Breast Cancer ICYMI

Patients with COVID-19 may be at increased risk of acute ischemic stroke compared with patients with influenza, according to a retrospective cohort study conducted at New York–Presbyterian Hospital and Weill Cornell Medicine, New York. “These findings suggest that clinicians should be vigilant for symptoms and signs of acute ischemic stroke in patients with COVID-19 so that time-sensitive interventions, such as thrombolysis and thrombectomy, can be instituted if possible to reduce the burden of long-term disability,” wrote Alexander E. Merkler and colleagues. Their report is in JAMA Neurology.

While several recent publications have “raised the possibility” of this link, none have had an appropriate control group, noted Dr. Merkler of the department of neurology, Weill Cornell Medicine. “Further elucidation of thrombotic mechanisms in patients with COVID-19 may yield better strategies to prevent disabling thrombotic complications like ischemic stroke,” he added.
 

An increased risk of stroke

The study included 1,916 adults with confirmed COVID-19 (median age 64 years) who were either hospitalized or visited an emergency department between March 4 and May 2, 2020. These cases were compared with a historical cohort of 1,486 patients (median age 62 years) who were hospitalized with laboratory-confirmed influenza A or B between January 1, 2016, and May 31, 2018.

Among the patients with COVID-19, a diagnosis of cerebrovascular disease during hospitalization, a brain computed tomography (CT), or brain magnetic resonance imaging (MRI) was an indication of possible ischemic stroke. These records were then independently reviewed by two board-certified attending neurologists (with a third resolving any disagreement) to adjudicate a final stroke diagnosis. In the influenza cohort, the Cornell Acute Stroke Academic Registry (CAESAR) was used to ascertain ischemic strokes.

The study identified 31 patients with stroke among the COVID-19 cohort (1.6%; 95% confidence interval, 1.1%-2.3%) and 3 in the influenza cohort (0.2%; 95% CI, 0.0%-0.6%). After adjustment for age, sex, and race, stroke risk was almost 8 times higher in the COVID-19 cohort (OR, 7.6; 95% CI, 2.3-25.2).

This association “persisted across multiple sensitivity analyses, with the magnitude of relative associations ranging from 4.0 to 9,” wrote the authors. “This included a sensitivity analysis that adjusted for the number of vascular risk factors and ICU admissions (OR, 4.6; 95% CI, 1.4-15.7).”

The median age of patients with COVID-19 and stroke was 69 years, and the median duration of COVID-19 symptom onset to stroke diagnosis was 16 days. Stroke symptoms were the presenting complaint in only 26% of the patients, while the remainder developing stroke while hospitalized, and more than a third (35%) of all strokes occurred in patients who were mechanically ventilated with severe COVID-19. Inpatient mortality was considerably higher among patients with COVID-19 with stroke versus without (32% vs. 14%; P = .003).

In patients with COVID-19 “most ischemic strokes occurred in older age groups, those with traditional stroke risk factors, and people of color,” wrote the authors. “We also noted that initial plasma D-dimer levels were nearly 3-fold higher in those who received a diagnosis of ischemic stroke than in those who did not” (1.930 mcg/mL vs. 0.682 mcg/mL).

The authors suggested several possible explanations for the elevated risk of stroke in COVID-19. Acute viral illnesses are known to trigger inflammation, and COVID-19 in particular is associated with “a vigorous inflammatory response accompanied by coagulopathy, with elevated D-dimer levels and the frequent presence of antiphospholipid antibodies,” they wrote. The infection is also associated with more severe respiratory syndrome compared with influenza, as well as a heightened risk for complications such as atrial arrhythmias, myocardial infarction, heart failure, myocarditis, and venous thromboses, all of which likely contribute to the risk of ischemic stroke.”
 

COVID or conventional risk factors?

Asked to comment on the study, Benedict Michael, MBChB (Hons), MRCP (Neurol), PhD, from the United Kingdom’s Coronerve Studies Group, a collaborative initiative to study the neurological features of COVID-19, said in an interview that “this study suggests many cases of stroke are occurring in older patients with multiple existing conventional and well recognized risks for stroke, and may simply represent decompensation during sepsis.”

Dr. Michael, a senior clinician scientist fellow at the University of Liverpool and an honorary consultant neurologist at the Walton Centre, was the senior author on a recently published UK-wide surveillance study on the neurological and neuropsychiatric complications of COVID-19 (Lancet Psychiatry. 2020 Jun 25. doi: 10.1016/S2215-0366[20]30287-X).

He said among patients in the New York study, “those with COVID and a stroke appeared to have many conventional risk factors for stroke (and often at higher percentages than COVID patients without a stroke), e.g. hypertension, overweight, diabetes, hyperlipidemia, existing vascular disease affecting the coronary arteries and atrial fibrillation. To establish evidence-based treatment pathways, clearly further studies are needed to determine the biological mechanisms underlying the seemingly higher rate of stroke with COVID-19 than influenza; but this must especially focus on those younger patients without conventional risk factors for stroke (which are largely not included in this study).”

SOURCE: Merkler AE et al. JAMA Neurol. doi: 10.1001/jamaneurol.2020.2730.

Patients with COVID-19 may be at increased risk of acute ischemic stroke compared with patients with influenza, according to a retrospective cohort study conducted at New York–Presbyterian Hospital and Weill Cornell Medicine, New York. “These findings suggest that clinicians should be vigilant for symptoms and signs of acute ischemic stroke in patients with COVID-19 so that time-sensitive interventions, such as thrombolysis and thrombectomy, can be instituted if possible to reduce the burden of long-term disability,” wrote Alexander E. Merkler and colleagues. Their report is in JAMA Neurology.

While several recent publications have “raised the possibility” of this link, none have had an appropriate control group, noted Dr. Merkler of the department of neurology, Weill Cornell Medicine. “Further elucidation of thrombotic mechanisms in patients with COVID-19 may yield better strategies to prevent disabling thrombotic complications like ischemic stroke,” he added.
 

An increased risk of stroke

The study included 1,916 adults with confirmed COVID-19 (median age 64 years) who were either hospitalized or visited an emergency department between March 4 and May 2, 2020. These cases were compared with a historical cohort of 1,486 patients (median age 62 years) who were hospitalized with laboratory-confirmed influenza A or B between January 1, 2016, and May 31, 2018.

Among the patients with COVID-19, a diagnosis of cerebrovascular disease during hospitalization, a brain computed tomography (CT), or brain magnetic resonance imaging (MRI) was an indication of possible ischemic stroke. These records were then independently reviewed by two board-certified attending neurologists (with a third resolving any disagreement) to adjudicate a final stroke diagnosis. In the influenza cohort, the Cornell Acute Stroke Academic Registry (CAESAR) was used to ascertain ischemic strokes.

The study identified 31 patients with stroke among the COVID-19 cohort (1.6%; 95% confidence interval, 1.1%-2.3%) and 3 in the influenza cohort (0.2%; 95% CI, 0.0%-0.6%). After adjustment for age, sex, and race, stroke risk was almost 8 times higher in the COVID-19 cohort (OR, 7.6; 95% CI, 2.3-25.2).

This association “persisted across multiple sensitivity analyses, with the magnitude of relative associations ranging from 4.0 to 9,” wrote the authors. “This included a sensitivity analysis that adjusted for the number of vascular risk factors and ICU admissions (OR, 4.6; 95% CI, 1.4-15.7).”

The median age of patients with COVID-19 and stroke was 69 years, and the median duration of COVID-19 symptom onset to stroke diagnosis was 16 days. Stroke symptoms were the presenting complaint in only 26% of the patients, while the remainder developing stroke while hospitalized, and more than a third (35%) of all strokes occurred in patients who were mechanically ventilated with severe COVID-19. Inpatient mortality was considerably higher among patients with COVID-19 with stroke versus without (32% vs. 14%; P = .003).

In patients with COVID-19 “most ischemic strokes occurred in older age groups, those with traditional stroke risk factors, and people of color,” wrote the authors. “We also noted that initial plasma D-dimer levels were nearly 3-fold higher in those who received a diagnosis of ischemic stroke than in those who did not” (1.930 mcg/mL vs. 0.682 mcg/mL).

The authors suggested several possible explanations for the elevated risk of stroke in COVID-19. Acute viral illnesses are known to trigger inflammation, and COVID-19 in particular is associated with “a vigorous inflammatory response accompanied by coagulopathy, with elevated D-dimer levels and the frequent presence of antiphospholipid antibodies,” they wrote. The infection is also associated with more severe respiratory syndrome compared with influenza, as well as a heightened risk for complications such as atrial arrhythmias, myocardial infarction, heart failure, myocarditis, and venous thromboses, all of which likely contribute to the risk of ischemic stroke.”
 

COVID or conventional risk factors?

Asked to comment on the study, Benedict Michael, MBChB (Hons), MRCP (Neurol), PhD, from the United Kingdom’s Coronerve Studies Group, a collaborative initiative to study the neurological features of COVID-19, said in an interview that “this study suggests many cases of stroke are occurring in older patients with multiple existing conventional and well recognized risks for stroke, and may simply represent decompensation during sepsis.”

Dr. Michael, a senior clinician scientist fellow at the University of Liverpool and an honorary consultant neurologist at the Walton Centre, was the senior author on a recently published UK-wide surveillance study on the neurological and neuropsychiatric complications of COVID-19 (Lancet Psychiatry. 2020 Jun 25. doi: 10.1016/S2215-0366[20]30287-X).

He said among patients in the New York study, “those with COVID and a stroke appeared to have many conventional risk factors for stroke (and often at higher percentages than COVID patients without a stroke), e.g. hypertension, overweight, diabetes, hyperlipidemia, existing vascular disease affecting the coronary arteries and atrial fibrillation. To establish evidence-based treatment pathways, clearly further studies are needed to determine the biological mechanisms underlying the seemingly higher rate of stroke with COVID-19 than influenza; but this must especially focus on those younger patients without conventional risk factors for stroke (which are largely not included in this study).”

SOURCE: Merkler AE et al. JAMA Neurol. doi: 10.1001/jamaneurol.2020.2730.

Patients with COVID-19 may be at increased risk of acute ischemic stroke compared with patients with influenza, according to a retrospective cohort study conducted at New York–Presbyterian Hospital and Weill Cornell Medicine, New York. “These findings suggest that clinicians should be vigilant for symptoms and signs of acute ischemic stroke in patients with COVID-19 so that time-sensitive interventions, such as thrombolysis and thrombectomy, can be instituted if possible to reduce the burden of long-term disability,” wrote Alexander E. Merkler and colleagues. Their report is in JAMA Neurology.

While several recent publications have “raised the possibility” of this link, none have had an appropriate control group, noted Dr. Merkler of the department of neurology, Weill Cornell Medicine. “Further elucidation of thrombotic mechanisms in patients with COVID-19 may yield better strategies to prevent disabling thrombotic complications like ischemic stroke,” he added.
 

An increased risk of stroke

The study included 1,916 adults with confirmed COVID-19 (median age 64 years) who were either hospitalized or visited an emergency department between March 4 and May 2, 2020. These cases were compared with a historical cohort of 1,486 patients (median age 62 years) who were hospitalized with laboratory-confirmed influenza A or B between January 1, 2016, and May 31, 2018.

Among the patients with COVID-19, a diagnosis of cerebrovascular disease during hospitalization, a brain computed tomography (CT), or brain magnetic resonance imaging (MRI) was an indication of possible ischemic stroke. These records were then independently reviewed by two board-certified attending neurologists (with a third resolving any disagreement) to adjudicate a final stroke diagnosis. In the influenza cohort, the Cornell Acute Stroke Academic Registry (CAESAR) was used to ascertain ischemic strokes.

The study identified 31 patients with stroke among the COVID-19 cohort (1.6%; 95% confidence interval, 1.1%-2.3%) and 3 in the influenza cohort (0.2%; 95% CI, 0.0%-0.6%). After adjustment for age, sex, and race, stroke risk was almost 8 times higher in the COVID-19 cohort (OR, 7.6; 95% CI, 2.3-25.2).

This association “persisted across multiple sensitivity analyses, with the magnitude of relative associations ranging from 4.0 to 9,” wrote the authors. “This included a sensitivity analysis that adjusted for the number of vascular risk factors and ICU admissions (OR, 4.6; 95% CI, 1.4-15.7).”

The median age of patients with COVID-19 and stroke was 69 years, and the median duration of COVID-19 symptom onset to stroke diagnosis was 16 days. Stroke symptoms were the presenting complaint in only 26% of the patients, while the remainder developing stroke while hospitalized, and more than a third (35%) of all strokes occurred in patients who were mechanically ventilated with severe COVID-19. Inpatient mortality was considerably higher among patients with COVID-19 with stroke versus without (32% vs. 14%; P = .003).

In patients with COVID-19 “most ischemic strokes occurred in older age groups, those with traditional stroke risk factors, and people of color,” wrote the authors. “We also noted that initial plasma D-dimer levels were nearly 3-fold higher in those who received a diagnosis of ischemic stroke than in those who did not” (1.930 mcg/mL vs. 0.682 mcg/mL).

The authors suggested several possible explanations for the elevated risk of stroke in COVID-19. Acute viral illnesses are known to trigger inflammation, and COVID-19 in particular is associated with “a vigorous inflammatory response accompanied by coagulopathy, with elevated D-dimer levels and the frequent presence of antiphospholipid antibodies,” they wrote. The infection is also associated with more severe respiratory syndrome compared with influenza, as well as a heightened risk for complications such as atrial arrhythmias, myocardial infarction, heart failure, myocarditis, and venous thromboses, all of which likely contribute to the risk of ischemic stroke.”
 

COVID or conventional risk factors?

Asked to comment on the study, Benedict Michael, MBChB (Hons), MRCP (Neurol), PhD, from the United Kingdom’s Coronerve Studies Group, a collaborative initiative to study the neurological features of COVID-19, said in an interview that “this study suggests many cases of stroke are occurring in older patients with multiple existing conventional and well recognized risks for stroke, and may simply represent decompensation during sepsis.”

Dr. Michael, a senior clinician scientist fellow at the University of Liverpool and an honorary consultant neurologist at the Walton Centre, was the senior author on a recently published UK-wide surveillance study on the neurological and neuropsychiatric complications of COVID-19 (Lancet Psychiatry. 2020 Jun 25. doi: 10.1016/S2215-0366[20]30287-X).

He said among patients in the New York study, “those with COVID and a stroke appeared to have many conventional risk factors for stroke (and often at higher percentages than COVID patients without a stroke), e.g. hypertension, overweight, diabetes, hyperlipidemia, existing vascular disease affecting the coronary arteries and atrial fibrillation. To establish evidence-based treatment pathways, clearly further studies are needed to determine the biological mechanisms underlying the seemingly higher rate of stroke with COVID-19 than influenza; but this must especially focus on those younger patients without conventional risk factors for stroke (which are largely not included in this study).”

SOURCE: Merkler AE et al. JAMA Neurol. doi: 10.1001/jamaneurol.2020.2730.

A “favorable” lifestyle was associated with a reduced risk of breast cancer even among women at high genetic risk for the disease in a study of more than 90,000 women, researchers reported.

The findings suggest that, regardless of genetic risk, women may be able to reduce their risk of developing breast cancer by getting adequate levels of exercise; maintaining a healthy weight; and limiting or eliminating use of alcohol, oral contraceptives, and hormone replacement therapy.

Kawthar Al Ajmi, MSc, of the University of Manchester (England), and colleagues published these findings in JAMA Network Open.

With almost a quarter of breast cancers thought to be preventable in the United Kingdom, “it is important to understand the contribution of modifiable risk factors ... and how they affect or add to the inherited genetic factors,” the researchers wrote.

