Patients in TROPION-PanTumor01 were not selected based on TROP2 expression or AGA status, Dr. Garon noted.
TROPION-PanTumor01 (NCT03401385), an ongoing multicenter, open-label, dose-expansion study evaluating datopotamab deruxtecan in solid tumors, including NSCLC in 210 patients, is assessing safety, pharmacokinetics, antitumor activity, and biomarkers. All included patients (n = 180; median age, 62 years; 56% female) had progressed after standard treatment or had measurable disease and had no standard treatment available. Stable/treated brain metastases were permitted.
Subgroup with AGAs
The current report includes outcomes from the subgroup of 34 patients with AGAs, who were treated with 4 (n = 8), 6 (n = 10), and 8 mg/kg (n = 16) of datopotamab deruxtecan. AGAs were EGFR in 29 patients, ALK in 3, and ROS1 and RET in 1 each. Most patients (82%) had received three or more prior regimens; 85% had prior TKI, and among EGFR mutation patients, 69% had received osimertinib. Prior systemic treatment consisted of immunotherapy in 41%, platinum-based chemotherapy in 91%, and tyrosine kinase inhibitor in 85%. The primary objectives were to establish the maximum tolerated dose, safety, and tolerability. Efficacy was a secondary outcome.
Treatment-emergent adverse events were reported in all patients, with grade 3 or higher events in 53%. Most common were grade 1-2 nausea, stomatitis, fatigue, and alopecia. Drug-attributed events in 88% were grade 3 or higher in 38%. Treatment-emergent adverse events led to discontinuation in 15%, dose interruption in 27% and dose reductions in 15%. One case of grade 5 interstitial lung disease, in the 8-mg group, was adjudicated as drug related. “The safety profile of Dato-DXd was manageable and consistent with that observed in the overall NSCLC population in TROPION-PanTumor01,” Dr. Garon said, “and were primarily nonhematologic.”
The objective response rate was 35%, all partial responses. The stable disease rate was 41%; the progressive disease rate was 6%. Median duration of response was 9.5 months (95% confidence interval, 3.3-NE). Dr. Garon noted that clinical activity was observed in EGFR (Ex 19del, L858R) including after osimertinib and across other AGAs.
Further evaluation ongoing
Further evaluation of datopotamab deruxtecan is ongoing in the TROPION-Lung05 study among NSCLC patients with AGAs after targeted therapy and platinum-based chemotherapy options have been exhausted. Eligible AGAs include EGFR (including exon 20 insertions), ALK, ROS1, RET, BRAF, NTRK and MET exon 14 skipping.
Session moderator David Gandara, MD, University of California Davis Health, questioned the rationale for targeting oncogene driven cancers with this particular drug: “Is this just because this is felt to be an unmet need, or is there higher expression or some other biologic rationale?”
Dr. Garon responded, “Why are we looking at these driver mutation–positive patients? I think it has less to do with mechanism and more to do with the differences in treatment between these driver mutation positive patients and the rest of the population. This is a group of patients which has TROP2, but TROP2 expression is seen really across non–small cell lung cancer. But, in fact, one of the reasons it has been postulated that TROP2 is not a good biomarker for this class of drugs to date, is that its expression is so ubiquitous in the disease.”
The study was funded by Daiichi Sankyo. Dr. Garon disclosed numerous pharmaceutical-related financial interests.
This article was updated Sept. 24, 2021.
FROM ESMO 2021
TULIP trial shows extended survival in HER2+ metastatic breast cancer
, according to Cristina Saura Manich, MD, Hospital Universitario Valle de Hebrón, Barcelona. In TULIP, trastuzumab duocarmazine (SYD985, Byondis B.V., NL) was compared with physician’s choice of chemotherapy, Dr. Saura said at the virtual European Society for Medical Oncology Congress 2021 on Sept. 18 (abstract LBA15).
Trastuzumab duocarmazine, Dr. Manich noted, is a novel HER2-targeting antibody–drug conjugate based on trastuzumab and a cleavable linker-duocarmycin (vc-seco-DUBA) payload. Its three-way mechanism of action includes uptake of the antibody–drug conjugate by internalization and intracellular release of the payload, and two bystander effects: proteolytic cleavage and subsequent release of payload in the tumor microenvironment and diffusion of active payload to neighboring tumor cells.
Two or more prior therapies for metastatic breast cancer
TULIP investigators enrolled 437 patients from 83 sites in 11 countries with HER2-positive locally advanced or metastatic breast cancer who had received two or more therapies for metastatic disease (treatment for brain metastases allowed). They were randomized 2:1 to SYD985 (1.2 mg/kg IV every 21 days [n = 291]) or physician’s choice (PC) [n = 146] of one of three trastuzumab-containing combinations or lapatinib plus capecitabine. Treatment was continued until progression or unacceptable toxicity. The primary endpoint was centrally assessed PFS.
Longer progression-free survival with SYD985
Median age was 57 years, and the median number of prior metastatic breast cancer regimens was 4.7. Centrally reviewed progression-free survival was significantly longer in the SYD985 group at 7.0 months (5.4-7.2) versus 4.9 months (4.0-5.5) for PC (hazard ratio [HR], 0.64, 95% confidence interval [CI], 0.49-0.84, P = .002). Subgroup analysis, also centrally reviewed, revealed numerical advantage for SYD985 over physician choice across all categories (except for ECOG status 2). Analysis of progression-free survival by investigators showed a similar benefit for SYD985 (6.9 months versus 4.6 months, HR, 0.60, P < .001).
A first look at median overall survival showed a nonsignificant advantage for SYD985 (20.4 months versus 16.3 months (HR, 0.83, 95% CI, 0.62-1.09, P = .153). The overall response rate (partial or complete response) was similar between groups at 27.8% for SYD985 and 29.5% for PC, with reductions in target lesion measurement at 70.2% and 32.2% for SYD985 and physician choice, respectively. The clinical benefit rates were 38.5% for SYD985 and 32.2% for physician choice.
Ocular toxicity
Most patients had at least one treatment-related adverse event (96.5% SD985, 96.4% PC), and grade 3 or higher event rates were similar between groups (52.8% SYD985, 48.2% PC). The most frequently reported adverse events for SYD985 were ocular toxicity, with conjunctivitis reported in 38.2%, and keratitis in 38.2%, with fatigue at 33.3%; for physician’s choice these were diarrhea (35.8%), nausea (31.4%), and fatigue (29.9%). Interstitial lung disease pneumonitis was reported for 7.6% (5.2% grade 1-2) of patients treated with SYD985, including two grade 5 events. Eye toxicity led to discontinuations in 20.8% of SYD985 patients, dose modifications in 22.9%, with dose modifications for interstitial lung disease/pneumonitis in 5.2% of SYD985 patients. Six fatalities (2.1%) were reported in the SYD985 group, with four attributed to treatment. Assessment of health-related quality of life showed no significant difference between groups.
Dr. Manich outlined risk mitigation strategies. Patients with prior keratitis were excluded and patients were given prophylactic lubricating eye drops and regular eye exams by ophthalmologists. Treatment was discontinued if grade 3 or higher keratitis developed, and was delayed if grade 3 conjunctivitis developed until it reduced to grade 2. Also, patients with prior pneumonitis were excluded and CT lung scans were evaluated for lung changes. New or worsening respiratory symptoms triggered a full diagnostic workup. Treatment was discontinued for grade 2 or higher pneumonitis and delayed until resolution for grade 1 pneumonitis.
Another option
“It is encouraging to observe clinically meaningful and potentially practice changing PFS improvements in patients receiving treatment in the third line and beyond,” said Aditya Bardia, MD, of Massachusetts General Hospital and Harvard Medical School, Boston. “Several agents have been approved as treatments for HER2-positive metastatic breast cancer in recent years – including T-DXd, neratinib, tucatinib, and margetuximab – and [vic-]trastuzumab duocarmazine could eventually be another option.”
“At this time, there is only a minor 2-month difference in progression-free survival and a nonsignificant overall survival difference,” said Fatima Cardoso, MD, of Champalimaud Cancer Center, Lisbon, Portugal. “With the high incidence of ocular toxicity and four toxic deaths, we cannot recommend this drug for clinical practice, in my opinion.”
Dr. Manich concluded, “SYD985 can provide a new treatment option for patients with pretreated locally advanced or metastatic HER2-positive metastatic breast cancer.”
The study was funded by Byondis B.V. The authors disclosed numerous pharmaceutical-related financial interests.
This article was updated Sept. 24, 2021.
, according to Cristina Saura Manich, MD, Hospital Universitario Valle de Hebrón, Barcelona. In TULIP, trastuzumab duocarmazine (SYD985, Byondis B.V., NL) was compared with physician’s choice of chemotherapy, Dr. Saura said at the virtual European Society for Medical Oncology Congress 2021 on Sept. 18 (abstract LBA15).
Trastuzumab duocarmazine, Dr. Manich noted, is a novel HER2-targeting antibody–drug conjugate based on trastuzumab and a cleavable linker-duocarmycin (vc-seco-DUBA) payload. Its three-way mechanism of action includes uptake of the antibody–drug conjugate by internalization and intracellular release of the payload, and two bystander effects: proteolytic cleavage and subsequent release of payload in the tumor microenvironment and diffusion of active payload to neighboring tumor cells.
Two or more prior therapies for metastatic breast cancer
TULIP investigators enrolled 437 patients from 83 sites in 11 countries with HER2-positive locally advanced or metastatic breast cancer who had received two or more therapies for metastatic disease (treatment for brain metastases allowed). They were randomized 2:1 to SYD985 (1.2 mg/kg IV every 21 days [n = 291]) or physician’s choice (PC) [n = 146] of one of three trastuzumab-containing combinations or lapatinib plus capecitabine. Treatment was continued until progression or unacceptable toxicity. The primary endpoint was centrally assessed PFS.
Longer progression-free survival with SYD985
Median age was 57 years, and the median number of prior metastatic breast cancer regimens was 4.7. Centrally reviewed progression-free survival was significantly longer in the SYD985 group at 7.0 months (5.4-7.2) versus 4.9 months (4.0-5.5) for PC (hazard ratio [HR], 0.64, 95% confidence interval [CI], 0.49-0.84, P = .002). Subgroup analysis, also centrally reviewed, revealed numerical advantage for SYD985 over physician choice across all categories (except for ECOG status 2). Analysis of progression-free survival by investigators showed a similar benefit for SYD985 (6.9 months versus 4.6 months, HR, 0.60, P < .001).
A first look at median overall survival showed a nonsignificant advantage for SYD985 (20.4 months versus 16.3 months (HR, 0.83, 95% CI, 0.62-1.09, P = .153). The overall response rate (partial or complete response) was similar between groups at 27.8% for SYD985 and 29.5% for PC, with reductions in target lesion measurement at 70.2% and 32.2% for SYD985 and physician choice, respectively. The clinical benefit rates were 38.5% for SYD985 and 32.2% for physician choice.
Ocular toxicity
Most patients had at least one treatment-related adverse event (96.5% SD985, 96.4% PC), and grade 3 or higher event rates were similar between groups (52.8% SYD985, 48.2% PC). The most frequently reported adverse events for SYD985 were ocular toxicity, with conjunctivitis reported in 38.2%, and keratitis in 38.2%, with fatigue at 33.3%; for physician’s choice these were diarrhea (35.8%), nausea (31.4%), and fatigue (29.9%). Interstitial lung disease pneumonitis was reported for 7.6% (5.2% grade 1-2) of patients treated with SYD985, including two grade 5 events. Eye toxicity led to discontinuations in 20.8% of SYD985 patients, dose modifications in 22.9%, with dose modifications for interstitial lung disease/pneumonitis in 5.2% of SYD985 patients. Six fatalities (2.1%) were reported in the SYD985 group, with four attributed to treatment. Assessment of health-related quality of life showed no significant difference between groups.
Dr. Manich outlined risk mitigation strategies. Patients with prior keratitis were excluded and patients were given prophylactic lubricating eye drops and regular eye exams by ophthalmologists. Treatment was discontinued if grade 3 or higher keratitis developed, and was delayed if grade 3 conjunctivitis developed until it reduced to grade 2. Also, patients with prior pneumonitis were excluded and CT lung scans were evaluated for lung changes. New or worsening respiratory symptoms triggered a full diagnostic workup. Treatment was discontinued for grade 2 or higher pneumonitis and delayed until resolution for grade 1 pneumonitis.
Another option
“It is encouraging to observe clinically meaningful and potentially practice changing PFS improvements in patients receiving treatment in the third line and beyond,” said Aditya Bardia, MD, of Massachusetts General Hospital and Harvard Medical School, Boston. “Several agents have been approved as treatments for HER2-positive metastatic breast cancer in recent years – including T-DXd, neratinib, tucatinib, and margetuximab – and [vic-]trastuzumab duocarmazine could eventually be another option.”
“At this time, there is only a minor 2-month difference in progression-free survival and a nonsignificant overall survival difference,” said Fatima Cardoso, MD, of Champalimaud Cancer Center, Lisbon, Portugal. “With the high incidence of ocular toxicity and four toxic deaths, we cannot recommend this drug for clinical practice, in my opinion.”