To that end, the team reviewed 91,217 white, postmenopausal women in the United Kingdom Biobank, an ongoing longitudinal study of the contribution of genetic, environmental, and lifestyle risk factors in disease. There were 2,728 women who developed breast cancer at a median follow-up of 10 years.

The investigators used a polygenic risk score to categorize subjects as low, intermediate, or high genetic risk. The score was constructed using 305 single-nucleotide variants.

Within each risk group, the researchers divided women by the presence or absence of five lifestyle factors previously associated with a lower risk of breast cancer: healthy weight, regular exercise, no use of hormone replacement therapy beyond 5 years, no oral contraceptive use, and alcohol intake no more than twice a week.

Women with four or more of these factors were deemed to have a favorable lifestyle. Women with two or three factors had an intermediate lifestyle, and women with fewer factors had an unfavorable lifestyle.
 

Results

The data showed an association between breast cancer and a body mass index of 25 or higher (relative risk, 1.14), no regular physical activity (RR, 1.12), alcohol intake at least three times per week (RR, 1.11), and use of hormone replacement therapy for 5 or more years (RR, 1.23). History of oral contraceptive use was not associated with breast cancer risk (RR, 1.02), but this factor remained a part of the lifestyle classification.

In the low genetic risk group, an intermediate lifestyle (hazard ratio, 1.40; 95% CI, 1.09-1.80) and an unfavorable lifestyle (HR, 1.63; 95% CI, 1.14-2.34) were both associated with a higher risk of breast cancer, compared with a favorable lifestyle.

In the intermediate genetic risk group, intermediate (HR, 1.37; 95% CI, 1.12-1.68) and unfavorable lifestyles (HR 1.94; 95% CI, 1.46-2.58) were again associated with higher breast cancer risk, compared with a favorable lifestyle .

Even in the high genetic risk group, intermediate (HR, 1.13; 95% CI, 0.98-1.31) and unfavorable lifestyles (HR, 1.39; 95% CI, 1.11-1.74) were associated with increased breast cancer risk. Results were adjusted for both age and family history.

In the end, “a healthier lifestyle ... appeared to be associated with a reduced level of risk for [breast cancer], even if the women were at higher genetic risk,” the researchers wrote. “Our findings suggest that women may be able to alter or reduce their risk of developing [breast cancer] by following healthier lifestyles,” regardless of genetic predisposition.
 

‘Surprising’ findings

It’s “surprising that these lifestyle changes lowered the risk of breast cancer,” said Charles Shapiro, MD, of the Icahn School of Medicine at Mount Sinai in New York, who was not involved in this study.

The study “requires replication,” he said. “On the other hand, these lifestyle changes promote overall health and certainly are associated with decreased risks of cardiovascular disease, the number one killer of women.”

“Patients always want to know what they can do above and beyond screening mammograms to reduce their risk of developing breast cancer,” said William Gradishar, MD, of Northwestern University in Chicago, who was not involved in the study.

“These data should empower patients that they can impact on their overall health and reduce the risk of developing breast cancer,” he said.

Among the study’s limitations, it’s unclear how the findings apply to nonwhite, nonpostmenopausal women, and the analysis did not differentiate between breast cancer subtypes.

In addition, although oral contraceptives have been linked to breast cancer in the past, there was no association in this study. Possible explanations could be that the investigators did not take into account duration of use, age of last use, and type or oral contraceptive used, they noted.

This research was funded by the National Institute for Health Research Manchester Biomedical Research Centre, the Alan Turing Institute, and a Cancer Research UK Integrated Cancer Epidemiology Programme grant. The investigators, Dr. Gradishar, and Dr. Shapiro have no relevant disclosures.

[email protected]

SOURCE: Al Ajmi K et al. JAMA Netw Open. 2020;3(4):e203760.

A “favorable” lifestyle was associated with a reduced risk of breast cancer even among women at high genetic risk for the disease in a study of more than 90,000 women, researchers reported.

The findings suggest that, regardless of genetic risk, women may be able to reduce their risk of developing breast cancer by getting adequate levels of exercise; maintaining a healthy weight; and limiting or eliminating use of alcohol, oral contraceptives, and hormone replacement therapy.

Kawthar Al Ajmi, MSc, of the University of Manchester (England), and colleagues published these findings in JAMA Network Open.

With almost a quarter of breast cancers thought to be preventable in the United Kingdom, “it is important to understand the contribution of modifiable risk factors ... and how they affect or add to the inherited genetic factors,” the researchers wrote.

To that end, the team reviewed 91,217 white, postmenopausal women in the United Kingdom Biobank, an ongoing longitudinal study of the contribution of genetic, environmental, and lifestyle risk factors in disease. There were 2,728 women who developed breast cancer at a median follow-up of 10 years.

The investigators used a polygenic risk score to categorize subjects as low, intermediate, or high genetic risk. The score was constructed using 305 single-nucleotide variants.

Within each risk group, the researchers divided women by the presence or absence of five lifestyle factors previously associated with a lower risk of breast cancer: healthy weight, regular exercise, no use of hormone replacement therapy beyond 5 years, no oral contraceptive use, and alcohol intake no more than twice a week.

Women with four or more of these factors were deemed to have a favorable lifestyle. Women with two or three factors had an intermediate lifestyle, and women with fewer factors had an unfavorable lifestyle.
 

Results

The data showed an association between breast cancer and a body mass index of 25 or higher (relative risk, 1.14), no regular physical activity (RR, 1.12), alcohol intake at least three times per week (RR, 1.11), and use of hormone replacement therapy for 5 or more years (RR, 1.23). History of oral contraceptive use was not associated with breast cancer risk (RR, 1.02), but this factor remained a part of the lifestyle classification.

In the low genetic risk group, an intermediate lifestyle (hazard ratio, 1.40; 95% CI, 1.09-1.80) and an unfavorable lifestyle (HR, 1.63; 95% CI, 1.14-2.34) were both associated with a higher risk of breast cancer, compared with a favorable lifestyle.

In the intermediate genetic risk group, intermediate (HR, 1.37; 95% CI, 1.12-1.68) and unfavorable lifestyles (HR 1.94; 95% CI, 1.46-2.58) were again associated with higher breast cancer risk, compared with a favorable lifestyle .

Even in the high genetic risk group, intermediate (HR, 1.13; 95% CI, 0.98-1.31) and unfavorable lifestyles (HR, 1.39; 95% CI, 1.11-1.74) were associated with increased breast cancer risk. Results were adjusted for both age and family history.

In the end, “a healthier lifestyle ... appeared to be associated with a reduced level of risk for [breast cancer], even if the women were at higher genetic risk,” the researchers wrote. “Our findings suggest that women may be able to alter or reduce their risk of developing [breast cancer] by following healthier lifestyles,” regardless of genetic predisposition.
 

‘Surprising’ findings

It’s “surprising that these lifestyle changes lowered the risk of breast cancer,” said Charles Shapiro, MD, of the Icahn School of Medicine at Mount Sinai in New York, who was not involved in this study.

The study “requires replication,” he said. “On the other hand, these lifestyle changes promote overall health and certainly are associated with decreased risks of cardiovascular disease, the number one killer of women.”

“Patients always want to know what they can do above and beyond screening mammograms to reduce their risk of developing breast cancer,” said William Gradishar, MD, of Northwestern University in Chicago, who was not involved in the study.

“These data should empower patients that they can impact on their overall health and reduce the risk of developing breast cancer,” he said.

Among the study’s limitations, it’s unclear how the findings apply to nonwhite, nonpostmenopausal women, and the analysis did not differentiate between breast cancer subtypes.

In addition, although oral contraceptives have been linked to breast cancer in the past, there was no association in this study. Possible explanations could be that the investigators did not take into account duration of use, age of last use, and type or oral contraceptive used, they noted.

This research was funded by the National Institute for Health Research Manchester Biomedical Research Centre, the Alan Turing Institute, and a Cancer Research UK Integrated Cancer Epidemiology Programme grant. The investigators, Dr. Gradishar, and Dr. Shapiro have no relevant disclosures.

[email protected]

SOURCE: Al Ajmi K et al. JAMA Netw Open. 2020;3(4):e203760.

A “favorable” lifestyle was associated with a reduced risk of breast cancer even among women at high genetic risk for the disease in a study of more than 90,000 women, researchers reported.

The findings suggest that, regardless of genetic risk, women may be able to reduce their risk of developing breast cancer by getting adequate levels of exercise; maintaining a healthy weight; and limiting or eliminating use of alcohol, oral contraceptives, and hormone replacement therapy.

Kawthar Al Ajmi, MSc, of the University of Manchester (England), and colleagues published these findings in JAMA Network Open.

With almost a quarter of breast cancers thought to be preventable in the United Kingdom, “it is important to understand the contribution of modifiable risk factors ... and how they affect or add to the inherited genetic factors,” the researchers wrote.

To that end, the team reviewed 91,217 white, postmenopausal women in the United Kingdom Biobank, an ongoing longitudinal study of the contribution of genetic, environmental, and lifestyle risk factors in disease. There were 2,728 women who developed breast cancer at a median follow-up of 10 years.

The investigators used a polygenic risk score to categorize subjects as low, intermediate, or high genetic risk. The score was constructed using 305 single-nucleotide variants.

Within each risk group, the researchers divided women by the presence or absence of five lifestyle factors previously associated with a lower risk of breast cancer: healthy weight, regular exercise, no use of hormone replacement therapy beyond 5 years, no oral contraceptive use, and alcohol intake no more than twice a week.

Women with four or more of these factors were deemed to have a favorable lifestyle. Women with two or three factors had an intermediate lifestyle, and women with fewer factors had an unfavorable lifestyle.
 

Results

The data showed an association between breast cancer and a body mass index of 25 or higher (relative risk, 1.14), no regular physical activity (RR, 1.12), alcohol intake at least three times per week (RR, 1.11), and use of hormone replacement therapy for 5 or more years (RR, 1.23). History of oral contraceptive use was not associated with breast cancer risk (RR, 1.02), but this factor remained a part of the lifestyle classification.

In the low genetic risk group, an intermediate lifestyle (hazard ratio, 1.40; 95% CI, 1.09-1.80) and an unfavorable lifestyle (HR, 1.63; 95% CI, 1.14-2.34) were both associated with a higher risk of breast cancer, compared with a favorable lifestyle.

In the intermediate genetic risk group, intermediate (HR, 1.37; 95% CI, 1.12-1.68) and unfavorable lifestyles (HR 1.94; 95% CI, 1.46-2.58) were again associated with higher breast cancer risk, compared with a favorable lifestyle .

Even in the high genetic risk group, intermediate (HR, 1.13; 95% CI, 0.98-1.31) and unfavorable lifestyles (HR, 1.39; 95% CI, 1.11-1.74) were associated with increased breast cancer risk. Results were adjusted for both age and family history.

In the end, “a healthier lifestyle ... appeared to be associated with a reduced level of risk for [breast cancer], even if the women were at higher genetic risk,” the researchers wrote. “Our findings suggest that women may be able to alter or reduce their risk of developing [breast cancer] by following healthier lifestyles,” regardless of genetic predisposition.
 

‘Surprising’ findings

It’s “surprising that these lifestyle changes lowered the risk of breast cancer,” said Charles Shapiro, MD, of the Icahn School of Medicine at Mount Sinai in New York, who was not involved in this study.

The study “requires replication,” he said. “On the other hand, these lifestyle changes promote overall health and certainly are associated with decreased risks of cardiovascular disease, the number one killer of women.”

“Patients always want to know what they can do above and beyond screening mammograms to reduce their risk of developing breast cancer,” said William Gradishar, MD, of Northwestern University in Chicago, who was not involved in the study.

“These data should empower patients that they can impact on their overall health and reduce the risk of developing breast cancer,” he said.

Among the study’s limitations, it’s unclear how the findings apply to nonwhite, nonpostmenopausal women, and the analysis did not differentiate between breast cancer subtypes.

In addition, although oral contraceptives have been linked to breast cancer in the past, there was no association in this study. Possible explanations could be that the investigators did not take into account duration of use, age of last use, and type or oral contraceptive used, they noted.

This research was funded by the National Institute for Health Research Manchester Biomedical Research Centre, the Alan Turing Institute, and a Cancer Research UK Integrated Cancer Epidemiology Programme grant. The investigators, Dr. Gradishar, and Dr. Shapiro have no relevant disclosures.

[email protected]

SOURCE: Al Ajmi K et al. JAMA Netw Open. 2020;3(4):e203760.

A new review outlined a three-stage classification of the impact of COVID-19 on the central nervous system and recommended all hospitalized patients with the virus undergo MRI to flag potential neurologic damage and inform postdischarge monitoring.

In stage 1, viral damage is limited to epithelial cells of the nose and mouth, and in stage 2 blood clots that form in the lungs may travel to the brain, leading to stroke. In stage 3, the virus crosses the blood-brain barrier and invades the brain.

“Our major take-home points are that patients with COVID-19 symptoms, such as shortness of breath, headache, or dizziness, may have neurological symptoms that, at the time of hospitalization, might not be noticed or prioritized, or whose neurological symptoms may become apparent only after they leave the hospital,” lead author Majid Fotuhi, MD, PhD, medical director of NeuroGrow Brain Fitness Center in McLean, Va., said.

“Hospitalized patients with COVID-19 should have a neurological evaluation and ideally a brain MRI before leaving the hospital; and, if there are abnormalities, they should follow up with a neurologist in 3-4 months,” said Dr. Fotuhi, who is also affiliate staff at Johns Hopkins Medicine, Baltimore.

The review was published online June 8 in the Journal of Alzheimer’s Disease.
 

Wreaks CNS havoc

It has become “increasingly evident” that SARS-CoV-2 can cause neurologic manifestations, including anosmia, seizures, stroke, confusion, encephalopathy, and total paralysis, the authors wrote.

They noted that SARS-CoV-2 binds to ACE2, which facilitates the conversion of angiotensin II to angiotensin. After ACE2 has bound to respiratory epithelial cells and then to epithelial cells in blood vessels, SARS-CoV-2 triggers the formation of a “cytokine storm.”

These cytokines, in turn, increase vascular permeability, edema, and widespread inflammation, as well as triggering “hypercoagulation cascades,” which cause small and large blood clots that affect multiple organs.

If SARS-CoV-2 crosses the blood-brain barrier, directly entering the brain, it can contribute to demyelination or neurodegeneration.

“We very thoroughly reviewed the literature published between Jan. 1 and May 1, 2020, about neurological issues [in COVID-19] and what I found interesting is that so many neurological things can happen due to a virus which is so small,” said Dr. Fotuhi.

“This virus’ DNA has such limited information, and yet it can wreak havoc on our nervous system because it kicks off such a potent defense system in our body that damages our nervous system,” he said.
 

Three-stage classification

• Stage 1: The extent of SARS-CoV-2 binding to the ACE2 receptors is limited to the nasal and gustatory epithelial cells, with the cytokine storm remaining “low and controlled.” During this stage, patients may experience smell or taste impairments, but often recover without any interventions.
• Stage 2: A “robust immune response” is activated by the virus, leading to inflammation in the blood vessels, increased hypercoagulability factors, and the formation of blood clots in cerebral arteries and veins. The patient may therefore experience either large or small strokes. Additional stage 2 symptoms include fatigue, hemiplegia, sensory loss, , tetraplegia, , or ataxia.
• Stage 3: The cytokine storm in the blood vessels is so severe that it causes an “explosive inflammatory response” and penetrates the blood-brain barrier, leading to the entry of cytokines, blood components, and viral particles into the brain parenchyma and causing neuronal cell death and encephalitis. This stage can be characterized by seizures, confusion, , coma, loss of consciousness, or death.

“Patients in stage 3 are more likely to have long-term consequences, because there is evidence that the virus particles have actually penetrated the brain, and we know that SARS-CoV-2 can remain dormant in neurons for many years,” said Dr. Fotuhi.

“Studies of coronaviruses have shown a link between the viruses and the risk of multiple sclerosis or Parkinson’s disease even decades later,” he added.

“Based on several reports in recent months, between 36% to 55% of patients with COVID-19 that are hospitalized have some neurological symptoms, but if you don’t look for them, you won’t see them,” Dr. Fotuhi noted.

As a result, patients should be monitored over time after discharge, as they may develop cognitive dysfunction down the road.

Additionally, “it is imperative for patients [hospitalized with COVID-19] to get a baseline MRI before leaving the hospital so that we have a starting point for future evaluation and treatment,” said Dr. Fotuhi.

“The good news is that neurological manifestations of COVID-19 are treatable,” and “can improve with intensive training,” including lifestyle changes – such as a heart-healthy diet, regular physical activity, stress reduction, improved sleep, biofeedback, and brain rehabilitation, Dr. Fotuhi added.
 

Routine MRI not necessary

Kenneth Tyler, MD, chair of the department of neurology at the University of Colorado at Denver, Aurora, disagreed that all hospitalized patients with COVID-19 should routinely receive an MRI.

“Whenever you are using a piece of equipment on patients who are COVID-19 infected, you risk introducing the infection to uninfected patients,” he said. Instead, “the indication is in patients who develop unexplained neurological manifestations – altered mental status or focal seizures, for example – because in those cases, you do need to understand whether there are underlying structural abnormalities,” said Dr. Tyler, who was not involved in the review.

Also commenting on the review, Vanja Douglas, MD, associate professor of clinical neurology, University of California, San Francisco, described the review as “thorough” and suggested it may “help us understand how to design observational studies to test whether the associations are due to severe respiratory illness or are specific to SARS-CoV-2 infection.”

Dr. Douglas, who was not involved in the review, added that it is “helpful in giving us a sense of which neurologic syndromes have been observed in COVID-19 patients, and therefore which patients neurologists may want to screen more carefully during the pandemic.”

The study had no specific funding. Dr. Fotuhi disclosed no relevant financial relationships. One coauthor reported receiving consulting fees as a member of the scientific advisory board for Brainreader and reports royalties for expert witness consultation in conjunction with Neurevolution. Dr. Tyler and Dr. Douglas disclosed no relevant financial relationships.

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

A new review outlined a three-stage classification of the impact of COVID-19 on the central nervous system and recommended all hospitalized patients with the virus undergo MRI to flag potential neurologic damage and inform postdischarge monitoring.

In stage 1, viral damage is limited to epithelial cells of the nose and mouth, and in stage 2 blood clots that form in the lungs may travel to the brain, leading to stroke. In stage 3, the virus crosses the blood-brain barrier and invades the brain.

“Our major take-home points are that patients with COVID-19 symptoms, such as shortness of breath, headache, or dizziness, may have neurological symptoms that, at the time of hospitalization, might not be noticed or prioritized, or whose neurological symptoms may become apparent only after they leave the hospital,” lead author Majid Fotuhi, MD, PhD, medical director of NeuroGrow Brain Fitness Center in McLean, Va., said.

“Hospitalized patients with COVID-19 should have a neurological evaluation and ideally a brain MRI before leaving the hospital; and, if there are abnormalities, they should follow up with a neurologist in 3-4 months,” said Dr. Fotuhi, who is also affiliate staff at Johns Hopkins Medicine, Baltimore.

The review was published online June 8 in the Journal of Alzheimer’s Disease.
 

Wreaks CNS havoc

It has become “increasingly evident” that SARS-CoV-2 can cause neurologic manifestations, including anosmia, seizures, stroke, confusion, encephalopathy, and total paralysis, the authors wrote.

They noted that SARS-CoV-2 binds to ACE2, which facilitates the conversion of angiotensin II to angiotensin. After ACE2 has bound to respiratory epithelial cells and then to epithelial cells in blood vessels, SARS-CoV-2 triggers the formation of a “cytokine storm.”

These cytokines, in turn, increase vascular permeability, edema, and widespread inflammation, as well as triggering “hypercoagulation cascades,” which cause small and large blood clots that affect multiple organs.

If SARS-CoV-2 crosses the blood-brain barrier, directly entering the brain, it can contribute to demyelination or neurodegeneration.

“We very thoroughly reviewed the literature published between Jan. 1 and May 1, 2020, about neurological issues [in COVID-19] and what I found interesting is that so many neurological things can happen due to a virus which is so small,” said Dr. Fotuhi.

“This virus’ DNA has such limited information, and yet it can wreak havoc on our nervous system because it kicks off such a potent defense system in our body that damages our nervous system,” he said.
 

Three-stage classification

• Stage 1: The extent of SARS-CoV-2 binding to the ACE2 receptors is limited to the nasal and gustatory epithelial cells, with the cytokine storm remaining “low and controlled.” During this stage, patients may experience smell or taste impairments, but often recover without any interventions.
• Stage 2: A “robust immune response” is activated by the virus, leading to inflammation in the blood vessels, increased hypercoagulability factors, and the formation of blood clots in cerebral arteries and veins. The patient may therefore experience either large or small strokes. Additional stage 2 symptoms include fatigue, hemiplegia, sensory loss, , tetraplegia, , or ataxia.
• Stage 3: The cytokine storm in the blood vessels is so severe that it causes an “explosive inflammatory response” and penetrates the blood-brain barrier, leading to the entry of cytokines, blood components, and viral particles into the brain parenchyma and causing neuronal cell death and encephalitis. This stage can be characterized by seizures, confusion, , coma, loss of consciousness, or death.

“Patients in stage 3 are more likely to have long-term consequences, because there is evidence that the virus particles have actually penetrated the brain, and we know that SARS-CoV-2 can remain dormant in neurons for many years,” said Dr. Fotuhi.

“Studies of coronaviruses have shown a link between the viruses and the risk of multiple sclerosis or Parkinson’s disease even decades later,” he added.

“Based on several reports in recent months, between 36% to 55% of patients with COVID-19 that are hospitalized have some neurological symptoms, but if you don’t look for them, you won’t see them,” Dr. Fotuhi noted.

As a result, patients should be monitored over time after discharge, as they may develop cognitive dysfunction down the road.

Additionally, “it is imperative for patients [hospitalized with COVID-19] to get a baseline MRI before leaving the hospital so that we have a starting point for future evaluation and treatment,” said Dr. Fotuhi.

“The good news is that neurological manifestations of COVID-19 are treatable,” and “can improve with intensive training,” including lifestyle changes – such as a heart-healthy diet, regular physical activity, stress reduction, improved sleep, biofeedback, and brain rehabilitation, Dr. Fotuhi added.
 

Routine MRI not necessary

Kenneth Tyler, MD, chair of the department of neurology at the University of Colorado at Denver, Aurora, disagreed that all hospitalized patients with COVID-19 should routinely receive an MRI.

“Whenever you are using a piece of equipment on patients who are COVID-19 infected, you risk introducing the infection to uninfected patients,” he said. Instead, “the indication is in patients who develop unexplained neurological manifestations – altered mental status or focal seizures, for example – because in those cases, you do need to understand whether there are underlying structural abnormalities,” said Dr. Tyler, who was not involved in the review.

Also commenting on the review, Vanja Douglas, MD, associate professor of clinical neurology, University of California, San Francisco, described the review as “thorough” and suggested it may “help us understand how to design observational studies to test whether the associations are due to severe respiratory illness or are specific to SARS-CoV-2 infection.”

Dr. Douglas, who was not involved in the review, added that it is “helpful in giving us a sense of which neurologic syndromes have been observed in COVID-19 patients, and therefore which patients neurologists may want to screen more carefully during the pandemic.”

The study had no specific funding. Dr. Fotuhi disclosed no relevant financial relationships. One coauthor reported receiving consulting fees as a member of the scientific advisory board for Brainreader and reports royalties for expert witness consultation in conjunction with Neurevolution. Dr. Tyler and Dr. Douglas disclosed no relevant financial relationships.

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

A new review outlined a three-stage classification of the impact of COVID-19 on the central nervous system and recommended all hospitalized patients with the virus undergo MRI to flag potential neurologic damage and inform postdischarge monitoring.

In stage 1, viral damage is limited to epithelial cells of the nose and mouth, and in stage 2 blood clots that form in the lungs may travel to the brain, leading to stroke. In stage 3, the virus crosses the blood-brain barrier and invades the brain.

“Our major take-home points are that patients with COVID-19 symptoms, such as shortness of breath, headache, or dizziness, may have neurological symptoms that, at the time of hospitalization, might not be noticed or prioritized, or whose neurological symptoms may become apparent only after they leave the hospital,” lead author Majid Fotuhi, MD, PhD, medical director of NeuroGrow Brain Fitness Center in McLean, Va., said.

“Hospitalized patients with COVID-19 should have a neurological evaluation and ideally a brain MRI before leaving the hospital; and, if there are abnormalities, they should follow up with a neurologist in 3-4 months,” said Dr. Fotuhi, who is also affiliate staff at Johns Hopkins Medicine, Baltimore.

The review was published online June 8 in the Journal of Alzheimer’s Disease.
 

Wreaks CNS havoc

It has become “increasingly evident” that SARS-CoV-2 can cause neurologic manifestations, including anosmia, seizures, stroke, confusion, encephalopathy, and total paralysis, the authors wrote.

They noted that SARS-CoV-2 binds to ACE2, which facilitates the conversion of angiotensin II to angiotensin. After ACE2 has bound to respiratory epithelial cells and then to epithelial cells in blood vessels, SARS-CoV-2 triggers the formation of a “cytokine storm.”

These cytokines, in turn, increase vascular permeability, edema, and widespread inflammation, as well as triggering “hypercoagulation cascades,” which cause small and large blood clots that affect multiple organs.

If SARS-CoV-2 crosses the blood-brain barrier, directly entering the brain, it can contribute to demyelination or neurodegeneration.

“We very thoroughly reviewed the literature published between Jan. 1 and May 1, 2020, about neurological issues [in COVID-19] and what I found interesting is that so many neurological things can happen due to a virus which is so small,” said Dr. Fotuhi.

“This virus’ DNA has such limited information, and yet it can wreak havoc on our nervous system because it kicks off such a potent defense system in our body that damages our nervous system,” he said.
 

Three-stage classification

• Stage 1: The extent of SARS-CoV-2 binding to the ACE2 receptors is limited to the nasal and gustatory epithelial cells, with the cytokine storm remaining “low and controlled.” During this stage, patients may experience smell or taste impairments, but often recover without any interventions.
• Stage 2: A “robust immune response” is activated by the virus, leading to inflammation in the blood vessels, increased hypercoagulability factors, and the formation of blood clots in cerebral arteries and veins. The patient may therefore experience either large or small strokes. Additional stage 2 symptoms include fatigue, hemiplegia, sensory loss, , tetraplegia, , or ataxia.
• Stage 3: The cytokine storm in the blood vessels is so severe that it causes an “explosive inflammatory response” and penetrates the blood-brain barrier, leading to the entry of cytokines, blood components, and viral particles into the brain parenchyma and causing neuronal cell death and encephalitis. This stage can be characterized by seizures, confusion, , coma, loss of consciousness, or death.

“Patients in stage 3 are more likely to have long-term consequences, because there is evidence that the virus particles have actually penetrated the brain, and we know that SARS-CoV-2 can remain dormant in neurons for many years,” said Dr. Fotuhi.

“Studies of coronaviruses have shown a link between the viruses and the risk of multiple sclerosis or Parkinson’s disease even decades later,” he added.

“Based on several reports in recent months, between 36% to 55% of patients with COVID-19 that are hospitalized have some neurological symptoms, but if you don’t look for them, you won’t see them,” Dr. Fotuhi noted.

As a result, patients should be monitored over time after discharge, as they may develop cognitive dysfunction down the road.

Additionally, “it is imperative for patients [hospitalized with COVID-19] to get a baseline MRI before leaving the hospital so that we have a starting point for future evaluation and treatment,” said Dr. Fotuhi.

“The good news is that neurological manifestations of COVID-19 are treatable,” and “can improve with intensive training,” including lifestyle changes – such as a heart-healthy diet, regular physical activity, stress reduction, improved sleep, biofeedback, and brain rehabilitation, Dr. Fotuhi added.
 

Routine MRI not necessary

Kenneth Tyler, MD, chair of the department of neurology at the University of Colorado at Denver, Aurora, disagreed that all hospitalized patients with COVID-19 should routinely receive an MRI.

“Whenever you are using a piece of equipment on patients who are COVID-19 infected, you risk introducing the infection to uninfected patients,” he said. Instead, “the indication is in patients who develop unexplained neurological manifestations – altered mental status or focal seizures, for example – because in those cases, you do need to understand whether there are underlying structural abnormalities,” said Dr. Tyler, who was not involved in the review.

Also commenting on the review, Vanja Douglas, MD, associate professor of clinical neurology, University of California, San Francisco, described the review as “thorough” and suggested it may “help us understand how to design observational studies to test whether the associations are due to severe respiratory illness or are specific to SARS-CoV-2 infection.”

Dr. Douglas, who was not involved in the review, added that it is “helpful in giving us a sense of which neurologic syndromes have been observed in COVID-19 patients, and therefore which patients neurologists may want to screen more carefully during the pandemic.”

The study had no specific funding. Dr. Fotuhi disclosed no relevant financial relationships. One coauthor reported receiving consulting fees as a member of the scientific advisory board for Brainreader and reports royalties for expert witness consultation in conjunction with Neurevolution. Dr. Tyler and Dr. Douglas disclosed no relevant financial relationships.

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

The Food and Drug Administration recently announced two new types of cancer that can be treated by the anti–PD-1 antibody pembrolizumab.

The new indications expand the use of pembrolizumab (Keytruda) to include treatment of patients with unresectable or metastatic tumor mutational burden–high (TMB-H) solid tumors as well as patients with cutaneous squamous cell carcinoma (cSCC). The FDA announced the new indications just 8 days apart, on June 16 and June 24.

In addition, on June 29, the FDA approved a third new indication for pembrolizumab, this time as first-line treatment for patients with unresectable or metastatic microsatellite instability–high or mismatch repair–deficient colorectal cancer.



The new approvals add to a wide range of oncology indications for which pembrolizumab can be used.

Accelerated approval to treat solid tumors

The FDA granted accelerated approval for pembrolizumab to treat children and adults with unresectable or metastatic TMB-H solid tumors that progressed after previous treatment or in instances where there are no satisfactory alternative treatment options.

The tumor mutational burden must be confirmed by an FDA-approved test. To that end, the FDA approved the FoundationOneCDx assay, which is designed to help physicians determine which patients meet the threshold for TMB-H malignancies (10 or more mutations per megabase).

The efficacy of pembrolizumab in TMB-H solid tumors was investigated in 10 cohorts from the multicenter, open-label KEYNOTE-158 trial. Participants received 200 mg of pembrolizumab intravenously every 3 weeks until their disease progressed or they experienced unacceptable toxicity.

Within this population, 102 patients had tumors that met the TMB-H definition. In this group, the overall response rate was 29%, including a 25% partial response rate and a 4% complete response rate.

The median duration of response was not reached, but 57% of participants experienced a response lasting 12 months or longer, and 50% had a response lasting 24 months or longer.

The most common adverse events associated with pembrolizumab in this trial were fatigue, musculoskeletal pain, decreased appetite, pruritus, diarrhea, nausea, rash, pyrexia, cough, dyspnea, constipation, pain, and abdominal pain. Pembrolizumab is associated with immune-mediated side effects, including pneumonitis, colitis, hepatitis, endocrinopathies, nephritis, and skin adverse reactions, the FDA noted.