Dr. Manich concluded, “SYD985 can provide a new treatment option for patients with pretreated locally advanced or metastatic HER2-positive metastatic breast cancer.”
The study was funded by Byondis B.V. The authors disclosed numerous pharmaceutical-related financial interests.
This article was updated Sept. 24, 2021.
, according to Cristina Saura Manich, MD, Hospital Universitario Valle de Hebrón, Barcelona. In TULIP, trastuzumab duocarmazine (SYD985, Byondis B.V., NL) was compared with physician’s choice of chemotherapy, Dr. Saura said at the virtual European Society for Medical Oncology Congress 2021 on Sept. 18 (abstract LBA15).
Trastuzumab duocarmazine, Dr. Manich noted, is a novel HER2-targeting antibody–drug conjugate based on trastuzumab and a cleavable linker-duocarmycin (vc-seco-DUBA) payload. Its three-way mechanism of action includes uptake of the antibody–drug conjugate by internalization and intracellular release of the payload, and two bystander effects: proteolytic cleavage and subsequent release of payload in the tumor microenvironment and diffusion of active payload to neighboring tumor cells.
Two or more prior therapies for metastatic breast cancer
TULIP investigators enrolled 437 patients from 83 sites in 11 countries with HER2-positive locally advanced or metastatic breast cancer who had received two or more therapies for metastatic disease (treatment for brain metastases allowed). They were randomized 2:1 to SYD985 (1.2 mg/kg IV every 21 days [n = 291]) or physician’s choice (PC) [n = 146] of one of three trastuzumab-containing combinations or lapatinib plus capecitabine. Treatment was continued until progression or unacceptable toxicity. The primary endpoint was centrally assessed PFS.
Longer progression-free survival with SYD985
Median age was 57 years, and the median number of prior metastatic breast cancer regimens was 4.7. Centrally reviewed progression-free survival was significantly longer in the SYD985 group at 7.0 months (5.4-7.2) versus 4.9 months (4.0-5.5) for PC (hazard ratio [HR], 0.64, 95% confidence interval [CI], 0.49-0.84, P = .002). Subgroup analysis, also centrally reviewed, revealed numerical advantage for SYD985 over physician choice across all categories (except for ECOG status 2). Analysis of progression-free survival by investigators showed a similar benefit for SYD985 (6.9 months versus 4.6 months, HR, 0.60, P < .001).
A first look at median overall survival showed a nonsignificant advantage for SYD985 (20.4 months versus 16.3 months (HR, 0.83, 95% CI, 0.62-1.09, P = .153). The overall response rate (partial or complete response) was similar between groups at 27.8% for SYD985 and 29.5% for PC, with reductions in target lesion measurement at 70.2% and 32.2% for SYD985 and physician choice, respectively. The clinical benefit rates were 38.5% for SYD985 and 32.2% for physician choice.
Ocular toxicity
Most patients had at least one treatment-related adverse event (96.5% SD985, 96.4% PC), and grade 3 or higher event rates were similar between groups (52.8% SYD985, 48.2% PC). The most frequently reported adverse events for SYD985 were ocular toxicity, with conjunctivitis reported in 38.2%, and keratitis in 38.2%, with fatigue at 33.3%; for physician’s choice these were diarrhea (35.8%), nausea (31.4%), and fatigue (29.9%). Interstitial lung disease pneumonitis was reported for 7.6% (5.2% grade 1-2) of patients treated with SYD985, including two grade 5 events. Eye toxicity led to discontinuations in 20.8% of SYD985 patients, dose modifications in 22.9%, with dose modifications for interstitial lung disease/pneumonitis in 5.2% of SYD985 patients. Six fatalities (2.1%) were reported in the SYD985 group, with four attributed to treatment. Assessment of health-related quality of life showed no significant difference between groups.
Dr. Manich outlined risk mitigation strategies. Patients with prior keratitis were excluded and patients were given prophylactic lubricating eye drops and regular eye exams by ophthalmologists. Treatment was discontinued if grade 3 or higher keratitis developed, and was delayed if grade 3 conjunctivitis developed until it reduced to grade 2. Also, patients with prior pneumonitis were excluded and CT lung scans were evaluated for lung changes. New or worsening respiratory symptoms triggered a full diagnostic workup. Treatment was discontinued for grade 2 or higher pneumonitis and delayed until resolution for grade 1 pneumonitis.
Another option
“It is encouraging to observe clinically meaningful and potentially practice changing PFS improvements in patients receiving treatment in the third line and beyond,” said Aditya Bardia, MD, of Massachusetts General Hospital and Harvard Medical School, Boston. “Several agents have been approved as treatments for HER2-positive metastatic breast cancer in recent years – including T-DXd, neratinib, tucatinib, and margetuximab – and [vic-]trastuzumab duocarmazine could eventually be another option.”
“At this time, there is only a minor 2-month difference in progression-free survival and a nonsignificant overall survival difference,” said Fatima Cardoso, MD, of Champalimaud Cancer Center, Lisbon, Portugal. “With the high incidence of ocular toxicity and four toxic deaths, we cannot recommend this drug for clinical practice, in my opinion.”
Dr. Manich concluded, “SYD985 can provide a new treatment option for patients with pretreated locally advanced or metastatic HER2-positive metastatic breast cancer.”
The study was funded by Byondis B.V. The authors disclosed numerous pharmaceutical-related financial interests.
This article was updated Sept. 24, 2021.
FROM ESMO 2021
ctDNA may be a better surrogate for survival than RECIST
according to Alexander Noor Shoushtari, MD, Memorial Sloan Kettering Cancer Center, New York.
Tebentafusp is the first therapy to demonstrate an overall survival (OS) benefit in uveal melanoma, Dr. Shoushtari noted in a 2021 European Society of Medical Oncology Congress virtual oral presentation Sept. 17 (abstract 17570). He noted further that, in prior research, OS was improved regardless of RECISTv1.1 best response, suggesting that better surrogate efficacy endpoints are needed.
Uveal melanoma is a rare melanoma type with low mutational burden, but frequent liver metastases. Benefit from immune checkpoint inhibitors is poor, and there is no established standard of care once the disease becomes metastatic. “Immune checkpoint inhibitors are not as good for treating this type of melanoma as they are for treating cutaneous disease, and traditionally preferred treatment is within clinical trials,” Dr. Shoushtari said. In frontline trials, 1-year survival has been in the 50% range. Tebentafusp is an investigational, first-in-class bispecific soluble T-cell receptor (TCR) therapeutic. It is designed to target gp100 (a melanoma-associated antigen) through a high-affinity TCR-binding domain and an anti-CD3 T-cell–engaging domain, which redirects T cells to kill gp100 positive melanocytic expressing tumor cells.
Prior research has demonstrated a disconnect between RECIST response classification and tebentafusp OS benefit. In the IMCgp100-202 study among patients treated first-line for metastatic uveal melanoma with tebentafusp or investigator choice, intent-to-treat analysis showed a survival probability benefit for tebentafusp (hazard ratio, 0.51; 95% CI, 0.37-0.71), with a best response of progressive disease population HR of 0.43 (95% CI, 0.27-0.68). While the RECIST response rate was only 9.1%, the HR for progression-free survival was 0.73 (95% CI, 0.58-0.94). “That suggests that RECIST is not a fantastic way to predict who will benefit from this drug,” Dr. Shoushtari stated.
Similarly in the IMCgp100-102 study of tebentafusp monotherapy in second-line metastatic uveal melanoma (n = 127), the RECIST response rate was 5%. Duration of response was 8.7 months and median OS was 16.8 months. Historical second-line OS has been reported at 7.8 months. The 1- and 2-year survival (62%/37%) compared favorably with historical rates (37%/15%), as well. Dr. Shoushtari noted that 92% of patients had detectable ctDNA with mutations in known uveal melanoma oncogenes. He pointed out that baseline ctDNA levels significantly correlated with tumor burden. Also, 70% of evaluable patients had any ctDNA reduction, with 0.5-3.2 log reduction in 99.9%, a 0.5 log reduction in 68% and 3 log reduction (cleared) in 14% of patients. ctDNA reduction, Dr. Shoushtari said, was associated with greater mean tumor shrinkage and with less tumor growth. Importantly, there was a linear correlation between ctDNA reduction and better OS (R2, 0.88, P < .0001).
Among all evaluable patients, comparing those with less than 0.5 log ctDNA reduction with those with at least a 0.5 log reduction showed a hazard ratio of 0.56 (95% CI, 0.32-0.95; P = .03). Among those whose best response was progressive disease, 35% had at least a 0.5 log reduction in ctDNA with an OS hazard ratio of 0.44 (95% CI, 0.2-0.94; P = .027), compared with less than a 0.5 log reduction. Among those whose best response was stable disease, 28% had at least 1 log reduction with a hazard ratio of 0.48 (95% CI 0.16-1.43; P = .16) for OS, compared with those with less than 1 log reduction. Dr. Shoushtari pointed out that “14% of patients cleared ctDNA, including some (n = 12) with best RECIST responses of stable or progressive disease. All patients with ctDNA clearance were alive beyond 1 year; with a hazard ratio, compared to those who had not cleared ctDNA, of 0.14 (95% CI, 0.03-0.57).
Summing up, Dr. Shoushtari said that ctDNA was detectable in more than 90% of second-line tebentafusp-treated patients with metastatic uveal melanoma and correlated with tumor burden. About 70% had ctDNA reduction versus 39% with tumor shrinkage and 5% RECIST response. The linear correlation between the magnitude of ctDNA reduction and improved OS on tebentafusp, was uncoupled from best RECIST response. “For tebentafusp, ctDNA reduction may be a better surrogate of overall survival than RECIST response.”
The ESMO-appointed discussant for the study, Christian Rolfo, MD, PhD, MBA, Icahan School of Medicine at Mount Sinai, New York, examined the tebentafusp study author’s claim that the radiographic assessment of tumors may underestimate the effect of tebentafusp, compared with ctDNA. The strengths of the study include, he said, that it is a drug- and tumor-specific evaluation of the role of ctDNA as a surrogate of response. “Its strength is that it shows an important correlation between ctDNA levels and overall survival, and that response rate is evaluated better with ctDNA.” A question that remains open, Dr. Rolfo added, is whether RECIST criteria are still a good comparator for biologic response.
The study was funded by Immunocore Dr. Shoushtari disclosed numerous pharmaceutical-related financial interests.
This article was updated Sept. 24, 2021.
according to Alexander Noor Shoushtari, MD, Memorial Sloan Kettering Cancer Center, New York.
Tebentafusp is the first therapy to demonstrate an overall survival (OS) benefit in uveal melanoma, Dr. Shoushtari noted in a 2021 European Society of Medical Oncology Congress virtual oral presentation Sept. 17 (abstract 17570). He noted further that, in prior research, OS was improved regardless of RECISTv1.1 best response, suggesting that better surrogate efficacy endpoints are needed.
Uveal melanoma is a rare melanoma type with low mutational burden, but frequent liver metastases. Benefit from immune checkpoint inhibitors is poor, and there is no established standard of care once the disease becomes metastatic. “Immune checkpoint inhibitors are not as good for treating this type of melanoma as they are for treating cutaneous disease, and traditionally preferred treatment is within clinical trials,” Dr. Shoushtari said. In frontline trials, 1-year survival has been in the 50% range. Tebentafusp is an investigational, first-in-class bispecific soluble T-cell receptor (TCR) therapeutic. It is designed to target gp100 (a melanoma-associated antigen) through a high-affinity TCR-binding domain and an anti-CD3 T-cell–engaging domain, which redirects T cells to kill gp100 positive melanocytic expressing tumor cells.
Prior research has demonstrated a disconnect between RECIST response classification and tebentafusp OS benefit. In the IMCgp100-202 study among patients treated first-line for metastatic uveal melanoma with tebentafusp or investigator choice, intent-to-treat analysis showed a survival probability benefit for tebentafusp (hazard ratio, 0.51; 95% CI, 0.37-0.71), with a best response of progressive disease population HR of 0.43 (95% CI, 0.27-0.68). While the RECIST response rate was only 9.1%, the HR for progression-free survival was 0.73 (95% CI, 0.58-0.94). “That suggests that RECIST is not a fantastic way to predict who will benefit from this drug,” Dr. Shoushtari stated.
Similarly in the IMCgp100-102 study of tebentafusp monotherapy in second-line metastatic uveal melanoma (n = 127), the RECIST response rate was 5%. Duration of response was 8.7 months and median OS was 16.8 months. Historical second-line OS has been reported at 7.8 months. The 1- and 2-year survival (62%/37%) compared favorably with historical rates (37%/15%), as well. Dr. Shoushtari noted that 92% of patients had detectable ctDNA with mutations in known uveal melanoma oncogenes. He pointed out that baseline ctDNA levels significantly correlated with tumor burden. Also, 70% of evaluable patients had any ctDNA reduction, with 0.5-3.2 log reduction in 99.9%, a 0.5 log reduction in 68% and 3 log reduction (cleared) in 14% of patients. ctDNA reduction, Dr. Shoushtari said, was associated with greater mean tumor shrinkage and with less tumor growth. Importantly, there was a linear correlation between ctDNA reduction and better OS (R2, 0.88, P < .0001).