Safety and efficacy of pembrolizumab in pediatric patients with TMB-H central nervous system cancers have not been established.
 

New option for recurrent or metastatic cSCC

Physicians treating patients with cSCC that is not curable by surgery or radiation now have pembrolizumab to consider as another treatment option.

The cSCC approval is based on results of the multicenter, open-label KEYNOTE-629 trial. The dosage regimen was 200 mg of pembrolizumab intravenously every 3 weeks until cancer progressed, unacceptable toxicity arose, or 24 months of treatment were completed.

The objective response rate was 34%, and the median duration of response was not reached.

Adverse events were similar to those occurring in patients who received pembrolizumab as a single agent in other clinical trials, the FDA noted.

The Food and Drug Administration recently announced two new types of cancer that can be treated by the anti–PD-1 antibody pembrolizumab.

The new indications expand the use of pembrolizumab (Keytruda) to include treatment of patients with unresectable or metastatic tumor mutational burden–high (TMB-H) solid tumors as well as patients with cutaneous squamous cell carcinoma (cSCC). The FDA announced the new indications just 8 days apart, on June 16 and June 24.

In addition, on June 29, the FDA approved a third new indication for pembrolizumab, this time as first-line treatment for patients with unresectable or metastatic microsatellite instability–high or mismatch repair–deficient colorectal cancer.



The new approvals add to a wide range of oncology indications for which pembrolizumab can be used.

Accelerated approval to treat solid tumors

The FDA granted accelerated approval for pembrolizumab to treat children and adults with unresectable or metastatic TMB-H solid tumors that progressed after previous treatment or in instances where there are no satisfactory alternative treatment options.

The tumor mutational burden must be confirmed by an FDA-approved test. To that end, the FDA approved the FoundationOneCDx assay, which is designed to help physicians determine which patients meet the threshold for TMB-H malignancies (10 or more mutations per megabase).

The efficacy of pembrolizumab in TMB-H solid tumors was investigated in 10 cohorts from the multicenter, open-label KEYNOTE-158 trial. Participants received 200 mg of pembrolizumab intravenously every 3 weeks until their disease progressed or they experienced unacceptable toxicity.

Within this population, 102 patients had tumors that met the TMB-H definition. In this group, the overall response rate was 29%, including a 25% partial response rate and a 4% complete response rate.

The median duration of response was not reached, but 57% of participants experienced a response lasting 12 months or longer, and 50% had a response lasting 24 months or longer.

The most common adverse events associated with pembrolizumab in this trial were fatigue, musculoskeletal pain, decreased appetite, pruritus, diarrhea, nausea, rash, pyrexia, cough, dyspnea, constipation, pain, and abdominal pain. Pembrolizumab is associated with immune-mediated side effects, including pneumonitis, colitis, hepatitis, endocrinopathies, nephritis, and skin adverse reactions, the FDA noted.

Safety and efficacy of pembrolizumab in pediatric patients with TMB-H central nervous system cancers have not been established.
 

New option for recurrent or metastatic cSCC

Physicians treating patients with cSCC that is not curable by surgery or radiation now have pembrolizumab to consider as another treatment option.

The cSCC approval is based on results of the multicenter, open-label KEYNOTE-629 trial. The dosage regimen was 200 mg of pembrolizumab intravenously every 3 weeks until cancer progressed, unacceptable toxicity arose, or 24 months of treatment were completed.

The objective response rate was 34%, and the median duration of response was not reached.

Adverse events were similar to those occurring in patients who received pembrolizumab as a single agent in other clinical trials, the FDA noted.

The Food and Drug Administration recently announced two new types of cancer that can be treated by the anti–PD-1 antibody pembrolizumab.

The new indications expand the use of pembrolizumab (Keytruda) to include treatment of patients with unresectable or metastatic tumor mutational burden–high (TMB-H) solid tumors as well as patients with cutaneous squamous cell carcinoma (cSCC). The FDA announced the new indications just 8 days apart, on June 16 and June 24.

In addition, on June 29, the FDA approved a third new indication for pembrolizumab, this time as first-line treatment for patients with unresectable or metastatic microsatellite instability–high or mismatch repair–deficient colorectal cancer.



The new approvals add to a wide range of oncology indications for which pembrolizumab can be used.

Accelerated approval to treat solid tumors

The FDA granted accelerated approval for pembrolizumab to treat children and adults with unresectable or metastatic TMB-H solid tumors that progressed after previous treatment or in instances where there are no satisfactory alternative treatment options.

The tumor mutational burden must be confirmed by an FDA-approved test. To that end, the FDA approved the FoundationOneCDx assay, which is designed to help physicians determine which patients meet the threshold for TMB-H malignancies (10 or more mutations per megabase).

The efficacy of pembrolizumab in TMB-H solid tumors was investigated in 10 cohorts from the multicenter, open-label KEYNOTE-158 trial. Participants received 200 mg of pembrolizumab intravenously every 3 weeks until their disease progressed or they experienced unacceptable toxicity.

Within this population, 102 patients had tumors that met the TMB-H definition. In this group, the overall response rate was 29%, including a 25% partial response rate and a 4% complete response rate.

The median duration of response was not reached, but 57% of participants experienced a response lasting 12 months or longer, and 50% had a response lasting 24 months or longer.

The most common adverse events associated with pembrolizumab in this trial were fatigue, musculoskeletal pain, decreased appetite, pruritus, diarrhea, nausea, rash, pyrexia, cough, dyspnea, constipation, pain, and abdominal pain. Pembrolizumab is associated with immune-mediated side effects, including pneumonitis, colitis, hepatitis, endocrinopathies, nephritis, and skin adverse reactions, the FDA noted.

Safety and efficacy of pembrolizumab in pediatric patients with TMB-H central nervous system cancers have not been established.
 

New option for recurrent or metastatic cSCC

Physicians treating patients with cSCC that is not curable by surgery or radiation now have pembrolizumab to consider as another treatment option.

The cSCC approval is based on results of the multicenter, open-label KEYNOTE-629 trial. The dosage regimen was 200 mg of pembrolizumab intravenously every 3 weeks until cancer progressed, unacceptable toxicity arose, or 24 months of treatment were completed.

The objective response rate was 34%, and the median duration of response was not reached.

Adverse events were similar to those occurring in patients who received pembrolizumab as a single agent in other clinical trials, the FDA noted.

The oral selective estrogen receptor degrader (SERD) LSZ102 plus either ribociclib or alpelisib shows manageable safety and encouraging clinical activity in heavily pretreated estrogen receptor (ER)–positive breast cancer patients who progressed after prior endocrine therapy, according to interim results of an open-label phase 1/1b study.

The effects seen in the study, which is the first to report on an oral SERD in combination with both CDK4/6 and PI3Ka inhibitors, occurred regardless of ESR1 and PIK3CA mutations, said Komal Jhaveri, MD, of Memorial Sloan Kettering Cancer Center in New York.

Dr. Jhaveri reported the results at the European Society of Medical Oncology: Breast Cancer virtual meeting.

The overall response rate (ORR) among 78 patients enrolled in an LSZ102 monotherapy arm (arm A) was 1.3%, and the progression-free survival (PFS) was 1.8 months. The clinical benefit rate (CBR) was 9.1%.

Among 76 patients enrolled in an LSZ102+ribociclib arm (arm B), the ORR was 15.8%, the PFS was 6.2 months, and the CBR was 35.5%.

Among the 39 patients enrolled in an LSZ102+alpelisib arm (arm C), the ORR was 5.4%, the PFS was 3.5 months, and the CBR was 18.9%.

After the data cutoff, one additional partial response (PR) was reported in arm C, Dr. Jhaveri said, noting that two of three confirmed responses were in known PIKC3A-mutant patients.

Study participants were aged 18 years and older with a confirmed diagnosis of ER-positive breast cancer and good performance status, as well as evidence of progression after endocrine therapy for metastatic disease or evidence of progression while on therapy or within 12 months from the end of adjuvant therapy.

“For all arms, prior fulvestrant, CDK46 inhibitor, or chemotherapy were allowed. For arm C, patients with or without PIK3C were eligible, and no prior treatment with PIK3, mTOR, or AKT inhibitors was allowed,” Dr. Jhaveri said.

Dosing in the LSZ102 monotherapy arm ranged from 200 to 900 mg. Arm B patients received LSZ102 at doses of 200-600 mg and ribociclib at doses of 200-600 mg. Both continuous ribociclib and 3 weeks on/1 week off dosing were evaluated. Arm C patients received LSZ102 at doses of 300-450 mg and alpelisib at 200-300 mg.

The recommended expansion doses were 450 mg daily of LSZ102 for arm A and 450 mg LSZ102 with 400 mg of daily ribociclib for arm B. For arm C, they were 300 mg LSZ102 with 250 mg of alpelisib daily.

Of note, two of three patients with a PR in arm C had received 300 mg LSZ102 and 300 mg alpelisib, Dr. Jhaveri said.

Arm A and arm B results were presented at the San Antonio Breast Cancer Symposium in 2018 and 2019, respectively. The current report updates those findings and presents arm C data for the first time, Dr. Jhaveri said.

LSZ102 was relatively well-tolerated as a single agent and in combination with ribociclib and alpelisib, according to Dr. Jhaveri. The most frequent adverse events were gastrointestinal toxicities, including nausea, vomiting, diarrhea, and decreased appetite, which occurred across all arms.

Neutropenia and aspartate aminotransferase abnormalities, including grade 3 cases, were reported in arm B and were most likely driven by the ribociclib, Dr. Jhaveri said. Grade 3 hypoglycemia and skin rash commonly occurred in arm C, most likely driven by the alpelisib.

Five dose-limiting toxicities occurred in four patients in arm A, three occurred in two patients in arm B, and seven occurred in seven patients in arm C.

Paired biopsies collected at the time of screening and at day 15 of cycle 1 showed consistent down-regulation of ER protein levels across arms.

“No substantial dose-dependent down-regulation of the ER was observed with increasing doses of LSZ,” Dr. Jhaveri said.

Circulating tumor DNA (ctDNA) analysis showed that the dominant mutations across the arms were ESR1, PIK3CA, and TP53. These were not shown to correlate with response and were not enriched upon progression in patients with matched baseline and end-of-treatment samples, she noted.

An exploratory analysis, conducted in “a preliminary attempt to correlate clinical activity with specific mutations,” showed that, in arms B and C, respectively, ORR, CBR, and PFS weren’t correlated with the presence or absence of ESR1 and PIK3CA mutations, respectively, or the absence of detectable ctDNA from baseline samples, Dr. Jhaveri said.

“While numerically higher responses and better CBR were seen in patients with undetectable ctDNA at baseline, no statistically significant difference in any of these outcomes was observed in arms B and C,” she said.

In arm C, the numbers were small at the time of data cutoff, but incoming data suggest relatively enhanced activity of the LSZ102 plus alpelisib combination in PIKC3A-mutant patients, she noted.

“We know that inhibiting ER signaling is the mainstay of treatment for ER-positive breast cancer,” Dr. Jhaveri explained, adding that aromatase inhibitors, estrogen receptor modulators, and SERDs are important classes of antiestrogenic agents, but fulvestrant is the only approved SERD. These are effective, but many patients develop resistance, she said.

“Proposed mechanisms for endocrine resistance include activation of the cell-cycle and cell-survival signaling pathways, or of the PI3K-AKT-mTOR pathway,” Dr. Jhaveri said. “To that end, ribociclib, a CDK46 inhibitor plus fulvestrant improved survival compared to fulvestrant alone in patients with ER-positive metastatic breast cancer.”

More recently, the PI3K inhibitor alpelisib plus fulvestrant also nearly doubled PFS vs. fulvestrant alone in PIKC3A-mutant, ER-positive metastatic breast cancer, which led to the approval of the combination in the United States.

Another mechanism of endocrine resistance includes acquisition of activating mutations in the estrogen receptor gene itself that allow tumors to survive and proliferate without depending on estrogen.

EGFR mutations appear to predict resistance to aromatase inhibitor therapies, but not outcomes in patients treated with fulvestrant. However, fulvestrant, which is delivered by intramuscular injection, has its own limitations, Dr. Jhaveri said.

“LSZ102 is a novel SERD that could achieve higher exposure than fulvestrant, leading to enhanced efficacy,” she said, noting that it was shown in preclinical models to have activity and to be synergistic in combination with ribociclib and alpelisib, forming the basis for the current study.

Invited discussant, Saverio Cinieri, MD, of Ospedale Antonio Perrino, Brindisi, Italy, said the study “elegantly demonstrated that estrogen receptor protein is down-regulated by LSZ102; [that] the genomic landscape of heavily pretreated patients is dominated by mutations in ESR1, PIK3CA, and TP53; [that] common mutations do not correlate with response and are not enriched on progression; [and that] ctDNA analysis at baseline shows similar outcomes with LSZ plus ribociclib or alpelisib, regardless of mutational status.”

LSZ102 is one of four new-generation SERDs in early-phase studies, he said, concluding that “in the COVID-19 era, the use of oral therapies will be even more necessary to limit access to the hospital.”

Dr. Cinieri also said that overcoming the limitations “of a molecule like the intramuscularly administered fulvestrant goes in this direction,” and that “the clinical efficacy and the biomolecular profile of LSZ102 seems to be able to meet these real needs.”

This study was funded by Novartis. Dr. Jhaveri reported advisory and consultancy roles and/or research grants or other funding to her institution from Novartis, ADC Therapeutics, Pfizer, and numerous other pharmaceutical and biotechnology companies. Dr. Cinieri reported relationships with Lily Oncology, Pfizer, Roche, AstraZeneca, Amgen, Novartis, including honoraria, grant and research support to his institution, advisory board participation, and scientific meeting support.

[email protected]

SOURCE: Jhaveri K et al. ESMO Breast Cancer, Abstract LBA1.

The oral selective estrogen receptor degrader (SERD) LSZ102 plus either ribociclib or alpelisib shows manageable safety and encouraging clinical activity in heavily pretreated estrogen receptor (ER)–positive breast cancer patients who progressed after prior endocrine therapy, according to interim results of an open-label phase 1/1b study.

The effects seen in the study, which is the first to report on an oral SERD in combination with both CDK4/6 and PI3Ka inhibitors, occurred regardless of ESR1 and PIK3CA mutations, said Komal Jhaveri, MD, of Memorial Sloan Kettering Cancer Center in New York.

Dr. Jhaveri reported the results at the European Society of Medical Oncology: Breast Cancer virtual meeting.

The overall response rate (ORR) among 78 patients enrolled in an LSZ102 monotherapy arm (arm A) was 1.3%, and the progression-free survival (PFS) was 1.8 months. The clinical benefit rate (CBR) was 9.1%.

Among 76 patients enrolled in an LSZ102+ribociclib arm (arm B), the ORR was 15.8%, the PFS was 6.2 months, and the CBR was 35.5%.

Among the 39 patients enrolled in an LSZ102+alpelisib arm (arm C), the ORR was 5.4%, the PFS was 3.5 months, and the CBR was 18.9%.

After the data cutoff, one additional partial response (PR) was reported in arm C, Dr. Jhaveri said, noting that two of three confirmed responses were in known PIKC3A-mutant patients.

Study participants were aged 18 years and older with a confirmed diagnosis of ER-positive breast cancer and good performance status, as well as evidence of progression after endocrine therapy for metastatic disease or evidence of progression while on therapy or within 12 months from the end of adjuvant therapy.

“For all arms, prior fulvestrant, CDK46 inhibitor, or chemotherapy were allowed. For arm C, patients with or without PIK3C were eligible, and no prior treatment with PIK3, mTOR, or AKT inhibitors was allowed,” Dr. Jhaveri said.