Among all evaluable patients, comparing those with less than 0.5 log ctDNA reduction with those with at least a 0.5 log reduction showed a hazard ratio of 0.56 (95% CI, 0.32-0.95; P = .03). Among those whose best response was progressive disease, 35% had at least a 0.5 log reduction in ctDNA with an OS hazard ratio of 0.44 (95% CI, 0.2-0.94; P = .027), compared with less than a 0.5 log reduction. Among those whose best response was stable disease, 28% had at least 1 log reduction with a hazard ratio of 0.48 (95% CI 0.16-1.43; P = .16) for OS, compared with those with less than 1 log reduction. Dr. Shoushtari pointed out that “14% of patients cleared ctDNA, including some (n = 12) with best RECIST responses of stable or progressive disease. All patients with ctDNA clearance were alive beyond 1 year; with a hazard ratio, compared to those who had not cleared ctDNA, of 0.14 (95% CI, 0.03-0.57).
Summing up, Dr. Shoushtari said that ctDNA was detectable in more than 90% of second-line tebentafusp-treated patients with metastatic uveal melanoma and correlated with tumor burden. About 70% had ctDNA reduction versus 39% with tumor shrinkage and 5% RECIST response. The linear correlation between the magnitude of ctDNA reduction and improved OS on tebentafusp, was uncoupled from best RECIST response. “For tebentafusp, ctDNA reduction may be a better surrogate of overall survival than RECIST response.”
The ESMO-appointed discussant for the study, Christian Rolfo, MD, PhD, MBA, Icahan School of Medicine at Mount Sinai, New York, examined the tebentafusp study author’s claim that the radiographic assessment of tumors may underestimate the effect of tebentafusp, compared with ctDNA. The strengths of the study include, he said, that it is a drug- and tumor-specific evaluation of the role of ctDNA as a surrogate of response. “Its strength is that it shows an important correlation between ctDNA levels and overall survival, and that response rate is evaluated better with ctDNA.” A question that remains open, Dr. Rolfo added, is whether RECIST criteria are still a good comparator for biologic response.
The study was funded by Immunocore Dr. Shoushtari disclosed numerous pharmaceutical-related financial interests.
This article was updated Sept. 24, 2021.
according to Alexander Noor Shoushtari, MD, Memorial Sloan Kettering Cancer Center, New York.
Tebentafusp is the first therapy to demonstrate an overall survival (OS) benefit in uveal melanoma, Dr. Shoushtari noted in a 2021 European Society of Medical Oncology Congress virtual oral presentation Sept. 17 (abstract 17570). He noted further that, in prior research, OS was improved regardless of RECISTv1.1 best response, suggesting that better surrogate efficacy endpoints are needed.
Uveal melanoma is a rare melanoma type with low mutational burden, but frequent liver metastases. Benefit from immune checkpoint inhibitors is poor, and there is no established standard of care once the disease becomes metastatic. “Immune checkpoint inhibitors are not as good for treating this type of melanoma as they are for treating cutaneous disease, and traditionally preferred treatment is within clinical trials,” Dr. Shoushtari said. In frontline trials, 1-year survival has been in the 50% range. Tebentafusp is an investigational, first-in-class bispecific soluble T-cell receptor (TCR) therapeutic. It is designed to target gp100 (a melanoma-associated antigen) through a high-affinity TCR-binding domain and an anti-CD3 T-cell–engaging domain, which redirects T cells to kill gp100 positive melanocytic expressing tumor cells.
Prior research has demonstrated a disconnect between RECIST response classification and tebentafusp OS benefit. In the IMCgp100-202 study among patients treated first-line for metastatic uveal melanoma with tebentafusp or investigator choice, intent-to-treat analysis showed a survival probability benefit for tebentafusp (hazard ratio, 0.51; 95% CI, 0.37-0.71), with a best response of progressive disease population HR of 0.43 (95% CI, 0.27-0.68). While the RECIST response rate was only 9.1%, the HR for progression-free survival was 0.73 (95% CI, 0.58-0.94). “That suggests that RECIST is not a fantastic way to predict who will benefit from this drug,” Dr. Shoushtari stated.
Similarly in the IMCgp100-102 study of tebentafusp monotherapy in second-line metastatic uveal melanoma (n = 127), the RECIST response rate was 5%. Duration of response was 8.7 months and median OS was 16.8 months. Historical second-line OS has been reported at 7.8 months. The 1- and 2-year survival (62%/37%) compared favorably with historical rates (37%/15%), as well. Dr. Shoushtari noted that 92% of patients had detectable ctDNA with mutations in known uveal melanoma oncogenes. He pointed out that baseline ctDNA levels significantly correlated with tumor burden. Also, 70% of evaluable patients had any ctDNA reduction, with 0.5-3.2 log reduction in 99.9%, a 0.5 log reduction in 68% and 3 log reduction (cleared) in 14% of patients. ctDNA reduction, Dr. Shoushtari said, was associated with greater mean tumor shrinkage and with less tumor growth. Importantly, there was a linear correlation between ctDNA reduction and better OS (R2, 0.88, P < .0001).
Among all evaluable patients, comparing those with less than 0.5 log ctDNA reduction with those with at least a 0.5 log reduction showed a hazard ratio of 0.56 (95% CI, 0.32-0.95; P = .03). Among those whose best response was progressive disease, 35% had at least a 0.5 log reduction in ctDNA with an OS hazard ratio of 0.44 (95% CI, 0.2-0.94; P = .027), compared with less than a 0.5 log reduction. Among those whose best response was stable disease, 28% had at least 1 log reduction with a hazard ratio of 0.48 (95% CI 0.16-1.43; P = .16) for OS, compared with those with less than 1 log reduction. Dr. Shoushtari pointed out that “14% of patients cleared ctDNA, including some (n = 12) with best RECIST responses of stable or progressive disease. All patients with ctDNA clearance were alive beyond 1 year; with a hazard ratio, compared to those who had not cleared ctDNA, of 0.14 (95% CI, 0.03-0.57).
Summing up, Dr. Shoushtari said that ctDNA was detectable in more than 90% of second-line tebentafusp-treated patients with metastatic uveal melanoma and correlated with tumor burden. About 70% had ctDNA reduction versus 39% with tumor shrinkage and 5% RECIST response. The linear correlation between the magnitude of ctDNA reduction and improved OS on tebentafusp, was uncoupled from best RECIST response. “For tebentafusp, ctDNA reduction may be a better surrogate of overall survival than RECIST response.”
The ESMO-appointed discussant for the study, Christian Rolfo, MD, PhD, MBA, Icahan School of Medicine at Mount Sinai, New York, examined the tebentafusp study author’s claim that the radiographic assessment of tumors may underestimate the effect of tebentafusp, compared with ctDNA. The strengths of the study include, he said, that it is a drug- and tumor-specific evaluation of the role of ctDNA as a surrogate of response. “Its strength is that it shows an important correlation between ctDNA levels and overall survival, and that response rate is evaluated better with ctDNA.” A question that remains open, Dr. Rolfo added, is whether RECIST criteria are still a good comparator for biologic response.
The study was funded by Immunocore Dr. Shoushtari disclosed numerous pharmaceutical-related financial interests.
This article was updated Sept. 24, 2021.
FROM ESMO 2021
Surge in new-onset tics in adults tied to COVID-19 stress
, new research suggests.
Results from a large, single-center study show several cases of tic-like movements and vocalizations with abrupt onset among older adolescents and adults during the pandemic. None had a previous diagnosis of a tic disorder. Among 10 patients, two were diagnosed with a purely functional movement disorder, four with an organic tic disorder, and four with both.
“Within our movement disorders clinic specifically ... we’ve been seeing an increased number of patients with an almost explosive onset of these tic-like movements and vocalizations later in life than what is typically seen with organic tic disorders and Tourette syndrome, which is typically in school-aged children,” said study investigator Caroline Olvera, MD, Rush University Medical Center, Chicago.
“Abrupt onset of symptoms can be seen in patients with tic disorders, although this is typically quoted as less than 10%, or even 5% is more characteristic of functional neurological disorders in general and also with psychogenic tics,” she added.
The findings were presented at the International Congress of Parkinson’s Disease and Movement Disorders.
Anxiety, other psychiatric conditions
Tic disorders typically start in childhood. However, the researchers observed an increase in the number of patients with abrupt onset of tic-like movements and vocalizations later in life, which is more often characteristic of functional neurological disorders.
To examine the profile, associated conditions, and risk factors in this population, the investigators conducted a thorough chart review of patients attending movement disorder clinics between March 2020, when the COVID pandemic was officially declared, and March 2021.
Patients with acute onset of tics were identified using the International Classification of Diseases codes for behavioral tics, tic vocalizations, and Tourette syndrome.
The charts were then narrowed down to patients with no previous diagnosis of these conditions. Most patients were videotaped for assessment by the rest of the movement disorder neurologists in the practice. Since the end of the study inclusion period in March 2021, Dr. Olvera estimates that the clinic experienced a doubling or tripling of the number of similar patients.
In the study cohort of 10 patients, the median age at presentation was 19 years (range, 15-41 years), nine were female, the gender of the other one was unknown, and the duration of tics was 8 weeks (range, 1-24 weeks) by the time they were first seen in the clinic. Four patients reported having COVID infection before tic onset.
All exhibited motor tics and nine had vocal tics. Two were diagnosed with a purely functional neurologic disorder, four with only an organic tic disorder, and four with organic tics with a functional overlay.
“All patients, including those with organic tic disorders, had a history of anxiety and also reported worsening anxiety in the setting of the COVID pandemic,” Dr. Olvera said.
The majority of patients were on a psychotropic medication prior to coming to the clinic, and these were primarily for anxiety and depression. Three patients had a history of suicidality, often very severe and leading to hospitalization, she noted.
“In terms of our conclusions from the project, we feel that this phenotype of acute explosive onset of tic-like movements and vocalizations in this older population of adults, compared with typical organic tic disorders and Tourette syndrome, appears novel to the pandemic,” she said.
She cautioned that functional and organic tics share many characteristics and therefore may be difficult to differentiate.
COVID stress
Commenting on the findings, Michele Tagliati, MD, director of the movement disorders program at Cedars-Sinai Medical Center, Los Angeles, said the research highlights how clinicians’ understanding of particular diseases can be challenged during extraordinary events such as COVID-19 and the heightened stress it causes.
“I’m not surprised that these [disorders] might have had a spike during a stressful time as COVID,” he said.
Patients are “really scared and really anxious, they’re afraid to die, and they’re afraid that their life will be over. So they might express their psychological difficulty, their discomfort, with these calls for help that look like tics. But they’re not what we consider physiological or organic things,” he added.
Dr. Tagliati added that he doesn’t believe rapid tic onset in adults is not a complication of the coronavirus infection, but rather a consequence of psychological pressure brought on by the pandemic.
Treating underlying anxiety may be a useful approach, possibly with the support of psychiatrists, which in many cases is enough to relieve the conditions and overcome the symptoms, he noted.
However, at other times, it’s not that simple, he added. Sometimes patients “fall through the cracks between neurology and psychiatry,” Dr. Tagliati said.
Dr. Olvera and Dr. Tagliati have disclosed no relevant financial relationships.
A version of this article first appeared on Medscape.com.
, new research suggests.
Results from a large, single-center study show several cases of tic-like movements and vocalizations with abrupt onset among older adolescents and adults during the pandemic. None had a previous diagnosis of a tic disorder. Among 10 patients, two were diagnosed with a purely functional movement disorder, four with an organic tic disorder, and four with both.
“Within our movement disorders clinic specifically ... we’ve been seeing an increased number of patients with an almost explosive onset of these tic-like movements and vocalizations later in life than what is typically seen with organic tic disorders and Tourette syndrome, which is typically in school-aged children,” said study investigator Caroline Olvera, MD, Rush University Medical Center, Chicago.
“Abrupt onset of symptoms can be seen in patients with tic disorders, although this is typically quoted as less than 10%, or even 5% is more characteristic of functional neurological disorders in general and also with psychogenic tics,” she added.
The findings were presented at the International Congress of Parkinson’s Disease and Movement Disorders.
Anxiety, other psychiatric conditions
Tic disorders typically start in childhood. However, the researchers observed an increase in the number of patients with abrupt onset of tic-like movements and vocalizations later in life, which is more often characteristic of functional neurological disorders.
To examine the profile, associated conditions, and risk factors in this population, the investigators conducted a thorough chart review of patients attending movement disorder clinics between March 2020, when the COVID pandemic was officially declared, and March 2021.
Patients with acute onset of tics were identified using the International Classification of Diseases codes for behavioral tics, tic vocalizations, and Tourette syndrome.
The charts were then narrowed down to patients with no previous diagnosis of these conditions. Most patients were videotaped for assessment by the rest of the movement disorder neurologists in the practice. Since the end of the study inclusion period in March 2021, Dr. Olvera estimates that the clinic experienced a doubling or tripling of the number of similar patients.
In the study cohort of 10 patients, the median age at presentation was 19 years (range, 15-41 years), nine were female, the gender of the other one was unknown, and the duration of tics was 8 weeks (range, 1-24 weeks) by the time they were first seen in the clinic. Four patients reported having COVID infection before tic onset.
All exhibited motor tics and nine had vocal tics. Two were diagnosed with a purely functional neurologic disorder, four with only an organic tic disorder, and four with organic tics with a functional overlay.
“All patients, including those with organic tic disorders, had a history of anxiety and also reported worsening anxiety in the setting of the COVID pandemic,” Dr. Olvera said.
The majority of patients were on a psychotropic medication prior to coming to the clinic, and these were primarily for anxiety and depression. Three patients had a history of suicidality, often very severe and leading to hospitalization, she noted.
“In terms of our conclusions from the project, we feel that this phenotype of acute explosive onset of tic-like movements and vocalizations in this older population of adults, compared with typical organic tic disorders and Tourette syndrome, appears novel to the pandemic,” she said.
She cautioned that functional and organic tics share many characteristics and therefore may be difficult to differentiate.
COVID stress
Commenting on the findings, Michele Tagliati, MD, director of the movement disorders program at Cedars-Sinai Medical Center, Los Angeles, said the research highlights how clinicians’ understanding of particular diseases can be challenged during extraordinary events such as COVID-19 and the heightened stress it causes.
“I’m not surprised that these [disorders] might have had a spike during a stressful time as COVID,” he said.
Patients are “really scared and really anxious, they’re afraid to die, and they’re afraid that their life will be over. So they might express their psychological difficulty, their discomfort, with these calls for help that look like tics. But they’re not what we consider physiological or organic things,” he added.
Dr. Tagliati added that he doesn’t believe rapid tic onset in adults is not a complication of the coronavirus infection, but rather a consequence of psychological pressure brought on by the pandemic.
Treating underlying anxiety may be a useful approach, possibly with the support of psychiatrists, which in many cases is enough to relieve the conditions and overcome the symptoms, he noted.
However, at other times, it’s not that simple, he added. Sometimes patients “fall through the cracks between neurology and psychiatry,” Dr. Tagliati said.
Dr. Olvera and Dr. Tagliati have disclosed no relevant financial relationships.
A version of this article first appeared on Medscape.com.
, new research suggests.
Results from a large, single-center study show several cases of tic-like movements and vocalizations with abrupt onset among older adolescents and adults during the pandemic. None had a previous diagnosis of a tic disorder. Among 10 patients, two were diagnosed with a purely functional movement disorder, four with an organic tic disorder, and four with both.
“Within our movement disorders clinic specifically ... we’ve been seeing an increased number of patients with an almost explosive onset of these tic-like movements and vocalizations later in life than what is typically seen with organic tic disorders and Tourette syndrome, which is typically in school-aged children,” said study investigator Caroline Olvera, MD, Rush University Medical Center, Chicago.
“Abrupt onset of symptoms can be seen in patients with tic disorders, although this is typically quoted as less than 10%, or even 5% is more characteristic of functional neurological disorders in general and also with psychogenic tics,” she added.
The findings were presented at the International Congress of Parkinson’s Disease and Movement Disorders.
Anxiety, other psychiatric conditions
Tic disorders typically start in childhood. However, the researchers observed an increase in the number of patients with abrupt onset of tic-like movements and vocalizations later in life, which is more often characteristic of functional neurological disorders.
To examine the profile, associated conditions, and risk factors in this population, the investigators conducted a thorough chart review of patients attending movement disorder clinics between March 2020, when the COVID pandemic was officially declared, and March 2021.
Patients with acute onset of tics were identified using the International Classification of Diseases codes for behavioral tics, tic vocalizations, and Tourette syndrome.
The charts were then narrowed down to patients with no previous diagnosis of these conditions. Most patients were videotaped for assessment by the rest of the movement disorder neurologists in the practice. Since the end of the study inclusion period in March 2021, Dr. Olvera estimates that the clinic experienced a doubling or tripling of the number of similar patients.
In the study cohort of 10 patients, the median age at presentation was 19 years (range, 15-41 years), nine were female, the gender of the other one was unknown, and the duration of tics was 8 weeks (range, 1-24 weeks) by the time they were first seen in the clinic. Four patients reported having COVID infection before tic onset.
All exhibited motor tics and nine had vocal tics. Two were diagnosed with a purely functional neurologic disorder, four with only an organic tic disorder, and four with organic tics with a functional overlay.
“All patients, including those with organic tic disorders, had a history of anxiety and also reported worsening anxiety in the setting of the COVID pandemic,” Dr. Olvera said.
The majority of patients were on a psychotropic medication prior to coming to the clinic, and these were primarily for anxiety and depression. Three patients had a history of suicidality, often very severe and leading to hospitalization, she noted.
“In terms of our conclusions from the project, we feel that this phenotype of acute explosive onset of tic-like movements and vocalizations in this older population of adults, compared with typical organic tic disorders and Tourette syndrome, appears novel to the pandemic,” she said.
She cautioned that functional and organic tics share many characteristics and therefore may be difficult to differentiate.
COVID stress
Commenting on the findings, Michele Tagliati, MD, director of the movement disorders program at Cedars-Sinai Medical Center, Los Angeles, said the research highlights how clinicians’ understanding of particular diseases can be challenged during extraordinary events such as COVID-19 and the heightened stress it causes.
“I’m not surprised that these [disorders] might have had a spike during a stressful time as COVID,” he said.
Patients are “really scared and really anxious, they’re afraid to die, and they’re afraid that their life will be over. So they might express their psychological difficulty, their discomfort, with these calls for help that look like tics. But they’re not what we consider physiological or organic things,” he added.
Dr. Tagliati added that he doesn’t believe rapid tic onset in adults is not a complication of the coronavirus infection, but rather a consequence of psychological pressure brought on by the pandemic.
Treating underlying anxiety may be a useful approach, possibly with the support of psychiatrists, which in many cases is enough to relieve the conditions and overcome the symptoms, he noted.
However, at other times, it’s not that simple, he added. Sometimes patients “fall through the cracks between neurology and psychiatry,” Dr. Tagliati said.
Dr. Olvera and Dr. Tagliati have disclosed no relevant financial relationships.
A version of this article first appeared on Medscape.com.
FROM MDS VIRTUAL CONGRESS 2021
Real-world data generate debate on definition of flare in axial spondyloarthritis
How best to define axial spondyloarthritis (axSpA) flares in practice remains the subject of some debate as evidenced by the discussion that followed an abstract presentation at the 12th International Congress on Spondyloarthritides.
It’s an important topic, said Maxime Breban, MD, PhD, of Ambroise Paré Hospital in Paris, as flares can adversely affect patient outcomes. The absence of flares may also a useful measure of how well a patient is responding to treatment in clinical trials and whether a treatment can be tapered.
“There have been many ways to define flares in the past and there is no consensus,” he observed.
Although the Assessment of Spondyloarthritis International Society (ASAS) devised 12 preliminary definitions of flare in 2016, “these were not that good when we moved to patients,” Dr. Breban suggested.
The ASAS definitions were based on patient vignettes, he explained, and used a combination of variables from the Bath Ankylosing Spondylitis Disease Activity Index (BASDAI), a visual analog scale (VAS) of pain, and the Ankylosing Spondylitis Disease Activity Score based on C-reactive protein (ASDAS-CRP).
The study that Dr. Breban presented looked at the performance of the ASAS preliminary definitions of axSpA flares in a real-life patient population, as well as prospectively determining how variations in BASDAI and VAS pain were associated with patient-perceived flares of disease.
A total of 99 patients took part in the study, recruited through a secure e-health platform called SPONDY+. Once a week, patients completed the BASDAI questionnaire and the pain VAS, and stated whether their disease had flared in the past week.
Receiver operating characteristic (ROC) curves were calculated to see how well the BASDAI and pain VAS identified patients who were experiencing a flare or had a recently resolved flare of axSpA.
Dr. Breban reported that variation in the BASDAI “appears a suitable variable to monitor the occurrence and resolution of patient-reported flare in axial spondylarthritis.”
In predicting a flare, the area under the curve (AUC) was significantly higher for the change in BASDAI than for the change in pain VAS, at a respective 0.81 and 0.77 (P = .01). However, both variables were similarly accurate in predicting the resolution of a flare, with respective AUCs of 0.78 and 0.80 (P = .3).
A 0.22-point increase in BASDAI was reported to be the best balance between sensitivity (70%) and specificity (79%) for a flare. However, this is “outside of what is possible within a test–retest situation,” Désirée van der Heijde, MD, PhD, of Leiden (the Netherlands) University Medical Center, said during discussion.
Dr. van der Heijde told Dr. Breban: “I understand that that comes out of your data, that that’s the best combination for sensitivity and specificity, but the next step is to decide if that makes sense.”
The ROC curves that Dr. Breban presented showed the range of sensitivities and specificities that could be achieved. If the specificity was increased to be 90% or higher, the specificity fell to 55%, with the change in BASDAI being an increase of 0.8 points. Conversely, bringing the sensitivity above 90% meant the specificity dropped to 39% and the change in BASDAI was a decrease of 0.1 point.
“So that means you can choose whatever you want as a cutoff,” Dr. Breban said. It depends on what you are aiming to do. “If you want to identify a flare, you can increase sensitivity, or specificity, according to what your purpose is,” he suggested.
“The next step, of course, is what to choose as a flare. Then it depends on how you want to use a flare if you want to use a flare to change the treatment,” agreed Dr. van der Heijde. “That was why, in the ASAS group, it was decided to have a high specificity so that you are not changing treatment all the time.”
In the data that Dr. Breban presented, the ASAS preliminary definitions were highly specific but lacked sensitivity. None of the ASAS definitions yielded sensitivity values higher than 37%, whereas specificity was higher than 95% for all of them.
The study’s design did not allow researchers to test the ASDAS-CRP as a definition of flare in its real-world patient sample. Thus, it is looking only at the patient’s perspective on flare, and there is a “huge discrepancy” between patient and physician-reported disease activity, Dr. van der Heijde noted. “So, I think before using your data to really choose the flare definition, I think we need to take it all into account.”
Maxime Dougados, MD, PhD, of Cochin Hospital in Paris, who has been “deeply involved in the elaboration of the definition of flare” added his thoughts: “Flare means for me, not a status, but a change,” he observed.
But if the aim of treating people with axSpA is to achieve a good or acceptable state of health, he questioned whether work should be continued to define the concept of a flare.
The definition of a flare was conceived for use in clinical trials mainly, Dr. van der Heijde noted. It helped to assess how changes in treatment might affect the outcomes of patients. In clinical practice, especially now with treat-to-target gaining more and more traction in axSpA, she agreed that perhaps the goal should be to focus more on the health status of patients.
Dr. Breban acknowledged that the SPONDY+ platform has been developed by bepatient with support from Merck Sharp & Dohme. No other disclosures were made.
How best to define axial spondyloarthritis (axSpA) flares in practice remains the subject of some debate as evidenced by the discussion that followed an abstract presentation at the 12th International Congress on Spondyloarthritides.
It’s an important topic, said Maxime Breban, MD, PhD, of Ambroise Paré Hospital in Paris, as flares can adversely affect patient outcomes. The absence of flares may also a useful measure of how well a patient is responding to treatment in clinical trials and whether a treatment can be tapered.
“There have been many ways to define flares in the past and there is no consensus,” he observed.
Although the Assessment of Spondyloarthritis International Society (ASAS) devised 12 preliminary definitions of flare in 2016, “these were not that good when we moved to patients,” Dr. Breban suggested.
The ASAS definitions were based on patient vignettes, he explained, and used a combination of variables from the Bath Ankylosing Spondylitis Disease Activity Index (BASDAI), a visual analog scale (VAS) of pain, and the Ankylosing Spondylitis Disease Activity Score based on C-reactive protein (ASDAS-CRP).
The study that Dr. Breban presented looked at the performance of the ASAS preliminary definitions of axSpA flares in a real-life patient population, as well as prospectively determining how variations in BASDAI and VAS pain were associated with patient-perceived flares of disease.
A total of 99 patients took part in the study, recruited through a secure e-health platform called SPONDY+. Once a week, patients completed the BASDAI questionnaire and the pain VAS, and stated whether their disease had flared in the past week.
Receiver operating characteristic (ROC) curves were calculated to see how well the BASDAI and pain VAS identified patients who were experiencing a flare or had a recently resolved flare of axSpA.
Dr. Breban reported that variation in the BASDAI “appears a suitable variable to monitor the occurrence and resolution of patient-reported flare in axial spondylarthritis.”
In predicting a flare, the area under the curve (AUC) was significantly higher for the change in BASDAI than for the change in pain VAS, at a respective 0.81 and 0.77 (P = .01). However, both variables were similarly accurate in predicting the resolution of a flare, with respective AUCs of 0.78 and 0.80 (P = .3).