Dosing in the LSZ102 monotherapy arm ranged from 200 to 900 mg. Arm B patients received LSZ102 at doses of 200-600 mg and ribociclib at doses of 200-600 mg. Both continuous ribociclib and 3 weeks on/1 week off dosing were evaluated. Arm C patients received LSZ102 at doses of 300-450 mg and alpelisib at 200-300 mg.

The recommended expansion doses were 450 mg daily of LSZ102 for arm A and 450 mg LSZ102 with 400 mg of daily ribociclib for arm B. For arm C, they were 300 mg LSZ102 with 250 mg of alpelisib daily.

Of note, two of three patients with a PR in arm C had received 300 mg LSZ102 and 300 mg alpelisib, Dr. Jhaveri said.

Arm A and arm B results were presented at the San Antonio Breast Cancer Symposium in 2018 and 2019, respectively. The current report updates those findings and presents arm C data for the first time, Dr. Jhaveri said.

LSZ102 was relatively well-tolerated as a single agent and in combination with ribociclib and alpelisib, according to Dr. Jhaveri. The most frequent adverse events were gastrointestinal toxicities, including nausea, vomiting, diarrhea, and decreased appetite, which occurred across all arms.

Neutropenia and aspartate aminotransferase abnormalities, including grade 3 cases, were reported in arm B and were most likely driven by the ribociclib, Dr. Jhaveri said. Grade 3 hypoglycemia and skin rash commonly occurred in arm C, most likely driven by the alpelisib.

Five dose-limiting toxicities occurred in four patients in arm A, three occurred in two patients in arm B, and seven occurred in seven patients in arm C.

Paired biopsies collected at the time of screening and at day 15 of cycle 1 showed consistent down-regulation of ER protein levels across arms.

“No substantial dose-dependent down-regulation of the ER was observed with increasing doses of LSZ,” Dr. Jhaveri said.

Circulating tumor DNA (ctDNA) analysis showed that the dominant mutations across the arms were ESR1, PIK3CA, and TP53. These were not shown to correlate with response and were not enriched upon progression in patients with matched baseline and end-of-treatment samples, she noted.

An exploratory analysis, conducted in “a preliminary attempt to correlate clinical activity with specific mutations,” showed that, in arms B and C, respectively, ORR, CBR, and PFS weren’t correlated with the presence or absence of ESR1 and PIK3CA mutations, respectively, or the absence of detectable ctDNA from baseline samples, Dr. Jhaveri said.

“While numerically higher responses and better CBR were seen in patients with undetectable ctDNA at baseline, no statistically significant difference in any of these outcomes was observed in arms B and C,” she said.

In arm C, the numbers were small at the time of data cutoff, but incoming data suggest relatively enhanced activity of the LSZ102 plus alpelisib combination in PIKC3A-mutant patients, she noted.

“We know that inhibiting ER signaling is the mainstay of treatment for ER-positive breast cancer,” Dr. Jhaveri explained, adding that aromatase inhibitors, estrogen receptor modulators, and SERDs are important classes of antiestrogenic agents, but fulvestrant is the only approved SERD. These are effective, but many patients develop resistance, she said.

“Proposed mechanisms for endocrine resistance include activation of the cell-cycle and cell-survival signaling pathways, or of the PI3K-AKT-mTOR pathway,” Dr. Jhaveri said. “To that end, ribociclib, a CDK46 inhibitor plus fulvestrant improved survival compared to fulvestrant alone in patients with ER-positive metastatic breast cancer.”

More recently, the PI3K inhibitor alpelisib plus fulvestrant also nearly doubled PFS vs. fulvestrant alone in PIKC3A-mutant, ER-positive metastatic breast cancer, which led to the approval of the combination in the United States.

Another mechanism of endocrine resistance includes acquisition of activating mutations in the estrogen receptor gene itself that allow tumors to survive and proliferate without depending on estrogen.

EGFR mutations appear to predict resistance to aromatase inhibitor therapies, but not outcomes in patients treated with fulvestrant. However, fulvestrant, which is delivered by intramuscular injection, has its own limitations, Dr. Jhaveri said.

“LSZ102 is a novel SERD that could achieve higher exposure than fulvestrant, leading to enhanced efficacy,” she said, noting that it was shown in preclinical models to have activity and to be synergistic in combination with ribociclib and alpelisib, forming the basis for the current study.

Invited discussant, Saverio Cinieri, MD, of Ospedale Antonio Perrino, Brindisi, Italy, said the study “elegantly demonstrated that estrogen receptor protein is down-regulated by LSZ102; [that] the genomic landscape of heavily pretreated patients is dominated by mutations in ESR1, PIK3CA, and TP53; [that] common mutations do not correlate with response and are not enriched on progression; [and that] ctDNA analysis at baseline shows similar outcomes with LSZ plus ribociclib or alpelisib, regardless of mutational status.”

LSZ102 is one of four new-generation SERDs in early-phase studies, he said, concluding that “in the COVID-19 era, the use of oral therapies will be even more necessary to limit access to the hospital.”

Dr. Cinieri also said that overcoming the limitations “of a molecule like the intramuscularly administered fulvestrant goes in this direction,” and that “the clinical efficacy and the biomolecular profile of LSZ102 seems to be able to meet these real needs.”

This study was funded by Novartis. Dr. Jhaveri reported advisory and consultancy roles and/or research grants or other funding to her institution from Novartis, ADC Therapeutics, Pfizer, and numerous other pharmaceutical and biotechnology companies. Dr. Cinieri reported relationships with Lily Oncology, Pfizer, Roche, AstraZeneca, Amgen, Novartis, including honoraria, grant and research support to his institution, advisory board participation, and scientific meeting support.

[email protected]

SOURCE: Jhaveri K et al. ESMO Breast Cancer, Abstract LBA1.

The oral selective estrogen receptor degrader (SERD) LSZ102 plus either ribociclib or alpelisib shows manageable safety and encouraging clinical activity in heavily pretreated estrogen receptor (ER)–positive breast cancer patients who progressed after prior endocrine therapy, according to interim results of an open-label phase 1/1b study.

The effects seen in the study, which is the first to report on an oral SERD in combination with both CDK4/6 and PI3Ka inhibitors, occurred regardless of ESR1 and PIK3CA mutations, said Komal Jhaveri, MD, of Memorial Sloan Kettering Cancer Center in New York.

Dr. Jhaveri reported the results at the European Society of Medical Oncology: Breast Cancer virtual meeting.

The overall response rate (ORR) among 78 patients enrolled in an LSZ102 monotherapy arm (arm A) was 1.3%, and the progression-free survival (PFS) was 1.8 months. The clinical benefit rate (CBR) was 9.1%.

Among 76 patients enrolled in an LSZ102+ribociclib arm (arm B), the ORR was 15.8%, the PFS was 6.2 months, and the CBR was 35.5%.

Among the 39 patients enrolled in an LSZ102+alpelisib arm (arm C), the ORR was 5.4%, the PFS was 3.5 months, and the CBR was 18.9%.

After the data cutoff, one additional partial response (PR) was reported in arm C, Dr. Jhaveri said, noting that two of three confirmed responses were in known PIKC3A-mutant patients.

Study participants were aged 18 years and older with a confirmed diagnosis of ER-positive breast cancer and good performance status, as well as evidence of progression after endocrine therapy for metastatic disease or evidence of progression while on therapy or within 12 months from the end of adjuvant therapy.

“For all arms, prior fulvestrant, CDK46 inhibitor, or chemotherapy were allowed. For arm C, patients with or without PIK3C were eligible, and no prior treatment with PIK3, mTOR, or AKT inhibitors was allowed,” Dr. Jhaveri said.

Dosing in the LSZ102 monotherapy arm ranged from 200 to 900 mg. Arm B patients received LSZ102 at doses of 200-600 mg and ribociclib at doses of 200-600 mg. Both continuous ribociclib and 3 weeks on/1 week off dosing were evaluated. Arm C patients received LSZ102 at doses of 300-450 mg and alpelisib at 200-300 mg.

The recommended expansion doses were 450 mg daily of LSZ102 for arm A and 450 mg LSZ102 with 400 mg of daily ribociclib for arm B. For arm C, they were 300 mg LSZ102 with 250 mg of alpelisib daily.

Of note, two of three patients with a PR in arm C had received 300 mg LSZ102 and 300 mg alpelisib, Dr. Jhaveri said.

Arm A and arm B results were presented at the San Antonio Breast Cancer Symposium in 2018 and 2019, respectively. The current report updates those findings and presents arm C data for the first time, Dr. Jhaveri said.

LSZ102 was relatively well-tolerated as a single agent and in combination with ribociclib and alpelisib, according to Dr. Jhaveri. The most frequent adverse events were gastrointestinal toxicities, including nausea, vomiting, diarrhea, and decreased appetite, which occurred across all arms.

Neutropenia and aspartate aminotransferase abnormalities, including grade 3 cases, were reported in arm B and were most likely driven by the ribociclib, Dr. Jhaveri said. Grade 3 hypoglycemia and skin rash commonly occurred in arm C, most likely driven by the alpelisib.

Five dose-limiting toxicities occurred in four patients in arm A, three occurred in two patients in arm B, and seven occurred in seven patients in arm C.

Paired biopsies collected at the time of screening and at day 15 of cycle 1 showed consistent down-regulation of ER protein levels across arms.

“No substantial dose-dependent down-regulation of the ER was observed with increasing doses of LSZ,” Dr. Jhaveri said.

Circulating tumor DNA (ctDNA) analysis showed that the dominant mutations across the arms were ESR1, PIK3CA, and TP53. These were not shown to correlate with response and were not enriched upon progression in patients with matched baseline and end-of-treatment samples, she noted.

An exploratory analysis, conducted in “a preliminary attempt to correlate clinical activity with specific mutations,” showed that, in arms B and C, respectively, ORR, CBR, and PFS weren’t correlated with the presence or absence of ESR1 and PIK3CA mutations, respectively, or the absence of detectable ctDNA from baseline samples, Dr. Jhaveri said.

“While numerically higher responses and better CBR were seen in patients with undetectable ctDNA at baseline, no statistically significant difference in any of these outcomes was observed in arms B and C,” she said.

In arm C, the numbers were small at the time of data cutoff, but incoming data suggest relatively enhanced activity of the LSZ102 plus alpelisib combination in PIKC3A-mutant patients, she noted.

“We know that inhibiting ER signaling is the mainstay of treatment for ER-positive breast cancer,” Dr. Jhaveri explained, adding that aromatase inhibitors, estrogen receptor modulators, and SERDs are important classes of antiestrogenic agents, but fulvestrant is the only approved SERD. These are effective, but many patients develop resistance, she said.

“Proposed mechanisms for endocrine resistance include activation of the cell-cycle and cell-survival signaling pathways, or of the PI3K-AKT-mTOR pathway,” Dr. Jhaveri said. “To that end, ribociclib, a CDK46 inhibitor plus fulvestrant improved survival compared to fulvestrant alone in patients with ER-positive metastatic breast cancer.”

More recently, the PI3K inhibitor alpelisib plus fulvestrant also nearly doubled PFS vs. fulvestrant alone in PIKC3A-mutant, ER-positive metastatic breast cancer, which led to the approval of the combination in the United States.

Another mechanism of endocrine resistance includes acquisition of activating mutations in the estrogen receptor gene itself that allow tumors to survive and proliferate without depending on estrogen.

EGFR mutations appear to predict resistance to aromatase inhibitor therapies, but not outcomes in patients treated with fulvestrant. However, fulvestrant, which is delivered by intramuscular injection, has its own limitations, Dr. Jhaveri said.

“LSZ102 is a novel SERD that could achieve higher exposure than fulvestrant, leading to enhanced efficacy,” she said, noting that it was shown in preclinical models to have activity and to be synergistic in combination with ribociclib and alpelisib, forming the basis for the current study.

Invited discussant, Saverio Cinieri, MD, of Ospedale Antonio Perrino, Brindisi, Italy, said the study “elegantly demonstrated that estrogen receptor protein is down-regulated by LSZ102; [that] the genomic landscape of heavily pretreated patients is dominated by mutations in ESR1, PIK3CA, and TP53; [that] common mutations do not correlate with response and are not enriched on progression; [and that] ctDNA analysis at baseline shows similar outcomes with LSZ plus ribociclib or alpelisib, regardless of mutational status.”

LSZ102 is one of four new-generation SERDs in early-phase studies, he said, concluding that “in the COVID-19 era, the use of oral therapies will be even more necessary to limit access to the hospital.”

Dr. Cinieri also said that overcoming the limitations “of a molecule like the intramuscularly administered fulvestrant goes in this direction,” and that “the clinical efficacy and the biomolecular profile of LSZ102 seems to be able to meet these real needs.”

This study was funded by Novartis. Dr. Jhaveri reported advisory and consultancy roles and/or research grants or other funding to her institution from Novartis, ADC Therapeutics, Pfizer, and numerous other pharmaceutical and biotechnology companies. Dr. Cinieri reported relationships with Lily Oncology, Pfizer, Roche, AstraZeneca, Amgen, Novartis, including honoraria, grant and research support to his institution, advisory board participation, and scientific meeting support.

[email protected]

SOURCE: Jhaveri K et al. ESMO Breast Cancer, Abstract LBA1.

The Food and Drug Administration approved a combination of pertuzumab (Perjeta, Genentech/Roche), trastuzumab (Herceptin, Genentech/Roche) and hyaluronidase (Phesgo, Genentech/Roche) that is administered subcutaneously – rather than intravenously – for the treatment of early and metastatic HER2-positive breast cancers.

Phesgo is initially used in combination with chemotherapy at an infusion center but could continue to be administered in a patient’s home by a qualified health care professional once chemotherapy is complete, according to the FDA.

Administration takes approximately 8 minutes for the initial loading dose and approximately 5 minutes for maintenance doses, according to a Genentech press statement. This compares favorably with the 150 minutes needed for the combined loading dose of intravenous pertuzumab and trastuzumab, and the 60-150 minutes for intravenous maintenance infusions, the company said.

“Currently, most patients with HER2-positive breast cancer receive trastuzumab and pertuzumab at infusion centers. With a new administration route, Phesgo offers an outpatient option for patients to receive trastuzumab and pertuzumab,” said Richard Pazdur, MD, director of the FDA’s Oncology Center of Excellence and acting director of the Office of Oncologic Diseases in the FDA’s Center for Drug Evaluation and Research, in an agency press release.

“The fixed-dose combination of trastuzumab and pertuzumab offers a simpler, faster, and easier treatment experience for patients with HER2-positive breast cancer,” said Antoinette Tan, MD, MHSc, chief of breast medical oncology at Levine Cancer Institute, Charlotte, N.C., in the company statement.

Dr. Tan also said that home administration “can be advantageous for patients and infusion centers.”

However, in April, the Community Oncology Alliance strenuously objected to this type of treatment in a patient’s home, as reported by Medscape Medical News.

The group, which represents U.S. community-based practices, said it “fundamentally opposes home infusion of chemotherapy, cancer immunotherapy, and cancer treatment supportive drugs because of serious patient safety concerns.”

The FDA’s approval was based on the results of the pivotal phase 3 FeDeriCa trial, a noninferiority study in patients with HER2-positive early breast cancer, which demonstrated that the new product had comparable efficacy and safety as intravenous pertuzumab and intravenous trastuzumab.

In terms of efficacy, the subcutaneous product demonstrated noninferior plasma levels of pertuzumab, which was the primary endpoint, when compared with IV administration of pertuzumab.

Safety was comparable between the two approaches, with no new safety signals using the subcutaneous delivery method, including no “meaningful difference” in cardiac toxicity, according to Genentech. However, there were more administration-related reactions with the new product. The most common adverse events in both groups were alopecia, nausea, diarrhea, and anemia.

The new product uses a drug delivery technology (Enhanze, Halozyme Therapeutics) that employs a proprietary enzyme that temporarily degrades hyaluronan, a glycosaminoglycan or chain of natural sugars in the body, to facilitate the dispersion and absorption of injected therapeutic drugs, according to Genentech.

In May, at the European Society for Medical Oncology Breast Cancer Virtual Meeting 2020, investigators of the phase 2 PHranceSCa study reported that “more than 80%” of patients preferred subcutaneous to intravenous administration of pertuzumab and trastuzumab.

This article first appeared on Medscape.com.

The Food and Drug Administration approved a combination of pertuzumab (Perjeta, Genentech/Roche), trastuzumab (Herceptin, Genentech/Roche) and hyaluronidase (Phesgo, Genentech/Roche) that is administered subcutaneously – rather than intravenously – for the treatment of early and metastatic HER2-positive breast cancers.

Phesgo is initially used in combination with chemotherapy at an infusion center but could continue to be administered in a patient’s home by a qualified health care professional once chemotherapy is complete, according to the FDA.

Administration takes approximately 8 minutes for the initial loading dose and approximately 5 minutes for maintenance doses, according to a Genentech press statement. This compares favorably with the 150 minutes needed for the combined loading dose of intravenous pertuzumab and trastuzumab, and the 60-150 minutes for intravenous maintenance infusions, the company said.

“Currently, most patients with HER2-positive breast cancer receive trastuzumab and pertuzumab at infusion centers. With a new administration route, Phesgo offers an outpatient option for patients to receive trastuzumab and pertuzumab,” said Richard Pazdur, MD, director of the FDA’s Oncology Center of Excellence and acting director of the Office of Oncologic Diseases in the FDA’s Center for Drug Evaluation and Research, in an agency press release.

“The fixed-dose combination of trastuzumab and pertuzumab offers a simpler, faster, and easier treatment experience for patients with HER2-positive breast cancer,” said Antoinette Tan, MD, MHSc, chief of breast medical oncology at Levine Cancer Institute, Charlotte, N.C., in the company statement.

Dr. Tan also said that home administration “can be advantageous for patients and infusion centers.”

However, in April, the Community Oncology Alliance strenuously objected to this type of treatment in a patient’s home, as reported by Medscape Medical News.

The group, which represents U.S. community-based practices, said it “fundamentally opposes home infusion of chemotherapy, cancer immunotherapy, and cancer treatment supportive drugs because of serious patient safety concerns.”

The FDA’s approval was based on the results of the pivotal phase 3 FeDeriCa trial, a noninferiority study in patients with HER2-positive early breast cancer, which demonstrated that the new product had comparable efficacy and safety as intravenous pertuzumab and intravenous trastuzumab.

In terms of efficacy, the subcutaneous product demonstrated noninferior plasma levels of pertuzumab, which was the primary endpoint, when compared with IV administration of pertuzumab.

Safety was comparable between the two approaches, with no new safety signals using the subcutaneous delivery method, including no “meaningful difference” in cardiac toxicity, according to Genentech. However, there were more administration-related reactions with the new product. The most common adverse events in both groups were alopecia, nausea, diarrhea, and anemia.

The new product uses a drug delivery technology (Enhanze, Halozyme Therapeutics) that employs a proprietary enzyme that temporarily degrades hyaluronan, a glycosaminoglycan or chain of natural sugars in the body, to facilitate the dispersion and absorption of injected therapeutic drugs, according to Genentech.

In May, at the European Society for Medical Oncology Breast Cancer Virtual Meeting 2020, investigators of the phase 2 PHranceSCa study reported that “more than 80%” of patients preferred subcutaneous to intravenous administration of pertuzumab and trastuzumab.

This article first appeared on Medscape.com.

The Food and Drug Administration approved a combination of pertuzumab (Perjeta, Genentech/Roche), trastuzumab (Herceptin, Genentech/Roche) and hyaluronidase (Phesgo, Genentech/Roche) that is administered subcutaneously – rather than intravenously – for the treatment of early and metastatic HER2-positive breast cancers.

Phesgo is initially used in combination with chemotherapy at an infusion center but could continue to be administered in a patient’s home by a qualified health care professional once chemotherapy is complete, according to the FDA.

Administration takes approximately 8 minutes for the initial loading dose and approximately 5 minutes for maintenance doses, according to a Genentech press statement. This compares favorably with the 150 minutes needed for the combined loading dose of intravenous pertuzumab and trastuzumab, and the 60-150 minutes for intravenous maintenance infusions, the company said.

“Currently, most patients with HER2-positive breast cancer receive trastuzumab and pertuzumab at infusion centers. With a new administration route, Phesgo offers an outpatient option for patients to receive trastuzumab and pertuzumab,” said Richard Pazdur, MD, director of the FDA’s Oncology Center of Excellence and acting director of the Office of Oncologic Diseases in the FDA’s Center for Drug Evaluation and Research, in an agency press release.

“The fixed-dose combination of trastuzumab and pertuzumab offers a simpler, faster, and easier treatment experience for patients with HER2-positive breast cancer,” said Antoinette Tan, MD, MHSc, chief of breast medical oncology at Levine Cancer Institute, Charlotte, N.C., in the company statement.

Dr. Tan also said that home administration “can be advantageous for patients and infusion centers.”

However, in April, the Community Oncology Alliance strenuously objected to this type of treatment in a patient’s home, as reported by Medscape Medical News.

The group, which represents U.S. community-based practices, said it “fundamentally opposes home infusion of chemotherapy, cancer immunotherapy, and cancer treatment supportive drugs because of serious patient safety concerns.”

The FDA’s approval was based on the results of the pivotal phase 3 FeDeriCa trial, a noninferiority study in patients with HER2-positive early breast cancer, which demonstrated that the new product had comparable efficacy and safety as intravenous pertuzumab and intravenous trastuzumab.

In terms of efficacy, the subcutaneous product demonstrated noninferior plasma levels of pertuzumab, which was the primary endpoint, when compared with IV administration of pertuzumab.

Safety was comparable between the two approaches, with no new safety signals using the subcutaneous delivery method, including no “meaningful difference” in cardiac toxicity, according to Genentech. However, there were more administration-related reactions with the new product. The most common adverse events in both groups were alopecia, nausea, diarrhea, and anemia.

The new product uses a drug delivery technology (Enhanze, Halozyme Therapeutics) that employs a proprietary enzyme that temporarily degrades hyaluronan, a glycosaminoglycan or chain of natural sugars in the body, to facilitate the dispersion and absorption of injected therapeutic drugs, according to Genentech.

In May, at the European Society for Medical Oncology Breast Cancer Virtual Meeting 2020, investigators of the phase 2 PHranceSCa study reported that “more than 80%” of patients preferred subcutaneous to intravenous administration of pertuzumab and trastuzumab.

This article first appeared on Medscape.com.

Longer-term follow-up from the ARUBA study confirms earlier results showing that intervention for patients with an unruptured brain arteriovenous malformation (AVM) does more harm than good.

Enrollment into the trial, which compared medical management alone with medical management with interventional therapy (neurosurgery, embolization, or stereotactic radiotherapy, alone or in combination), was stopped prematurely in 2013 after 33 months of follow-up because of a much higher rate of death and stroke in the intervention group.
 

Reaffirming the benefit of no intervention

Now the investigators are reporting extended follow-up to 50 months. The results were very similar to those at 33 months.

The current 50-month follow-up results show that 15 of 110 patients in the medical group had died or had a stroke (3.39 per 100 patient-years) versus 41 of 116 (12.32 per 100 patient-years) in the intervention group. The results reaffirm the strong benefit of not undergoing intervention (hazard ratio, 0.31; 95% confidence interval, 0.17-0.56).

These latest results were published in the July issue of the Lancet Neurology.

“With an AVM, the natural reflex is to try and fix it, but our trial shows that the tools we have to do that seem to be more damaging than just living with the AVM. If we try to take it out, the stroke risk is three to five times higher than just leaving it alone,” coauthor Christian Stapf, MD, a professor at the University of Montreal, said in an interview.

Dr. Stapf explained that an AVM is a congenital abnormality in the linking of the arteries to the veins. “There are an excess number of arteries and veins. They usually sit there silently, but they can trigger seizures, as they can tickle the neurons in the vicinity.”

It is estimated that one to two AVMs are found spontaneously in every 100,000 persons every year, but this is dependent on the availability of MRI, and many go undetected, he noted. In MRI studies in healthy volunteers, the rate was about one AVM in every 2,000 individuals.
 

Challenging standard practice

With AVMs, rupture and intracerebral hemorrhage occur at a rate of about 1%-2% per year. Until the ARUBA results were published, the standard practice was to intervene to embolize or excise the malformation, Dr. Stapf said.

“The standard treatment was intervention. The experiment was not to do it. We were challenging standard practice, and the trial was not popular with interventionalists,” he said.

The initial study, which was published in 2014, received much criticism from the interventionalist community. Among the criticisms were that the selection criteria for enrollment limited its generalizability, fewer patients than expected in the intervention arm were referred for microvascular surgery, and the follow-up was too short to allow a meaningful comparison.

“The study received criticism, but this was mainly from interventionalists, who were having their income threatened,” Dr. Stapf said. “This was very unhappy news for them, especially in the U.S., with the fee-for-service system.”

But he says these longer-term results, together with additional analyses and data from other cohorts, reinforce their initial conclusions.

The current report also shows a benefit in functional outcome in the medical group. “After 5 years, patients are twice as likely to have a neurological handicap, defined as a score of 2 or higher on the modified Rankin scale in the intervention group,” he noted. “We also found that more patients in the intervention group had deficits not related to stroke, such as an increase in seizures.”

Results of subgroup analysis were consistent in all patient groups.

The “study was designed for 400 patients, but we only recruited about half that number. But even so, the effect of intervention on stroke is so strong there is no subgroup where it looks favorable,” Dr. Stapf said. “This result was not heterogeneous. The same effect is seen regardless of age, gender, presence of symptoms, size of AVM, location, anatomy, drainage. No matter how you look, there is no benefit for intervention.”

He also referred to a Scottish population-based cohort study that showed a similar risk reduction from not intervening. “This was an unselected population of every unruptured AVM patient in Scotland, which found a 65% relative reduction in death/stroke over 12 years. We found a 69% reduction. The Scottish study did not select any particular types of patients but showed the same result as us,” he noted. “It is hard to argue against these findings.”

Regarding the claim of selection bias, Dr. Stapf acknowledged that the study excluded patients who were judged to be in need of intervention and those judged to be at very low risk and who would not be considered for an intervention.

“But when we compared our cohort to two other unselected cohorts, they look very similar, apart from the fact that very large AVMs were not entered in our study, as they were considered too difficult to treat,” he said. “If there is a selection bias at all, it actually trends towards the intervention group, as we excluded those at the highest treatment risk, but we still showed more benefit of not intervening.”

He also says the microvascular surgery rates were consistent with real-world practice, with about 25% of patients undergoing such surgery. “This is similar to the Scottish population study. Our trial also showed a similar result in patients treated with the various different interventions – they all showed a much higher risk than not intervening,” he added.

He says practice has changed since the trial was first reported. “There are far fewer interventions now for unruptured AVMs. Most interventionalists have accepted the results now, although there are some who continue to find reasons to criticize the trial and carry on with the procedures.”

He says his advice to patients who have an unruptured AVM is to forget about it. “There doesn’t seem to be a trigger for rupture,” he said. “It doesn’t seem to be dependent on blood pressure or physical activity, and we can’t tell if it’s just about to go by looking at it. They are very different from an aneurysm in that regard.

“When I explain to patients that they are at an increased stroke risk and tell them about the results of the ARUBA study, they say they would prefer to get that stroke later in life than earlier. These patents can live for 30 or 40 years without a stroke.

“But, yes, there remains a major unmet need. We need to find a way to protect these patients. In future, we might find a better way of intervening, but at this point in time, the treatment we have is more dangerous than doing nothing,” he said.
 

Longer follow-up needed

In an editorial that accompanies the current study, Peter M. Rothwell, MD, of the University of Oxford, England, also dismisses much of the criticism of the ARUBA study. On the issue of external validity, he said: “I do not think that this is really any greater an issue for ARUBA than for most other similar trials.”

But Dr. Rothwell does believe that follow-up for longer than 5 years is needed. “To really understand the benefit/risk balance, we would need a 20- or 30-year follow-up. These patients are often in their 20s, 30s, or 40s, so we really need to know their cumulative risk over decades,” he said in an interview.

Noting that the study was funded by the National Institute of Neurological Disorders and Stroke (NINDS), Dr. Rothwell said funding should have been provided for much longer follow-up. “Patients who generously agreed to be randomly assigned in ARUBA and future similar patients have been let down by NINDS.

“We probably now won’t ever know the very–long-term impact, although the Scottish population study is following patients longer term,” he added.

“After this trial was first published, the guidelines recommended not to intervene. These latest results will not change that,” he said.

The ARUBA trial was funded internationally by the National Institutes of Health/NINDS. Dr. Stapf and Dr. Rothwell have disclosed no relevant financial relationships.

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

Longer-term follow-up from the ARUBA study confirms earlier results showing that intervention for patients with an unruptured brain arteriovenous malformation (AVM) does more harm than good.

Enrollment into the trial, which compared medical management alone with medical management with interventional therapy (neurosurgery, embolization, or stereotactic radiotherapy, alone or in combination), was stopped prematurely in 2013 after 33 months of follow-up because of a much higher rate of death and stroke in the intervention group.
 

Reaffirming the benefit of no intervention

Now the investigators are reporting extended follow-up to 50 months. The results were very similar to those at 33 months.

The current 50-month follow-up results show that 15 of 110 patients in the medical group had died or had a stroke (3.39 per 100 patient-years) versus 41 of 116 (12.32 per 100 patient-years) in the intervention group. The results reaffirm the strong benefit of not undergoing intervention (hazard ratio, 0.31; 95% confidence interval, 0.17-0.56).

These latest results were published in the July issue of the Lancet Neurology.

“With an AVM, the natural reflex is to try and fix it, but our trial shows that the tools we have to do that seem to be more damaging than just living with the AVM. If we try to take it out, the stroke risk is three to five times higher than just leaving it alone,” coauthor Christian Stapf, MD, a professor at the University of Montreal, said in an interview.

Dr. Stapf explained that an AVM is a congenital abnormality in the linking of the arteries to the veins. “There are an excess number of arteries and veins. They usually sit there silently, but they can trigger seizures, as they can tickle the neurons in the vicinity.”

It is estimated that one to two AVMs are found spontaneously in every 100,000 persons every year, but this is dependent on the availability of MRI, and many go undetected, he noted. In MRI studies in healthy volunteers, the rate was about one AVM in every 2,000 individuals.
 

Challenging standard practice

With AVMs, rupture and intracerebral hemorrhage occur at a rate of about 1%-2% per year. Until the ARUBA results were published, the standard practice was to intervene to embolize or excise the malformation, Dr. Stapf said.

“The standard treatment was intervention. The experiment was not to do it. We were challenging standard practice, and the trial was not popular with interventionalists,” he said.

The initial study, which was published in 2014, received much criticism from the interventionalist community. Among the criticisms were that the selection criteria for enrollment limited its generalizability, fewer patients than expected in the intervention arm were referred for microvascular surgery, and the follow-up was too short to allow a meaningful comparison.

“The study received criticism, but this was mainly from interventionalists, who were having their income threatened,” Dr. Stapf said. “This was very unhappy news for them, especially in the U.S., with the fee-for-service system.”