A 0.22-point increase in BASDAI was reported to be the best balance between sensitivity (70%) and specificity (79%) for a flare. However, this is “outside of what is possible within a test–retest situation,” Désirée van der Heijde, MD, PhD, of Leiden (the Netherlands) University Medical Center, said during discussion.
Dr. van der Heijde told Dr. Breban: “I understand that that comes out of your data, that that’s the best combination for sensitivity and specificity, but the next step is to decide if that makes sense.”
The ROC curves that Dr. Breban presented showed the range of sensitivities and specificities that could be achieved. If the specificity was increased to be 90% or higher, the specificity fell to 55%, with the change in BASDAI being an increase of 0.8 points. Conversely, bringing the sensitivity above 90% meant the specificity dropped to 39% and the change in BASDAI was a decrease of 0.1 point.
“So that means you can choose whatever you want as a cutoff,” Dr. Breban said. It depends on what you are aiming to do. “If you want to identify a flare, you can increase sensitivity, or specificity, according to what your purpose is,” he suggested.
“The next step, of course, is what to choose as a flare. Then it depends on how you want to use a flare if you want to use a flare to change the treatment,” agreed Dr. van der Heijde. “That was why, in the ASAS group, it was decided to have a high specificity so that you are not changing treatment all the time.”
In the data that Dr. Breban presented, the ASAS preliminary definitions were highly specific but lacked sensitivity. None of the ASAS definitions yielded sensitivity values higher than 37%, whereas specificity was higher than 95% for all of them.
The study’s design did not allow researchers to test the ASDAS-CRP as a definition of flare in its real-world patient sample. Thus, it is looking only at the patient’s perspective on flare, and there is a “huge discrepancy” between patient and physician-reported disease activity, Dr. van der Heijde noted. “So, I think before using your data to really choose the flare definition, I think we need to take it all into account.”
Maxime Dougados, MD, PhD, of Cochin Hospital in Paris, who has been “deeply involved in the elaboration of the definition of flare” added his thoughts: “Flare means for me, not a status, but a change,” he observed.
But if the aim of treating people with axSpA is to achieve a good or acceptable state of health, he questioned whether work should be continued to define the concept of a flare.
The definition of a flare was conceived for use in clinical trials mainly, Dr. van der Heijde noted. It helped to assess how changes in treatment might affect the outcomes of patients. In clinical practice, especially now with treat-to-target gaining more and more traction in axSpA, she agreed that perhaps the goal should be to focus more on the health status of patients.
Dr. Breban acknowledged that the SPONDY+ platform has been developed by bepatient with support from Merck Sharp & Dohme. No other disclosures were made.
How best to define axial spondyloarthritis (axSpA) flares in practice remains the subject of some debate as evidenced by the discussion that followed an abstract presentation at the 12th International Congress on Spondyloarthritides.
It’s an important topic, said Maxime Breban, MD, PhD, of Ambroise Paré Hospital in Paris, as flares can adversely affect patient outcomes. The absence of flares may also a useful measure of how well a patient is responding to treatment in clinical trials and whether a treatment can be tapered.
“There have been many ways to define flares in the past and there is no consensus,” he observed.
Although the Assessment of Spondyloarthritis International Society (ASAS) devised 12 preliminary definitions of flare in 2016, “these were not that good when we moved to patients,” Dr. Breban suggested.
The ASAS definitions were based on patient vignettes, he explained, and used a combination of variables from the Bath Ankylosing Spondylitis Disease Activity Index (BASDAI), a visual analog scale (VAS) of pain, and the Ankylosing Spondylitis Disease Activity Score based on C-reactive protein (ASDAS-CRP).
The study that Dr. Breban presented looked at the performance of the ASAS preliminary definitions of axSpA flares in a real-life patient population, as well as prospectively determining how variations in BASDAI and VAS pain were associated with patient-perceived flares of disease.
A total of 99 patients took part in the study, recruited through a secure e-health platform called SPONDY+. Once a week, patients completed the BASDAI questionnaire and the pain VAS, and stated whether their disease had flared in the past week.
Receiver operating characteristic (ROC) curves were calculated to see how well the BASDAI and pain VAS identified patients who were experiencing a flare or had a recently resolved flare of axSpA.
Dr. Breban reported that variation in the BASDAI “appears a suitable variable to monitor the occurrence and resolution of patient-reported flare in axial spondylarthritis.”
In predicting a flare, the area under the curve (AUC) was significantly higher for the change in BASDAI than for the change in pain VAS, at a respective 0.81 and 0.77 (P = .01). However, both variables were similarly accurate in predicting the resolution of a flare, with respective AUCs of 0.78 and 0.80 (P = .3).
A 0.22-point increase in BASDAI was reported to be the best balance between sensitivity (70%) and specificity (79%) for a flare. However, this is “outside of what is possible within a test–retest situation,” Désirée van der Heijde, MD, PhD, of Leiden (the Netherlands) University Medical Center, said during discussion.
Dr. van der Heijde told Dr. Breban: “I understand that that comes out of your data, that that’s the best combination for sensitivity and specificity, but the next step is to decide if that makes sense.”
The ROC curves that Dr. Breban presented showed the range of sensitivities and specificities that could be achieved. If the specificity was increased to be 90% or higher, the specificity fell to 55%, with the change in BASDAI being an increase of 0.8 points. Conversely, bringing the sensitivity above 90% meant the specificity dropped to 39% and the change in BASDAI was a decrease of 0.1 point.
“So that means you can choose whatever you want as a cutoff,” Dr. Breban said. It depends on what you are aiming to do. “If you want to identify a flare, you can increase sensitivity, or specificity, according to what your purpose is,” he suggested.
“The next step, of course, is what to choose as a flare. Then it depends on how you want to use a flare if you want to use a flare to change the treatment,” agreed Dr. van der Heijde. “That was why, in the ASAS group, it was decided to have a high specificity so that you are not changing treatment all the time.”
In the data that Dr. Breban presented, the ASAS preliminary definitions were highly specific but lacked sensitivity. None of the ASAS definitions yielded sensitivity values higher than 37%, whereas specificity was higher than 95% for all of them.
The study’s design did not allow researchers to test the ASDAS-CRP as a definition of flare in its real-world patient sample. Thus, it is looking only at the patient’s perspective on flare, and there is a “huge discrepancy” between patient and physician-reported disease activity, Dr. van der Heijde noted. “So, I think before using your data to really choose the flare definition, I think we need to take it all into account.”
Maxime Dougados, MD, PhD, of Cochin Hospital in Paris, who has been “deeply involved in the elaboration of the definition of flare” added his thoughts: “Flare means for me, not a status, but a change,” he observed.
But if the aim of treating people with axSpA is to achieve a good or acceptable state of health, he questioned whether work should be continued to define the concept of a flare.
The definition of a flare was conceived for use in clinical trials mainly, Dr. van der Heijde noted. It helped to assess how changes in treatment might affect the outcomes of patients. In clinical practice, especially now with treat-to-target gaining more and more traction in axSpA, she agreed that perhaps the goal should be to focus more on the health status of patients.
Dr. Breban acknowledged that the SPONDY+ platform has been developed by bepatient with support from Merck Sharp & Dohme. No other disclosures were made.
FROM THE 2021 SPA CONGRESS
Study supports add-on therapy for germline and wildtype BRCA mutations
The initial improvement that was seen in pathologic complete response (pCR) rates with the addition of carboplatin to paclitaxel and standard neoadjuvant chemotherapy translated into improved event-free survival (EFS) rates in patients with resectable TNBC more than 4 years after surgery.
The benefits of adding carboplatin to paclitaxel, followed by four cycles of AC (doxorubicin and cyclophosphamide) chemotherapy, were seen both in patients with germline BRCA mutations and those with wildtype BRCA.
The trial results also demonstrated, however, that there were no short- or long-term benefits to adding veliparib (ABT-888), a poly (ADP-ribose) polymerase (PARP) inhibitor, to the mix.
Although pCR and EFS rates were significantly improved with the combination of paclitaxel and carboplatin compared with paclitaxel alone, there were no significant differences when veliparib was added in either pCR, EFS, or overall survival (OS).
“These findings overall support the inclusion of carboplatin into neoadjuvant chemotherapy for stage 2 and 3 triple-negative breast cancer patients, regardless of germline BRCA status,” concluded lead author Sibylle Loibl, MD, PhD, chief executive officer and chair of the German Breast Group.
She presented the new data during an oral session at the virtual European Society for Medical Oncology (ESMO) Congress 2021.
The BrighTNess results show that “neoadjuvant carboplatin plus paclitaxel is superior to paclitaxel alone, with high pCR rates and benefit of event-free survival rates with manageable toxicity and no safety signals,” commented invited discussant Monica Arnedos, MD, PhD, head of the breast cancer research program at the Institut Bergonié in Bordeaux, France.
The findings also put to rest the notion that patients with germline BRCA mutations would not benefit from carboplatin treatment because of extreme sensitivity to standard neoadjuvant chemotherapy.
“The BrighTNess study says otherwise,” Dr. Arnedos said. “Today we’ve seen that the pCR improved event-free survival regardless of the germline BRCA mutated status, so BRCA-mutated germline patients require neoadjuvant carboplatin.”
The new data may lead to changes in breast cancer guidelines, she suggested.
Prior to these results, the evidence was that “platinum salts as neoadjuvant chemotherapy increased pCR rates in triple-negative breast cancer patients, but this was associated with more toxicity, and with higher rates of treatment discontinuation and dose reduction, without strong evidence of long-term benefit. This led to a lack of consensus to recommend platinum salts in this setting between the different breast cancer guidelines.”
The new BrighTNess data showed that the improved pCR rates translated into an EFS benefit in both platinum-containing groups of the trial, a finding that is consistent with the KEYNOTE-522 trial, which showed that adding pembrolizumab (Keytruda) to chemotherapy improved pCR in patients with early TNBC.
The BrighTNess results suggest that patients with high- or moderate-risk TNBC could be treated in the neoadjuvant setting with paclitaxel and carboplatin followed by standard chemotherapy concurrently with pembrolizumab, followed by surgery, and adjuvant therapy with pembrolizumab plus olaparib (Lynparza) for patients with germline BRCA mutations, or capecitabine for patients without mutations, Dr. Arnedos proposed.
BrighTNess study details
The BrighTNess trial involved 634 patients with previously untreated histologically or cytologically confirmed stage 2-3 TNBC who were candidates for potentially curative surgery and had a good performance status. They were randomly assigned to receive either paclitaxel plus carboplatin and veliparib, paclitaxel plus carboplatin only, or paclitaxel alone prior to four cycles of chemotherapy with doxorubicin and cyclophosphamide (AC).
Initial results, published in 2018 in The Lancet Oncology, showed that the addition of veliparib to carboplatin and paclitaxel improved pCR rates compared with paclitaxel alone but not paclitaxel plus carboplatin. The trial data supported the addition of carboplatin to standard neoadjuvant chemotherapy but not veliparib, the investigators stated at the time.
Now at the ESMO meeting, Dr. Loibl presented longer follow-up results.
After a median follow-up of 4.5 years, the hazard ratio (HR) for event-free survival with the paclitaxel/carboplatin/veliparib combination compared with paclitaxel alone was 0.63 (P = .016). In a post-hoc analysis, the adjusted HR was 0.57 (P = .018).
In a subgroup of 309 patients who had initial pCRs, the HR for EFS compared with patients without a pCR was 0.26 (P < .0001). Among patients with germline BRCA mutation, the HR for EFS for those who had a pCR was 0.14 (P = .0004), and among those with germline wildtype BRCA and a pCR the HR was 0.29 (P < .0001).
However, there were no significant differences in OS a median of 4.5 years after surgery.
An analysis of the frequency of myelodysplastic syndrome, acute myeloid leukemia, or other second primary malignancies also showed no significant differences between the groups, Dr. Loibl noted.
Although there were higher rates of hematologic malignancies with the addition of carboplatin, with or without veliparib, these adverse events did not compromise either treatment delivery of the benefits of carboplatin on the primary pCR endpoint, she added.
The BrighTNess trial was supported by AbbVie. Dr. Loibl has reported receiving grants and honoraria from AbbVie and others, including Medscape. Dr. Arnedos has reported receiving honoraria, travel grants, and/or research grants from AstraZeneca, Novartis, Pfizer, and Roche.
A version of this article first appeared on Medscape.com.
The initial improvement that was seen in pathologic complete response (pCR) rates with the addition of carboplatin to paclitaxel and standard neoadjuvant chemotherapy translated into improved event-free survival (EFS) rates in patients with resectable TNBC more than 4 years after surgery.
The benefits of adding carboplatin to paclitaxel, followed by four cycles of AC (doxorubicin and cyclophosphamide) chemotherapy, were seen both in patients with germline BRCA mutations and those with wildtype BRCA.
The trial results also demonstrated, however, that there were no short- or long-term benefits to adding veliparib (ABT-888), a poly (ADP-ribose) polymerase (PARP) inhibitor, to the mix.