But he says these longer-term results, together with additional analyses and data from other cohorts, reinforce their initial conclusions.

The current report also shows a benefit in functional outcome in the medical group. “After 5 years, patients are twice as likely to have a neurological handicap, defined as a score of 2 or higher on the modified Rankin scale in the intervention group,” he noted. “We also found that more patients in the intervention group had deficits not related to stroke, such as an increase in seizures.”

Results of subgroup analysis were consistent in all patient groups.

The “study was designed for 400 patients, but we only recruited about half that number. But even so, the effect of intervention on stroke is so strong there is no subgroup where it looks favorable,” Dr. Stapf said. “This result was not heterogeneous. The same effect is seen regardless of age, gender, presence of symptoms, size of AVM, location, anatomy, drainage. No matter how you look, there is no benefit for intervention.”

He also referred to a Scottish population-based cohort study that showed a similar risk reduction from not intervening. “This was an unselected population of every unruptured AVM patient in Scotland, which found a 65% relative reduction in death/stroke over 12 years. We found a 69% reduction. The Scottish study did not select any particular types of patients but showed the same result as us,” he noted. “It is hard to argue against these findings.”

Regarding the claim of selection bias, Dr. Stapf acknowledged that the study excluded patients who were judged to be in need of intervention and those judged to be at very low risk and who would not be considered for an intervention.

“But when we compared our cohort to two other unselected cohorts, they look very similar, apart from the fact that very large AVMs were not entered in our study, as they were considered too difficult to treat,” he said. “If there is a selection bias at all, it actually trends towards the intervention group, as we excluded those at the highest treatment risk, but we still showed more benefit of not intervening.”

He also says the microvascular surgery rates were consistent with real-world practice, with about 25% of patients undergoing such surgery. “This is similar to the Scottish population study. Our trial also showed a similar result in patients treated with the various different interventions – they all showed a much higher risk than not intervening,” he added.

He says practice has changed since the trial was first reported. “There are far fewer interventions now for unruptured AVMs. Most interventionalists have accepted the results now, although there are some who continue to find reasons to criticize the trial and carry on with the procedures.”

He says his advice to patients who have an unruptured AVM is to forget about it. “There doesn’t seem to be a trigger for rupture,” he said. “It doesn’t seem to be dependent on blood pressure or physical activity, and we can’t tell if it’s just about to go by looking at it. They are very different from an aneurysm in that regard.

“When I explain to patients that they are at an increased stroke risk and tell them about the results of the ARUBA study, they say they would prefer to get that stroke later in life than earlier. These patents can live for 30 or 40 years without a stroke.

“But, yes, there remains a major unmet need. We need to find a way to protect these patients. In future, we might find a better way of intervening, but at this point in time, the treatment we have is more dangerous than doing nothing,” he said.
 

Longer follow-up needed

In an editorial that accompanies the current study, Peter M. Rothwell, MD, of the University of Oxford, England, also dismisses much of the criticism of the ARUBA study. On the issue of external validity, he said: “I do not think that this is really any greater an issue for ARUBA than for most other similar trials.”

But Dr. Rothwell does believe that follow-up for longer than 5 years is needed. “To really understand the benefit/risk balance, we would need a 20- or 30-year follow-up. These patients are often in their 20s, 30s, or 40s, so we really need to know their cumulative risk over decades,” he said in an interview.

Noting that the study was funded by the National Institute of Neurological Disorders and Stroke (NINDS), Dr. Rothwell said funding should have been provided for much longer follow-up. “Patients who generously agreed to be randomly assigned in ARUBA and future similar patients have been let down by NINDS.

“We probably now won’t ever know the very–long-term impact, although the Scottish population study is following patients longer term,” he added.

“After this trial was first published, the guidelines recommended not to intervene. These latest results will not change that,” he said.

The ARUBA trial was funded internationally by the National Institutes of Health/NINDS. Dr. Stapf and Dr. Rothwell have disclosed no relevant financial relationships.

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

Longer-term follow-up from the ARUBA study confirms earlier results showing that intervention for patients with an unruptured brain arteriovenous malformation (AVM) does more harm than good.

Enrollment into the trial, which compared medical management alone with medical management with interventional therapy (neurosurgery, embolization, or stereotactic radiotherapy, alone or in combination), was stopped prematurely in 2013 after 33 months of follow-up because of a much higher rate of death and stroke in the intervention group.
 

Reaffirming the benefit of no intervention

Now the investigators are reporting extended follow-up to 50 months. The results were very similar to those at 33 months.

The current 50-month follow-up results show that 15 of 110 patients in the medical group had died or had a stroke (3.39 per 100 patient-years) versus 41 of 116 (12.32 per 100 patient-years) in the intervention group. The results reaffirm the strong benefit of not undergoing intervention (hazard ratio, 0.31; 95% confidence interval, 0.17-0.56).

These latest results were published in the July issue of the Lancet Neurology.

“With an AVM, the natural reflex is to try and fix it, but our trial shows that the tools we have to do that seem to be more damaging than just living with the AVM. If we try to take it out, the stroke risk is three to five times higher than just leaving it alone,” coauthor Christian Stapf, MD, a professor at the University of Montreal, said in an interview.

Dr. Stapf explained that an AVM is a congenital abnormality in the linking of the arteries to the veins. “There are an excess number of arteries and veins. They usually sit there silently, but they can trigger seizures, as they can tickle the neurons in the vicinity.”

It is estimated that one to two AVMs are found spontaneously in every 100,000 persons every year, but this is dependent on the availability of MRI, and many go undetected, he noted. In MRI studies in healthy volunteers, the rate was about one AVM in every 2,000 individuals.
 

Challenging standard practice

With AVMs, rupture and intracerebral hemorrhage occur at a rate of about 1%-2% per year. Until the ARUBA results were published, the standard practice was to intervene to embolize or excise the malformation, Dr. Stapf said.

“The standard treatment was intervention. The experiment was not to do it. We were challenging standard practice, and the trial was not popular with interventionalists,” he said.

The initial study, which was published in 2014, received much criticism from the interventionalist community. Among the criticisms were that the selection criteria for enrollment limited its generalizability, fewer patients than expected in the intervention arm were referred for microvascular surgery, and the follow-up was too short to allow a meaningful comparison.

“The study received criticism, but this was mainly from interventionalists, who were having their income threatened,” Dr. Stapf said. “This was very unhappy news for them, especially in the U.S., with the fee-for-service system.”

But he says these longer-term results, together with additional analyses and data from other cohorts, reinforce their initial conclusions.

The current report also shows a benefit in functional outcome in the medical group. “After 5 years, patients are twice as likely to have a neurological handicap, defined as a score of 2 or higher on the modified Rankin scale in the intervention group,” he noted. “We also found that more patients in the intervention group had deficits not related to stroke, such as an increase in seizures.”

Results of subgroup analysis were consistent in all patient groups.

The “study was designed for 400 patients, but we only recruited about half that number. But even so, the effect of intervention on stroke is so strong there is no subgroup where it looks favorable,” Dr. Stapf said. “This result was not heterogeneous. The same effect is seen regardless of age, gender, presence of symptoms, size of AVM, location, anatomy, drainage. No matter how you look, there is no benefit for intervention.”

He also referred to a Scottish population-based cohort study that showed a similar risk reduction from not intervening. “This was an unselected population of every unruptured AVM patient in Scotland, which found a 65% relative reduction in death/stroke over 12 years. We found a 69% reduction. The Scottish study did not select any particular types of patients but showed the same result as us,” he noted. “It is hard to argue against these findings.”

Regarding the claim of selection bias, Dr. Stapf acknowledged that the study excluded patients who were judged to be in need of intervention and those judged to be at very low risk and who would not be considered for an intervention.

“But when we compared our cohort to two other unselected cohorts, they look very similar, apart from the fact that very large AVMs were not entered in our study, as they were considered too difficult to treat,” he said. “If there is a selection bias at all, it actually trends towards the intervention group, as we excluded those at the highest treatment risk, but we still showed more benefit of not intervening.”

He also says the microvascular surgery rates were consistent with real-world practice, with about 25% of patients undergoing such surgery. “This is similar to the Scottish population study. Our trial also showed a similar result in patients treated with the various different interventions – they all showed a much higher risk than not intervening,” he added.

He says practice has changed since the trial was first reported. “There are far fewer interventions now for unruptured AVMs. Most interventionalists have accepted the results now, although there are some who continue to find reasons to criticize the trial and carry on with the procedures.”

He says his advice to patients who have an unruptured AVM is to forget about it. “There doesn’t seem to be a trigger for rupture,” he said. “It doesn’t seem to be dependent on blood pressure or physical activity, and we can’t tell if it’s just about to go by looking at it. They are very different from an aneurysm in that regard.

“When I explain to patients that they are at an increased stroke risk and tell them about the results of the ARUBA study, they say they would prefer to get that stroke later in life than earlier. These patents can live for 30 or 40 years without a stroke.

“But, yes, there remains a major unmet need. We need to find a way to protect these patients. In future, we might find a better way of intervening, but at this point in time, the treatment we have is more dangerous than doing nothing,” he said.
 

Longer follow-up needed

In an editorial that accompanies the current study, Peter M. Rothwell, MD, of the University of Oxford, England, also dismisses much of the criticism of the ARUBA study. On the issue of external validity, he said: “I do not think that this is really any greater an issue for ARUBA than for most other similar trials.”

But Dr. Rothwell does believe that follow-up for longer than 5 years is needed. “To really understand the benefit/risk balance, we would need a 20- or 30-year follow-up. These patients are often in their 20s, 30s, or 40s, so we really need to know their cumulative risk over decades,” he said in an interview.

Noting that the study was funded by the National Institute of Neurological Disorders and Stroke (NINDS), Dr. Rothwell said funding should have been provided for much longer follow-up. “Patients who generously agreed to be randomly assigned in ARUBA and future similar patients have been let down by NINDS.

“We probably now won’t ever know the very–long-term impact, although the Scottish population study is following patients longer term,” he added.

“After this trial was first published, the guidelines recommended not to intervene. These latest results will not change that,” he said.

The ARUBA trial was funded internationally by the National Institutes of Health/NINDS. Dr. Stapf and Dr. Rothwell have disclosed no relevant financial relationships.

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

The US Food and Drug Administration (FDA) has approved fenfluramine (Fintepla, Zogenix) oral solution, a Schedule IV controlled substance, for the treatment of seizures associated with Dravet syndrome in children age 2 years and older.

Dravet syndrome is a rare childhood-onset epilepsy characterized by frequent, drug-resistant convulsive seizures that may contribute to intellectual disability and impairments in motor control, behavior, and cognition, as well as an increased risk of sudden unexpected death in epilepsy (SUDEP).

Dravet syndrome takes a “tremendous toll on both patients and their families. Fintepla offers an additional effective treatment option for the treatment of seizures associated with Dravet syndrome,” Billy Dunn, MD, director, Office of Neuroscience in the FDA’s Center for Drug Evaluation and Research, said in a news release.

The FDA approved fenfluramine for Dravet syndrome based on the results of two randomized, double-blind, placebo-controlled phase 3 trials involving children ages 2 to 18 years with Dravet syndrome.

In both studies, children treated with fenfluramine experienced significantly greater reductions in the frequency of convulsive seizures than did their peers who received placebo. These reductions occurred within 3 to 4 weeks, and remained generally consistent over the 14- to 15-week treatment periods, the FDA said.

“There remains a huge unmet need for the many Dravet syndrome patients who continue to experience frequent severe seizures even while taking one or more of the currently available antiseizure medications,” Joseph Sullivan, MD, who worked on the fenfluramine for Dravet syndrome studies, said in a news release. 

Given the “profound reductions” in convulsive seizure frequency seen in the clinical trials, combined with the “ongoing, robust safety monitoring,” fenfluramine offers “an extremely important treatment option for Dravet syndrome patients,” said Dr. Sullivan, director of the Pediatric Epilepsy Center of Excellence at the University of California San Francisco (UCSF) Benioff Children’s Hospital.

Fenfluramine is an anorectic agent that was used to treat obesity until it was removed from the market in 1997 over reports of increased risk of valvular heart disease when prescribed in higher doses and most often when prescribed with phentermine. The combination of the two drugs was known as fen-phen.

In the clinical trials of Dravet syndrome, the most common adverse reactions were decreased appetite; somnolence, sedation, lethargy; diarrhea; constipation; abnormal echocardiogram; fatigue, malaise, asthenia; ataxia, balance disorder, gait disturbance; increased blood pressure; drooling, salivary hypersecretion; pyrexia; upper respiratory tract infection; vomiting; decreased weight; fall; and status epilepticus.

The Fintepla label has a boxed warning stating that the drug is associated with valvular heart disease (VHD) and pulmonary arterial hypertension (PAH). Due to these risks, patients must undergo echocardiography before treatment, every 6 months during treatment, and once 3 to 6 months after treatment is stopped.

If signs of VHD, PAH, or other cardiac abnormalities are present, clinicians should weigh the benefits and risks of continuing treatment with Fintepla, the FDA said.

Fintepla is available only through a risk evaluation and mitigation strategy (REMS) program, which requires physicians who prescribe the drug and pharmacies that dispense it to be certified in the Fintepla REMS and that patients be enrolled in the program.

As part of the REMS requirements, prescribers and patients must adhere to the required cardiac monitoring to receive the drug.

Fintepla will be available to certified prescribers in the United States in July. Zogenix is launching Zogenix Central, a comprehensive support service that will provide ongoing product assistance to patients, caregivers, and their medical teams. Further information is available online.
 

This article first appeared on Medscape.com.

The US Food and Drug Administration (FDA) has approved fenfluramine (Fintepla, Zogenix) oral solution, a Schedule IV controlled substance, for the treatment of seizures associated with Dravet syndrome in children age 2 years and older.

Dravet syndrome is a rare childhood-onset epilepsy characterized by frequent, drug-resistant convulsive seizures that may contribute to intellectual disability and impairments in motor control, behavior, and cognition, as well as an increased risk of sudden unexpected death in epilepsy (SUDEP).

Dravet syndrome takes a “tremendous toll on both patients and their families. Fintepla offers an additional effective treatment option for the treatment of seizures associated with Dravet syndrome,” Billy Dunn, MD, director, Office of Neuroscience in the FDA’s Center for Drug Evaluation and Research, said in a news release.

The FDA approved fenfluramine for Dravet syndrome based on the results of two randomized, double-blind, placebo-controlled phase 3 trials involving children ages 2 to 18 years with Dravet syndrome.

In both studies, children treated with fenfluramine experienced significantly greater reductions in the frequency of convulsive seizures than did their peers who received placebo. These reductions occurred within 3 to 4 weeks, and remained generally consistent over the 14- to 15-week treatment periods, the FDA said.

“There remains a huge unmet need for the many Dravet syndrome patients who continue to experience frequent severe seizures even while taking one or more of the currently available antiseizure medications,” Joseph Sullivan, MD, who worked on the fenfluramine for Dravet syndrome studies, said in a news release. 

Given the “profound reductions” in convulsive seizure frequency seen in the clinical trials, combined with the “ongoing, robust safety monitoring,” fenfluramine offers “an extremely important treatment option for Dravet syndrome patients,” said Dr. Sullivan, director of the Pediatric Epilepsy Center of Excellence at the University of California San Francisco (UCSF) Benioff Children’s Hospital.

Fenfluramine is an anorectic agent that was used to treat obesity until it was removed from the market in 1997 over reports of increased risk of valvular heart disease when prescribed in higher doses and most often when prescribed with phentermine. The combination of the two drugs was known as fen-phen.