Although pCR and EFS rates were significantly improved with the combination of paclitaxel and carboplatin compared with paclitaxel alone, there were no significant differences when veliparib was added in either pCR, EFS, or overall survival (OS).
“These findings overall support the inclusion of carboplatin into neoadjuvant chemotherapy for stage 2 and 3 triple-negative breast cancer patients, regardless of germline BRCA status,” concluded lead author Sibylle Loibl, MD, PhD, chief executive officer and chair of the German Breast Group.
She presented the new data during an oral session at the virtual European Society for Medical Oncology (ESMO) Congress 2021.
The BrighTNess results show that “neoadjuvant carboplatin plus paclitaxel is superior to paclitaxel alone, with high pCR rates and benefit of event-free survival rates with manageable toxicity and no safety signals,” commented invited discussant Monica Arnedos, MD, PhD, head of the breast cancer research program at the Institut Bergonié in Bordeaux, France.
The findings also put to rest the notion that patients with germline BRCA mutations would not benefit from carboplatin treatment because of extreme sensitivity to standard neoadjuvant chemotherapy.
“The BrighTNess study says otherwise,” Dr. Arnedos said. “Today we’ve seen that the pCR improved event-free survival regardless of the germline BRCA mutated status, so BRCA-mutated germline patients require neoadjuvant carboplatin.”
The new data may lead to changes in breast cancer guidelines, she suggested.
Prior to these results, the evidence was that “platinum salts as neoadjuvant chemotherapy increased pCR rates in triple-negative breast cancer patients, but this was associated with more toxicity, and with higher rates of treatment discontinuation and dose reduction, without strong evidence of long-term benefit. This led to a lack of consensus to recommend platinum salts in this setting between the different breast cancer guidelines.”
The new BrighTNess data showed that the improved pCR rates translated into an EFS benefit in both platinum-containing groups of the trial, a finding that is consistent with the KEYNOTE-522 trial, which showed that adding pembrolizumab (Keytruda) to chemotherapy improved pCR in patients with early TNBC.
The BrighTNess results suggest that patients with high- or moderate-risk TNBC could be treated in the neoadjuvant setting with paclitaxel and carboplatin followed by standard chemotherapy concurrently with pembrolizumab, followed by surgery, and adjuvant therapy with pembrolizumab plus olaparib (Lynparza) for patients with germline BRCA mutations, or capecitabine for patients without mutations, Dr. Arnedos proposed.
BrighTNess study details
The BrighTNess trial involved 634 patients with previously untreated histologically or cytologically confirmed stage 2-3 TNBC who were candidates for potentially curative surgery and had a good performance status. They were randomly assigned to receive either paclitaxel plus carboplatin and veliparib, paclitaxel plus carboplatin only, or paclitaxel alone prior to four cycles of chemotherapy with doxorubicin and cyclophosphamide (AC).
Initial results, published in 2018 in The Lancet Oncology, showed that the addition of veliparib to carboplatin and paclitaxel improved pCR rates compared with paclitaxel alone but not paclitaxel plus carboplatin. The trial data supported the addition of carboplatin to standard neoadjuvant chemotherapy but not veliparib, the investigators stated at the time.
Now at the ESMO meeting, Dr. Loibl presented longer follow-up results.
After a median follow-up of 4.5 years, the hazard ratio (HR) for event-free survival with the paclitaxel/carboplatin/veliparib combination compared with paclitaxel alone was 0.63 (P = .016). In a post-hoc analysis, the adjusted HR was 0.57 (P = .018).
In a subgroup of 309 patients who had initial pCRs, the HR for EFS compared with patients without a pCR was 0.26 (P < .0001). Among patients with germline BRCA mutation, the HR for EFS for those who had a pCR was 0.14 (P = .0004), and among those with germline wildtype BRCA and a pCR the HR was 0.29 (P < .0001).
However, there were no significant differences in OS a median of 4.5 years after surgery.
An analysis of the frequency of myelodysplastic syndrome, acute myeloid leukemia, or other second primary malignancies also showed no significant differences between the groups, Dr. Loibl noted.
Although there were higher rates of hematologic malignancies with the addition of carboplatin, with or without veliparib, these adverse events did not compromise either treatment delivery of the benefits of carboplatin on the primary pCR endpoint, she added.
The BrighTNess trial was supported by AbbVie. Dr. Loibl has reported receiving grants and honoraria from AbbVie and others, including Medscape. Dr. Arnedos has reported receiving honoraria, travel grants, and/or research grants from AstraZeneca, Novartis, Pfizer, and Roche.
A version of this article first appeared on Medscape.com.
The initial improvement that was seen in pathologic complete response (pCR) rates with the addition of carboplatin to paclitaxel and standard neoadjuvant chemotherapy translated into improved event-free survival (EFS) rates in patients with resectable TNBC more than 4 years after surgery.
The benefits of adding carboplatin to paclitaxel, followed by four cycles of AC (doxorubicin and cyclophosphamide) chemotherapy, were seen both in patients with germline BRCA mutations and those with wildtype BRCA.
The trial results also demonstrated, however, that there were no short- or long-term benefits to adding veliparib (ABT-888), a poly (ADP-ribose) polymerase (PARP) inhibitor, to the mix.
Although pCR and EFS rates were significantly improved with the combination of paclitaxel and carboplatin compared with paclitaxel alone, there were no significant differences when veliparib was added in either pCR, EFS, or overall survival (OS).
“These findings overall support the inclusion of carboplatin into neoadjuvant chemotherapy for stage 2 and 3 triple-negative breast cancer patients, regardless of germline BRCA status,” concluded lead author Sibylle Loibl, MD, PhD, chief executive officer and chair of the German Breast Group.
She presented the new data during an oral session at the virtual European Society for Medical Oncology (ESMO) Congress 2021.
The BrighTNess results show that “neoadjuvant carboplatin plus paclitaxel is superior to paclitaxel alone, with high pCR rates and benefit of event-free survival rates with manageable toxicity and no safety signals,” commented invited discussant Monica Arnedos, MD, PhD, head of the breast cancer research program at the Institut Bergonié in Bordeaux, France.
The findings also put to rest the notion that patients with germline BRCA mutations would not benefit from carboplatin treatment because of extreme sensitivity to standard neoadjuvant chemotherapy.
“The BrighTNess study says otherwise,” Dr. Arnedos said. “Today we’ve seen that the pCR improved event-free survival regardless of the germline BRCA mutated status, so BRCA-mutated germline patients require neoadjuvant carboplatin.”
The new data may lead to changes in breast cancer guidelines, she suggested.
Prior to these results, the evidence was that “platinum salts as neoadjuvant chemotherapy increased pCR rates in triple-negative breast cancer patients, but this was associated with more toxicity, and with higher rates of treatment discontinuation and dose reduction, without strong evidence of long-term benefit. This led to a lack of consensus to recommend platinum salts in this setting between the different breast cancer guidelines.”
The new BrighTNess data showed that the improved pCR rates translated into an EFS benefit in both platinum-containing groups of the trial, a finding that is consistent with the KEYNOTE-522 trial, which showed that adding pembrolizumab (Keytruda) to chemotherapy improved pCR in patients with early TNBC.
The BrighTNess results suggest that patients with high- or moderate-risk TNBC could be treated in the neoadjuvant setting with paclitaxel and carboplatin followed by standard chemotherapy concurrently with pembrolizumab, followed by surgery, and adjuvant therapy with pembrolizumab plus olaparib (Lynparza) for patients with germline BRCA mutations, or capecitabine for patients without mutations, Dr. Arnedos proposed.
BrighTNess study details
The BrighTNess trial involved 634 patients with previously untreated histologically or cytologically confirmed stage 2-3 TNBC who were candidates for potentially curative surgery and had a good performance status. They were randomly assigned to receive either paclitaxel plus carboplatin and veliparib, paclitaxel plus carboplatin only, or paclitaxel alone prior to four cycles of chemotherapy with doxorubicin and cyclophosphamide (AC).
Initial results, published in 2018 in The Lancet Oncology, showed that the addition of veliparib to carboplatin and paclitaxel improved pCR rates compared with paclitaxel alone but not paclitaxel plus carboplatin. The trial data supported the addition of carboplatin to standard neoadjuvant chemotherapy but not veliparib, the investigators stated at the time.
Now at the ESMO meeting, Dr. Loibl presented longer follow-up results.
After a median follow-up of 4.5 years, the hazard ratio (HR) for event-free survival with the paclitaxel/carboplatin/veliparib combination compared with paclitaxel alone was 0.63 (P = .016). In a post-hoc analysis, the adjusted HR was 0.57 (P = .018).
In a subgroup of 309 patients who had initial pCRs, the HR for EFS compared with patients without a pCR was 0.26 (P < .0001). Among patients with germline BRCA mutation, the HR for EFS for those who had a pCR was 0.14 (P = .0004), and among those with germline wildtype BRCA and a pCR the HR was 0.29 (P < .0001).
However, there were no significant differences in OS a median of 4.5 years after surgery.
An analysis of the frequency of myelodysplastic syndrome, acute myeloid leukemia, or other second primary malignancies also showed no significant differences between the groups, Dr. Loibl noted.
Although there were higher rates of hematologic malignancies with the addition of carboplatin, with or without veliparib, these adverse events did not compromise either treatment delivery of the benefits of carboplatin on the primary pCR endpoint, she added.
The BrighTNess trial was supported by AbbVie. Dr. Loibl has reported receiving grants and honoraria from AbbVie and others, including Medscape. Dr. Arnedos has reported receiving honoraria, travel grants, and/or research grants from AstraZeneca, Novartis, Pfizer, and Roche.
A version of this article first appeared on Medscape.com.
Nivo/ipi combo now ‘standard of care’ in mesothelioma
After 3 years, 23% of patients who received combination immunotherapy were still alive, in comparison with 15% of patients in the chemotherapy arm.
Combination immunotherapy continued to provide a “durable and long-term benefit” compared with chemotherapy, commented Solange Peters, MD, from the Oncology Department, Center Hospitalier Universitaire Vaudois, Lausanne, Switzerland.
The new data from the additional 12 months of follow-up “confirm nivolumab plus ipilimumab as a standard of care for unresectable MPM, regardless of histology,” she commented.
She presented the update on September 17 at the annual meeting of the European Society of Medical Oncology (ESMO). She is the current president of the organization.
Previously, 2-year data from this study showed that the combination yielded a median overall survival of 18.1 months, compared to 14.1 months with standard-of-care chemotherapy.
As reported by this news organization, this translated into a 26% improvement in overall survival; 41% of patients in the immunotherapy arm were still alive at 2 years, versus 27% in the chemotherapy group.
On the basis of these data, the combination was subsequently approved in the United States, the European Union, and elsewhere for the first-line treatment of adults with unresectable MPM.
The new data come from a 3-year update, as well as an exploratory biomarker analysis. The new data show significantly improved overall survival with the combination immunotherapy. Among those who responded to immunotherapy, response was ongoing for 28% of patients at 3 years.
Benefit was seen even for patients who discontinued the treatment because of treatment-related adverse events, indicating that discontinuance does not appear to have a negative impact on the long-term benefits, Dr. Peters commented.
In addition, the new analysis suggested that patients with a high score on a four-gene inflammatory signature did particularly well with nivolumab plus ipilimumab, whereas chemotherapy patients did worse if they had nonepithelioid disease, a finding not seen with immunotherapy.
The discussant for this abstract, Pilar Garrido, MD, PhD, associate professor of medicine at the Universidad de Alcalá, Madrid, said that despite the impressive findings, there is a “critical need” to establish predictive biomarkers in MPM.
This is particularly pressing in cases involving early progression, inasmuch as median progression-free survival (PFS) in CheckMate 743 was similar overall, and chemotherapy performed better than immunotherapy in the first 8 months.
There is also a need to be able to identify patients who will have an ongoing response at 3 years, as well as to clarify the impact of toxicity, given that the median duration of response was 20 months following discontinuation of treatment after just 4 months.
Dr. Garrido cautioned that the exploratory analyses were of “limited value,” because RNA data for the gene signature analysis were available for only 54% of patients, and the study was not powered to detect differences on the basis of programmed cell death–ligand-1 (PD-L1) expression.
Summarizing, Dr. Garrido said that although the current results showed that combination immunotherapy “continued to provide” a survival benefit in “a subgroup of patients,” the “better characterization of predictive biomarkers” will be “crucial” to improving these results.
Study details
Dr. Peters reminded the audience that the CheckMate 743 trial involved patients with unresectable MPM who had not previously received any systemic therapy and who had a good performance status.
A total of 605 patients were enrolled. They were randomly assigned in a 1:1 ratio to receive either nivolumab plus ipilimumab for up to 2 years or six cycles of pemetrexed plus cisplatin or carboplatin.
The median age of the patients was 69 years, and 77% were men. The baseline characteristics were well balanced between the two treatment groups; 75% to 76% had epithelioid disease, and for 74% to 80% of patients, baseline PD-L1 expression was greater than or equal to 1%.
Subgroup analysis indicated that combination immunotherapy was beneficial regardless of patient age, sex, performance status, and smoking status.
However, the new analysis suggested that the improvement in overall survival depended on PD-L1 expression, at a hazard ratio for combination immunotherapy versus chemotherapy of 0.71 in patients with expression of greater than or equal to 1%, compared with 0.99 for patients with expression of less than 1%.
Dr. Peters explained that the performance of nivolumab plus ipilimumab was identical in both PD-L1 expression groups, but it was the chemotherapy arm that performed markedly better for patients with expression of less than 1%.
An inverse finding was observed when patients were stratified by tumor histology.
In those with epithelioid disease, the median overall survival with combination immunotherapy was 18.2 months, versus 16.7 with chemotherapy, at a hazard ratio of 0.85.
At 36 months, 24% of immunotherapy patients were still alive, as were 19% of those given standard-of-care chemotherapy.
Among patients with nonepithelioid disease, however, median overall survival was 18.1 months with nivolumab plus ipilimumab, versus just 8.8 months with chemotherapy, at a hazard ratio of 0.48. At 3 years, 22% of patients who received combination immunotherapy were still alive, compared with 4% of those who received chemotherapy.
Other results showed that PFS was only slightly longer with combination immunotherapy, at 6.8 months versus 7.2 months, for a hazard ratio of 0.92.
Yet at 36 months, 14% of patients who received nivolumab plus ipilimumab had not experienced disease progression, versus just 1% of those in the chemotherapy arm.
This difference was even more pronounced when the researchers assessed objective response rates: 28% of patients who received combination immunotherapy were still responding at 36 months, versus 0% among patients given chemotherapy.
This translated into a median duration of response of 11.6 months for nivolumab plus ipilimumab, versus 6.7 months with chemotherapy.
The safety assessment showed that rates of treatment-related adverse events of any grade and of grade 3-4 were similar between the combination immunotherapy and chemotherapy arms.
However, rates of treatment-related adverse events that led to discontinuation of all components of the regimen were higher with immunotherapy, at 17% for events of any grade and 13% for events of grade 3-4, compared with 8% and 5%, respectively, with chemotherapy.
Serious treatment-related adverse events were more common with nivolumab plus ipilimumab. Events of grade 3-4 occurred in 13% of patients with nivolumab plus ipilimumab, versus 5% with chemotherapy.
Dr. Peters showed that this did not severely affect overall survival, however. Among patients who discontinued combination immunotherapy, the median duration of response was 20.0 months.
Median overall survival in these patients was 25.4 months, and the 3-year overall survival rate was 37%.
The study was funded by Bristol-Myers Squibb. Dr. Peters and Dr. Garrido reported relationships with numerous sources in industry.
A version of this article first appeared on Medscape.com.
After 3 years, 23% of patients who received combination immunotherapy were still alive, in comparison with 15% of patients in the chemotherapy arm.
Combination immunotherapy continued to provide a “durable and long-term benefit” compared with chemotherapy, commented Solange Peters, MD, from the Oncology Department, Center Hospitalier Universitaire Vaudois, Lausanne, Switzerland.
The new data from the additional 12 months of follow-up “confirm nivolumab plus ipilimumab as a standard of care for unresectable MPM, regardless of histology,” she commented.
She presented the update on September 17 at the annual meeting of the European Society of Medical Oncology (ESMO). She is the current president of the organization.
Previously, 2-year data from this study showed that the combination yielded a median overall survival of 18.1 months, compared to 14.1 months with standard-of-care chemotherapy.
As reported by this news organization, this translated into a 26% improvement in overall survival; 41% of patients in the immunotherapy arm were still alive at 2 years, versus 27% in the chemotherapy group.
On the basis of these data, the combination was subsequently approved in the United States, the European Union, and elsewhere for the first-line treatment of adults with unresectable MPM.
The new data come from a 3-year update, as well as an exploratory biomarker analysis. The new data show significantly improved overall survival with the combination immunotherapy. Among those who responded to immunotherapy, response was ongoing for 28% of patients at 3 years.
Benefit was seen even for patients who discontinued the treatment because of treatment-related adverse events, indicating that discontinuance does not appear to have a negative impact on the long-term benefits, Dr. Peters commented.
In addition, the new analysis suggested that patients with a high score on a four-gene inflammatory signature did particularly well with nivolumab plus ipilimumab, whereas chemotherapy patients did worse if they had nonepithelioid disease, a finding not seen with immunotherapy.
The discussant for this abstract, Pilar Garrido, MD, PhD, associate professor of medicine at the Universidad de Alcalá, Madrid, said that despite the impressive findings, there is a “critical need” to establish predictive biomarkers in MPM.
This is particularly pressing in cases involving early progression, inasmuch as median progression-free survival (PFS) in CheckMate 743 was similar overall, and chemotherapy performed better than immunotherapy in the first 8 months.
There is also a need to be able to identify patients who will have an ongoing response at 3 years, as well as to clarify the impact of toxicity, given that the median duration of response was 20 months following discontinuation of treatment after just 4 months.
Dr. Garrido cautioned that the exploratory analyses were of “limited value,” because RNA data for the gene signature analysis were available for only 54% of patients, and the study was not powered to detect differences on the basis of programmed cell death–ligand-1 (PD-L1) expression.
Summarizing, Dr. Garrido said that although the current results showed that combination immunotherapy “continued to provide” a survival benefit in “a subgroup of patients,” the “better characterization of predictive biomarkers” will be “crucial” to improving these results.
Study details
Dr. Peters reminded the audience that the CheckMate 743 trial involved patients with unresectable MPM who had not previously received any systemic therapy and who had a good performance status.
A total of 605 patients were enrolled. They were randomly assigned in a 1:1 ratio to receive either nivolumab plus ipilimumab for up to 2 years or six cycles of pemetrexed plus cisplatin or carboplatin.
The median age of the patients was 69 years, and 77% were men. The baseline characteristics were well balanced between the two treatment groups; 75% to 76% had epithelioid disease, and for 74% to 80% of patients, baseline PD-L1 expression was greater than or equal to 1%.
Subgroup analysis indicated that combination immunotherapy was beneficial regardless of patient age, sex, performance status, and smoking status.
However, the new analysis suggested that the improvement in overall survival depended on PD-L1 expression, at a hazard ratio for combination immunotherapy versus chemotherapy of 0.71 in patients with expression of greater than or equal to 1%, compared with 0.99 for patients with expression of less than 1%.
Dr. Peters explained that the performance of nivolumab plus ipilimumab was identical in both PD-L1 expression groups, but it was the chemotherapy arm that performed markedly better for patients with expression of less than 1%.
An inverse finding was observed when patients were stratified by tumor histology.
In those with epithelioid disease, the median overall survival with combination immunotherapy was 18.2 months, versus 16.7 with chemotherapy, at a hazard ratio of 0.85.
At 36 months, 24% of immunotherapy patients were still alive, as were 19% of those given standard-of-care chemotherapy.
Among patients with nonepithelioid disease, however, median overall survival was 18.1 months with nivolumab plus ipilimumab, versus just 8.8 months with chemotherapy, at a hazard ratio of 0.48. At 3 years, 22% of patients who received combination immunotherapy were still alive, compared with 4% of those who received chemotherapy.
Other results showed that PFS was only slightly longer with combination immunotherapy, at 6.8 months versus 7.2 months, for a hazard ratio of 0.92.
Yet at 36 months, 14% of patients who received nivolumab plus ipilimumab had not experienced disease progression, versus just 1% of those in the chemotherapy arm.
This difference was even more pronounced when the researchers assessed objective response rates: 28% of patients who received combination immunotherapy were still responding at 36 months, versus 0% among patients given chemotherapy.
This translated into a median duration of response of 11.6 months for nivolumab plus ipilimumab, versus 6.7 months with chemotherapy.
The safety assessment showed that rates of treatment-related adverse events of any grade and of grade 3-4 were similar between the combination immunotherapy and chemotherapy arms.
However, rates of treatment-related adverse events that led to discontinuation of all components of the regimen were higher with immunotherapy, at 17% for events of any grade and 13% for events of grade 3-4, compared with 8% and 5%, respectively, with chemotherapy.
Serious treatment-related adverse events were more common with nivolumab plus ipilimumab. Events of grade 3-4 occurred in 13% of patients with nivolumab plus ipilimumab, versus 5% with chemotherapy.
Dr. Peters showed that this did not severely affect overall survival, however. Among patients who discontinued combination immunotherapy, the median duration of response was 20.0 months.
Median overall survival in these patients was 25.4 months, and the 3-year overall survival rate was 37%.
The study was funded by Bristol-Myers Squibb. Dr. Peters and Dr. Garrido reported relationships with numerous sources in industry.
A version of this article first appeared on Medscape.com.
After 3 years, 23% of patients who received combination immunotherapy were still alive, in comparison with 15% of patients in the chemotherapy arm.
Combination immunotherapy continued to provide a “durable and long-term benefit” compared with chemotherapy, commented Solange Peters, MD, from the Oncology Department, Center Hospitalier Universitaire Vaudois, Lausanne, Switzerland.
The new data from the additional 12 months of follow-up “confirm nivolumab plus ipilimumab as a standard of care for unresectable MPM, regardless of histology,” she commented.
She presented the update on September 17 at the annual meeting of the European Society of Medical Oncology (ESMO). She is the current president of the organization.
Previously, 2-year data from this study showed that the combination yielded a median overall survival of 18.1 months, compared to 14.1 months with standard-of-care chemotherapy.
As reported by this news organization, this translated into a 26% improvement in overall survival; 41% of patients in the immunotherapy arm were still alive at 2 years, versus 27% in the chemotherapy group.
On the basis of these data, the combination was subsequently approved in the United States, the European Union, and elsewhere for the first-line treatment of adults with unresectable MPM.
The new data come from a 3-year update, as well as an exploratory biomarker analysis. The new data show significantly improved overall survival with the combination immunotherapy. Among those who responded to immunotherapy, response was ongoing for 28% of patients at 3 years.
Benefit was seen even for patients who discontinued the treatment because of treatment-related adverse events, indicating that discontinuance does not appear to have a negative impact on the long-term benefits, Dr. Peters commented.
In addition, the new analysis suggested that patients with a high score on a four-gene inflammatory signature did particularly well with nivolumab plus ipilimumab, whereas chemotherapy patients did worse if they had nonepithelioid disease, a finding not seen with immunotherapy.
The discussant for this abstract, Pilar Garrido, MD, PhD, associate professor of medicine at the Universidad de Alcalá, Madrid, said that despite the impressive findings, there is a “critical need” to establish predictive biomarkers in MPM.
This is particularly pressing in cases involving early progression, inasmuch as median progression-free survival (PFS) in CheckMate 743 was similar overall, and chemotherapy performed better than immunotherapy in the first 8 months.
There is also a need to be able to identify patients who will have an ongoing response at 3 years, as well as to clarify the impact of toxicity, given that the median duration of response was 20 months following discontinuation of treatment after just 4 months.
Dr. Garrido cautioned that the exploratory analyses were of “limited value,” because RNA data for the gene signature analysis were available for only 54% of patients, and the study was not powered to detect differences on the basis of programmed cell death–ligand-1 (PD-L1) expression.
Summarizing, Dr. Garrido said that although the current results showed that combination immunotherapy “continued to provide” a survival benefit in “a subgroup of patients,” the “better characterization of predictive biomarkers” will be “crucial” to improving these results.
Study details
Dr. Peters reminded the audience that the CheckMate 743 trial involved patients with unresectable MPM who had not previously received any systemic therapy and who had a good performance status.
A total of 605 patients were enrolled. They were randomly assigned in a 1:1 ratio to receive either nivolumab plus ipilimumab for up to 2 years or six cycles of pemetrexed plus cisplatin or carboplatin.
The median age of the patients was 69 years, and 77% were men. The baseline characteristics were well balanced between the two treatment groups; 75% to 76% had epithelioid disease, and for 74% to 80% of patients, baseline PD-L1 expression was greater than or equal to 1%.
Subgroup analysis indicated that combination immunotherapy was beneficial regardless of patient age, sex, performance status, and smoking status.
However, the new analysis suggested that the improvement in overall survival depended on PD-L1 expression, at a hazard ratio for combination immunotherapy versus chemotherapy of 0.71 in patients with expression of greater than or equal to 1%, compared with 0.99 for patients with expression of less than 1%.
Dr. Peters explained that the performance of nivolumab plus ipilimumab was identical in both PD-L1 expression groups, but it was the chemotherapy arm that performed markedly better for patients with expression of less than 1%.
An inverse finding was observed when patients were stratified by tumor histology.
In those with epithelioid disease, the median overall survival with combination immunotherapy was 18.2 months, versus 16.7 with chemotherapy, at a hazard ratio of 0.85.
At 36 months, 24% of immunotherapy patients were still alive, as were 19% of those given standard-of-care chemotherapy.
Among patients with nonepithelioid disease, however, median overall survival was 18.1 months with nivolumab plus ipilimumab, versus just 8.8 months with chemotherapy, at a hazard ratio of 0.48. At 3 years, 22% of patients who received combination immunotherapy were still alive, compared with 4% of those who received chemotherapy.
Other results showed that PFS was only slightly longer with combination immunotherapy, at 6.8 months versus 7.2 months, for a hazard ratio of 0.92.
Yet at 36 months, 14% of patients who received nivolumab plus ipilimumab had not experienced disease progression, versus just 1% of those in the chemotherapy arm.
This difference was even more pronounced when the researchers assessed objective response rates: 28% of patients who received combination immunotherapy were still responding at 36 months, versus 0% among patients given chemotherapy.
This translated into a median duration of response of 11.6 months for nivolumab plus ipilimumab, versus 6.7 months with chemotherapy.
The safety assessment showed that rates of treatment-related adverse events of any grade and of grade 3-4 were similar between the combination immunotherapy and chemotherapy arms.
However, rates of treatment-related adverse events that led to discontinuation of all components of the regimen were higher with immunotherapy, at 17% for events of any grade and 13% for events of grade 3-4, compared with 8% and 5%, respectively, with chemotherapy.
Serious treatment-related adverse events were more common with nivolumab plus ipilimumab. Events of grade 3-4 occurred in 13% of patients with nivolumab plus ipilimumab, versus 5% with chemotherapy.
Dr. Peters showed that this did not severely affect overall survival, however. Among patients who discontinued combination immunotherapy, the median duration of response was 20.0 months.
Median overall survival in these patients was 25.4 months, and the 3-year overall survival rate was 37%.
The study was funded by Bristol-Myers Squibb. Dr. Peters and Dr. Garrido reported relationships with numerous sources in industry.
A version of this article first appeared on Medscape.com.
Most community-based oncologists skip biomarker testing
A recent survey shows that fewer than half of community oncologists use biomarker testing to guide patient discussions about treatment, which compares with 73% of academic clinicians.
The findings, reported at the 2020 World Conference on Lung Cancer, which was rescheduled for January 2021, highlight the potential for unequal application of the latest advances in cancer genomics and targeted therapies throughout the health care system, which could worsen existing disparities in underserved populations, according to Leigh Boehmer, PharmD, medical director for the Association of Community Cancer Centers, Rockville, Md.
The survey – a mixed-methods approach for assessing practice patterns, attitudes, barriers, and resource needs related to biomarker testing among clinicians – was developed by the ACCC in partnership with the LUNGevity Foundation and administered to clinicians caring for patients with non–small cell lung cancer who are uninsured or covered by Medicaid.
Of 99 respondents, more than 85% were physicians and 68% worked in a community setting. Only 40% indicated they were very familiar or extremely familiar with 2018 Molecular Testing Guidelines for Lung Cancer from the College of American Pathologists, the International Association for the Study of Lung Cancer, and the Association for Molecular Pathology.
Clinicians were most confident about selecting appropriate tests to use, interpreting test results, and prognosticating based on test results, with 77%, 74%, and 74%, respectively, saying they are very confident or extremely confident in those areas. They were less confident about determining when to order testing and in coordinating care across the multidisciplinary team, with 59% and 64%, respectively, saying they were very confident or extremely confident in those areas, Dr. Boehmer reported at the conference.
The shortcomings with respect to communication across teams were echoed in two focus groups convened to further validate the survey results, he noted.
As for the reasons why clinicians ordered biomarker testing, 88% and 82% of community and academic clinicians, respectively, said they did so to help make targeted treatment decisions.
“Only 48% of community clinicians indicated that they use biomarker testing to guide patient discussions, compared to 73% of academic clinicians,” he said. “That finding was considered statistically significant.”
With respect to decision-making about biomarker testing, 41% said they prefer to share the responsibility with patients, whereas 52% said they prefer to make the final decision.
“Shedding further light on this situation, focus group participants expressed that patients lacked comprehension and interest about what testing entails and what testing means for their treatment options,” Dr. Boehmer noted.
In order to make more informed decisions about biomarker testing, respondents said they need more information on financial resources for patient assistance (26%) and education around both published guidelines and practical implications of the clinical data (21%).
When asked about patients’ information needs, 23% said their patients need psychosocial support, 22% said they need financial assistance, and 9% said their patients have no additional resource needs.
However, only 27% said they provide patients with resources related to psychosocial support services, and only 44% share financial assistance information, he said.
Further, the fact that 9% said their patients need no additional resources represents “a disconnect” from the findings of the survey and focus groups, he added.
“We believe that this study identifies key areas of ongoing clinician need related to biomarker testing, including things like increased guideline familiarity, practical applications of guideline-concordant testing, and … how to optimally coordinate multidisciplinary care delivery,” Dr. Boehmer said. “Professional organizations … in partnership with patient advocacy organizations or groups should focus on developing those patient education materials … and tools for improving patient-clinician discussions about biomarker testing.”
The ACCC will be working with the LUNGevity Foundation and the Center for Business Models in Healthcare to develop an intervention to ensure that such discussions are “easily integrated into the care process for every patient,” he noted.
Such efforts are important for ensuring that clinicians are informed about the value of biomarker testing and about guidelines for testing so that patients receive the best possible care, said invited discussant Joshua Sabari, MD, of New York University Langone Health’s Perlmutter Cancer Center.
“I know that, in clinic, when meeting a new patient with non–small cell lung cancer, it’s critical to understand the driver alteration, not only for prognosis, but also for goals-of-care discussion, as well as potential treatment option,” Dr. Sabari said.
Dr. Boehmer reported consulting for Pfizer. Dr. Sabari reported consulting and advisory board membership for multiple pharmaceutical companies.
A recent survey shows that fewer than half of community oncologists use biomarker testing to guide patient discussions about treatment, which compares with 73% of academic clinicians.
The findings, reported at the 2020 World Conference on Lung Cancer, which was rescheduled for January 2021, highlight the potential for unequal application of the latest advances in cancer genomics and targeted therapies throughout the health care system, which could worsen existing disparities in underserved populations, according to Leigh Boehmer, PharmD, medical director for the Association of Community Cancer Centers, Rockville, Md.
The survey – a mixed-methods approach for assessing practice patterns, attitudes, barriers, and resource needs related to biomarker testing among clinicians – was developed by the ACCC in partnership with the LUNGevity Foundation and administered to clinicians caring for patients with non–small cell lung cancer who are uninsured or covered by Medicaid.
Of 99 respondents, more than 85% were physicians and 68% worked in a community setting. Only 40% indicated they were very familiar or extremely familiar with 2018 Molecular Testing Guidelines for Lung Cancer from the College of American Pathologists, the International Association for the Study of Lung Cancer, and the Association for Molecular Pathology.
Clinicians were most confident about selecting appropriate tests to use, interpreting test results, and prognosticating based on test results, with 77%, 74%, and 74%, respectively, saying they are very confident or extremely confident in those areas. They were less confident about determining when to order testing and in coordinating care across the multidisciplinary team, with 59% and 64%, respectively, saying they were very confident or extremely confident in those areas, Dr. Boehmer reported at the conference.
The shortcomings with respect to communication across teams were echoed in two focus groups convened to further validate the survey results, he noted.
As for the reasons why clinicians ordered biomarker testing, 88% and 82% of community and academic clinicians, respectively, said they did so to help make targeted treatment decisions.
“Only 48% of community clinicians indicated that they use biomarker testing to guide patient discussions, compared to 73% of academic clinicians,” he said. “That finding was considered statistically significant.”
With respect to decision-making about biomarker testing, 41% said they prefer to share the responsibility with patients, whereas 52% said they prefer to make the final decision.
“Shedding further light on this situation, focus group participants expressed that patients lacked comprehension and interest about what testing entails and what testing means for their treatment options,” Dr. Boehmer noted.
In order to make more informed decisions about biomarker testing, respondents said they need more information on financial resources for patient assistance (26%) and education around both published guidelines and practical implications of the clinical data (21%).
When asked about patients’ information needs, 23% said their patients need psychosocial support, 22% said they need financial assistance, and 9% said their patients have no additional resource needs.
However, only 27% said they provide patients with resources related to psychosocial support services, and only 44% share financial assistance information, he said.
Further, the fact that 9% said their patients need no additional resources represents “a disconnect” from the findings of the survey and focus groups, he added.
“We believe that this study identifies key areas of ongoing clinician need related to biomarker testing, including things like increased guideline familiarity, practical applications of guideline-concordant testing, and … how to optimally coordinate multidisciplinary care delivery,” Dr. Boehmer said. “Professional organizations … in partnership with patient advocacy organizations or groups should focus on developing those patient education materials … and tools for improving patient-clinician discussions about biomarker testing.”
The ACCC will be working with the LUNGevity Foundation and the Center for Business Models in Healthcare to develop an intervention to ensure that such discussions are “easily integrated into the care process for every patient,” he noted.
Such efforts are important for ensuring that clinicians are informed about the value of biomarker testing and about guidelines for testing so that patients receive the best possible care, said invited discussant Joshua Sabari, MD, of New York University Langone Health’s Perlmutter Cancer Center.
“I know that, in clinic, when meeting a new patient with non–small cell lung cancer, it’s critical to understand the driver alteration, not only for prognosis, but also for goals-of-care discussion, as well as potential treatment option,” Dr. Sabari said.
Dr. Boehmer reported consulting for Pfizer. Dr. Sabari reported consulting and advisory board membership for multiple pharmaceutical companies.
A recent survey shows that fewer than half of community oncologists use biomarker testing to guide patient discussions about treatment, which compares with 73% of academic clinicians.
The findings, reported at the 2020 World Conference on Lung Cancer, which was rescheduled for January 2021, highlight the potential for unequal application of the latest advances in cancer genomics and targeted therapies throughout the health care system, which could worsen existing disparities in underserved populations, according to Leigh Boehmer, PharmD, medical director for the Association of Community Cancer Centers, Rockville, Md.
The survey – a mixed-methods approach for assessing practice patterns, attitudes, barriers, and resource needs related to biomarker testing among clinicians – was developed by the ACCC in partnership with the LUNGevity Foundation and administered to clinicians caring for patients with non–small cell lung cancer who are uninsured or covered by Medicaid.
Of 99 respondents, more than 85% were physicians and 68% worked in a community setting. Only 40% indicated they were very familiar or extremely familiar with 2018 Molecular Testing Guidelines for Lung Cancer from the College of American Pathologists, the International Association for the Study of Lung Cancer, and the Association for Molecular Pathology.
Clinicians were most confident about selecting appropriate tests to use, interpreting test results, and prognosticating based on test results, with 77%, 74%, and 74%, respectively, saying they are very confident or extremely confident in those areas. They were less confident about determining when to order testing and in coordinating care across the multidisciplinary team, with 59% and 64%, respectively, saying they were very confident or extremely confident in those areas, Dr. Boehmer reported at the conference.
The shortcomings with respect to communication across teams were echoed in two focus groups convened to further validate the survey results, he noted.
As for the reasons why clinicians ordered biomarker testing, 88% and 82% of community and academic clinicians, respectively, said they did so to help make targeted treatment decisions.
“Only 48% of community clinicians indicated that they use biomarker testing to guide patient discussions, compared to 73% of academic clinicians,” he said. “That finding was considered statistically significant.”
With respect to decision-making about biomarker testing, 41% said they prefer to share the responsibility with patients, whereas 52% said they prefer to make the final decision.
“Shedding further light on this situation, focus group participants expressed that patients lacked comprehension and interest about what testing entails and what testing means for their treatment options,” Dr. Boehmer noted.
In order to make more informed decisions about biomarker testing, respondents said they need more information on financial resources for patient assistance (26%) and education around both published guidelines and practical implications of the clinical data (21%).
When asked about patients’ information needs, 23% said their patients need psychosocial support, 22% said they need financial assistance, and 9% said their patients have no additional resource needs.
However, only 27% said they provide patients with resources related to psychosocial support services, and only 44% share financial assistance information, he said.
Further, the fact that 9% said their patients need no additional resources represents “a disconnect” from the findings of the survey and focus groups, he added.
“We believe that this study identifies key areas of ongoing clinician need related to biomarker testing, including things like increased guideline familiarity, practical applications of guideline-concordant testing, and … how to optimally coordinate multidisciplinary care delivery,” Dr. Boehmer said. “Professional organizations … in partnership with patient advocacy organizations or groups should focus on developing those patient education materials … and tools for improving patient-clinician discussions about biomarker testing.”
The ACCC will be working with the LUNGevity Foundation and the Center for Business Models in Healthcare to develop an intervention to ensure that such discussions are “easily integrated into the care process for every patient,” he noted.
Such efforts are important for ensuring that clinicians are informed about the value of biomarker testing and about guidelines for testing so that patients receive the best possible care, said invited discussant Joshua Sabari, MD, of New York University Langone Health’s Perlmutter Cancer Center.
“I know that, in clinic, when meeting a new patient with non–small cell lung cancer, it’s critical to understand the driver alteration, not only for prognosis, but also for goals-of-care discussion, as well as potential treatment option,” Dr. Sabari said.
Dr. Boehmer reported consulting for Pfizer. Dr. Sabari reported consulting and advisory board membership for multiple pharmaceutical companies.
REPORTING FROM WCLC 2020