In the clinical trials of Dravet syndrome, the most common adverse reactions were decreased appetite; somnolence, sedation, lethargy; diarrhea; constipation; abnormal echocardiogram; fatigue, malaise, asthenia; ataxia, balance disorder, gait disturbance; increased blood pressure; drooling, salivary hypersecretion; pyrexia; upper respiratory tract infection; vomiting; decreased weight; fall; and status epilepticus.

The Fintepla label has a boxed warning stating that the drug is associated with valvular heart disease (VHD) and pulmonary arterial hypertension (PAH). Due to these risks, patients must undergo echocardiography before treatment, every 6 months during treatment, and once 3 to 6 months after treatment is stopped.

If signs of VHD, PAH, or other cardiac abnormalities are present, clinicians should weigh the benefits and risks of continuing treatment with Fintepla, the FDA said.

Fintepla is available only through a risk evaluation and mitigation strategy (REMS) program, which requires physicians who prescribe the drug and pharmacies that dispense it to be certified in the Fintepla REMS and that patients be enrolled in the program.

As part of the REMS requirements, prescribers and patients must adhere to the required cardiac monitoring to receive the drug.

Fintepla will be available to certified prescribers in the United States in July. Zogenix is launching Zogenix Central, a comprehensive support service that will provide ongoing product assistance to patients, caregivers, and their medical teams. Further information is available online.
 

This article first appeared on Medscape.com.

The US Food and Drug Administration (FDA) has approved fenfluramine (Fintepla, Zogenix) oral solution, a Schedule IV controlled substance, for the treatment of seizures associated with Dravet syndrome in children age 2 years and older.

Dravet syndrome is a rare childhood-onset epilepsy characterized by frequent, drug-resistant convulsive seizures that may contribute to intellectual disability and impairments in motor control, behavior, and cognition, as well as an increased risk of sudden unexpected death in epilepsy (SUDEP).

Dravet syndrome takes a “tremendous toll on both patients and their families. Fintepla offers an additional effective treatment option for the treatment of seizures associated with Dravet syndrome,” Billy Dunn, MD, director, Office of Neuroscience in the FDA’s Center for Drug Evaluation and Research, said in a news release.

The FDA approved fenfluramine for Dravet syndrome based on the results of two randomized, double-blind, placebo-controlled phase 3 trials involving children ages 2 to 18 years with Dravet syndrome.

In both studies, children treated with fenfluramine experienced significantly greater reductions in the frequency of convulsive seizures than did their peers who received placebo. These reductions occurred within 3 to 4 weeks, and remained generally consistent over the 14- to 15-week treatment periods, the FDA said.

“There remains a huge unmet need for the many Dravet syndrome patients who continue to experience frequent severe seizures even while taking one or more of the currently available antiseizure medications,” Joseph Sullivan, MD, who worked on the fenfluramine for Dravet syndrome studies, said in a news release. 

Given the “profound reductions” in convulsive seizure frequency seen in the clinical trials, combined with the “ongoing, robust safety monitoring,” fenfluramine offers “an extremely important treatment option for Dravet syndrome patients,” said Dr. Sullivan, director of the Pediatric Epilepsy Center of Excellence at the University of California San Francisco (UCSF) Benioff Children’s Hospital.

Fenfluramine is an anorectic agent that was used to treat obesity until it was removed from the market in 1997 over reports of increased risk of valvular heart disease when prescribed in higher doses and most often when prescribed with phentermine. The combination of the two drugs was known as fen-phen.

In the clinical trials of Dravet syndrome, the most common adverse reactions were decreased appetite; somnolence, sedation, lethargy; diarrhea; constipation; abnormal echocardiogram; fatigue, malaise, asthenia; ataxia, balance disorder, gait disturbance; increased blood pressure; drooling, salivary hypersecretion; pyrexia; upper respiratory tract infection; vomiting; decreased weight; fall; and status epilepticus.

The Fintepla label has a boxed warning stating that the drug is associated with valvular heart disease (VHD) and pulmonary arterial hypertension (PAH). Due to these risks, patients must undergo echocardiography before treatment, every 6 months during treatment, and once 3 to 6 months after treatment is stopped.

If signs of VHD, PAH, or other cardiac abnormalities are present, clinicians should weigh the benefits and risks of continuing treatment with Fintepla, the FDA said.

Fintepla is available only through a risk evaluation and mitigation strategy (REMS) program, which requires physicians who prescribe the drug and pharmacies that dispense it to be certified in the Fintepla REMS and that patients be enrolled in the program.

As part of the REMS requirements, prescribers and patients must adhere to the required cardiac monitoring to receive the drug.

Fintepla will be available to certified prescribers in the United States in July. Zogenix is launching Zogenix Central, a comprehensive support service that will provide ongoing product assistance to patients, caregivers, and their medical teams. Further information is available online.
 

This article first appeared on Medscape.com.

Combining a personalized cancer vaccine with an immune checkpoint inhibitor induced neoantigen-specific immune responses in most patients with advanced solid tumors in a phase 1b study.

Only two clinical responses were seen in this early investigation of the vaccine, RO7198457, combined with the PD-L1 inhibitor atezolizumab. However, T-cell responses were observed in about three-quarters of the patients evaluated, according to study investigator Juanita Lopez, MB BChir, PhD.

Those immune responses, coupled with preliminary evidence of infiltration of RO7198457-stimulated T cells into tumors, suggest the viability of this individualized anticancer strategy, according to Dr. Lopez, a consultant medical oncologist at The Royal Marsden NHS Foundation Trust and The Institute of Cancer Research, London.

“Failure of T-cell priming is a major cause of lack of response to immune checkpoint inhibitors,” Dr. Lopez said in an interview. “We hoped that, by eliciting a tumor-specific T-cell response, we would be able to overcome this.”

Preclinical data suggested the combination of vaccine and immune checkpoint inhibitors improved outcomes, which prompted the current study, added Dr. Lopez, who presented results from this study at the American Association for Cancer Research virtual meeting II.

Dr. Lopez noted that mutated neoantigens are recognized as foreign and have been shown to induce stronger T-cell responses, compared with shared antigens, likely because of a lack of central tolerance.

“Most of these mutated neoantigens are not shared between the patients, and therefore, targeted neoantigen-specific therapy requires an individualized approach,” she explained.

RO7198457 is manufactured on a per-patient basis and includes as many as 20 tumor-specific neoepitopes.
 

Study details

Dr. Lopez presented results from dose-escalation and expansion cohorts of the study, which included 142 patients with advanced solid tumors. The patients had colorectal, skin, kidney, lung, urothelial, breast, gynecologic, and head and neck cancers.

Most patients had low or no PD-L1 expression, and nearly 40% had received prior treatment with a checkpoint inhibitor.

Patients received nine doses of RO7198457 at 25-50 mcg during the 12-week induction stage. They then received RO7198457 every eight cycles until disease progression. Patients received atezolizumab at 1,200 mg on day 1 of each 21-day cycle.

Induction of proinflammatory cytokines was observed at each dose tested, and ex vivo T-cell responses were noted in 46 of 63 patients evaluated, or 73%.

T-cell receptors specific to RO7198457 were present posttreatment in a patient with rectal cancer, providing some preliminary evidence suggesting infiltration of RO7198457-stimulated T cells in the tumor, Dr. Lopez said.

There were two clinical responses. A patient with rectal cancer had a complete response, and a patient with triple-negative breast cancer had a partial response.

The combination of RO7198457 with atezolizumab was generally well tolerated, and the maximum tolerated dose was not reached, Dr. Lopez said. Most adverse events were grade 1/2, and immune-mediated adverse events were rare.
 

Implications and next steps

This study furthers earlier observations from neoantigen vaccine studies by linking dosing of the vaccine to dosing with immune checkpoint inhibitor, rather than giving the vaccine in the period leading up to immune checkpoint inhibitor administration, according to former AACR President Elaine R. Mardis, PhD, of Nationwide Children’s Hospital and The Ohio State University College of Medicine, both in Columbus.

That said, the implications for clinical practice remain unclear, according to Dr. Mardis.

“This combination did elicit an immune response that was highly specific for the neoantigen vaccine, but most patients did not receive a clinical benefit of disease response,” Dr. Mardis said in an interview. “This tells us the combination approach used was, overall, not quite right, and we need to continue to innovate in this area.”

The low clinical response rate in the study was likely caused in part by the fact that patients had very advanced disease and were heavily pretreated, according to Dr. Lopez

Randomized phase 2 studies of RO7198457 are now underway, Dr. Lopez said. One is a study of RO7198457 plus atezolizumab as adjuvant treatment for non–small cell lung cancer (NCT04267237). Another is testing RO7198457 in combination with pembrolizumab as first-line treatment for melanoma (NCT03815058).

The current study was funded by Genentech and BioNTech. Dr. Lopez reported disclosures related to Roche/Genentech, Basilea Pharmaceutica, and Genmab. Dr. Mardis reported disclosures related to Quiagen NV, PACT Pharma, Kiadis Pharma NV, and Interpreta.

SOURCE: Lopez J et al. AACR 2020, Abstract CT301.

Combining a personalized cancer vaccine with an immune checkpoint inhibitor induced neoantigen-specific immune responses in most patients with advanced solid tumors in a phase 1b study.

Only two clinical responses were seen in this early investigation of the vaccine, RO7198457, combined with the PD-L1 inhibitor atezolizumab. However, T-cell responses were observed in about three-quarters of the patients evaluated, according to study investigator Juanita Lopez, MB BChir, PhD.

Those immune responses, coupled with preliminary evidence of infiltration of RO7198457-stimulated T cells into tumors, suggest the viability of this individualized anticancer strategy, according to Dr. Lopez, a consultant medical oncologist at The Royal Marsden NHS Foundation Trust and The Institute of Cancer Research, London.

“Failure of T-cell priming is a major cause of lack of response to immune checkpoint inhibitors,” Dr. Lopez said in an interview. “We hoped that, by eliciting a tumor-specific T-cell response, we would be able to overcome this.”

Preclinical data suggested the combination of vaccine and immune checkpoint inhibitors improved outcomes, which prompted the current study, added Dr. Lopez, who presented results from this study at the American Association for Cancer Research virtual meeting II.

Dr. Lopez noted that mutated neoantigens are recognized as foreign and have been shown to induce stronger T-cell responses, compared with shared antigens, likely because of a lack of central tolerance.

“Most of these mutated neoantigens are not shared between the patients, and therefore, targeted neoantigen-specific therapy requires an individualized approach,” she explained.

RO7198457 is manufactured on a per-patient basis and includes as many as 20 tumor-specific neoepitopes.
 

Study details

Dr. Lopez presented results from dose-escalation and expansion cohorts of the study, which included 142 patients with advanced solid tumors. The patients had colorectal, skin, kidney, lung, urothelial, breast, gynecologic, and head and neck cancers.

Most patients had low or no PD-L1 expression, and nearly 40% had received prior treatment with a checkpoint inhibitor.

Patients received nine doses of RO7198457 at 25-50 mcg during the 12-week induction stage. They then received RO7198457 every eight cycles until disease progression. Patients received atezolizumab at 1,200 mg on day 1 of each 21-day cycle.

Induction of proinflammatory cytokines was observed at each dose tested, and ex vivo T-cell responses were noted in 46 of 63 patients evaluated, or 73%.

T-cell receptors specific to RO7198457 were present posttreatment in a patient with rectal cancer, providing some preliminary evidence suggesting infiltration of RO7198457-stimulated T cells in the tumor, Dr. Lopez said.

There were two clinical responses. A patient with rectal cancer had a complete response, and a patient with triple-negative breast cancer had a partial response.

The combination of RO7198457 with atezolizumab was generally well tolerated, and the maximum tolerated dose was not reached, Dr. Lopez said. Most adverse events were grade 1/2, and immune-mediated adverse events were rare.
 

Implications and next steps

This study furthers earlier observations from neoantigen vaccine studies by linking dosing of the vaccine to dosing with immune checkpoint inhibitor, rather than giving the vaccine in the period leading up to immune checkpoint inhibitor administration, according to former AACR President Elaine R. Mardis, PhD, of Nationwide Children’s Hospital and The Ohio State University College of Medicine, both in Columbus.

That said, the implications for clinical practice remain unclear, according to Dr. Mardis.

“This combination did elicit an immune response that was highly specific for the neoantigen vaccine, but most patients did not receive a clinical benefit of disease response,” Dr. Mardis said in an interview. “This tells us the combination approach used was, overall, not quite right, and we need to continue to innovate in this area.”

The low clinical response rate in the study was likely caused in part by the fact that patients had very advanced disease and were heavily pretreated, according to Dr. Lopez

Randomized phase 2 studies of RO7198457 are now underway, Dr. Lopez said. One is a study of RO7198457 plus atezolizumab as adjuvant treatment for non–small cell lung cancer (NCT04267237). Another is testing RO7198457 in combination with pembrolizumab as first-line treatment for melanoma (NCT03815058).

The current study was funded by Genentech and BioNTech. Dr. Lopez reported disclosures related to Roche/Genentech, Basilea Pharmaceutica, and Genmab. Dr. Mardis reported disclosures related to Quiagen NV, PACT Pharma, Kiadis Pharma NV, and Interpreta.

SOURCE: Lopez J et al. AACR 2020, Abstract CT301.

Combining a personalized cancer vaccine with an immune checkpoint inhibitor induced neoantigen-specific immune responses in most patients with advanced solid tumors in a phase 1b study.

Only two clinical responses were seen in this early investigation of the vaccine, RO7198457, combined with the PD-L1 inhibitor atezolizumab. However, T-cell responses were observed in about three-quarters of the patients evaluated, according to study investigator Juanita Lopez, MB BChir, PhD.

Those immune responses, coupled with preliminary evidence of infiltration of RO7198457-stimulated T cells into tumors, suggest the viability of this individualized anticancer strategy, according to Dr. Lopez, a consultant medical oncologist at The Royal Marsden NHS Foundation Trust and The Institute of Cancer Research, London.

“Failure of T-cell priming is a major cause of lack of response to immune checkpoint inhibitors,” Dr. Lopez said in an interview. “We hoped that, by eliciting a tumor-specific T-cell response, we would be able to overcome this.”

Preclinical data suggested the combination of vaccine and immune checkpoint inhibitors improved outcomes, which prompted the current study, added Dr. Lopez, who presented results from this study at the American Association for Cancer Research virtual meeting II.

Dr. Lopez noted that mutated neoantigens are recognized as foreign and have been shown to induce stronger T-cell responses, compared with shared antigens, likely because of a lack of central tolerance.

“Most of these mutated neoantigens are not shared between the patients, and therefore, targeted neoantigen-specific therapy requires an individualized approach,” she explained.

RO7198457 is manufactured on a per-patient basis and includes as many as 20 tumor-specific neoepitopes.
 

Study details

Dr. Lopez presented results from dose-escalation and expansion cohorts of the study, which included 142 patients with advanced solid tumors. The patients had colorectal, skin, kidney, lung, urothelial, breast, gynecologic, and head and neck cancers.

Most patients had low or no PD-L1 expression, and nearly 40% had received prior treatment with a checkpoint inhibitor.

Patients received nine doses of RO7198457 at 25-50 mcg during the 12-week induction stage. They then received RO7198457 every eight cycles until disease progression. Patients received atezolizumab at 1,200 mg on day 1 of each 21-day cycle.

Induction of proinflammatory cytokines was observed at each dose tested, and ex vivo T-cell responses were noted in 46 of 63 patients evaluated, or 73%.

T-cell receptors specific to RO7198457 were present posttreatment in a patient with rectal cancer, providing some preliminary evidence suggesting infiltration of RO7198457-stimulated T cells in the tumor, Dr. Lopez said.

There were two clinical responses. A patient with rectal cancer had a complete response, and a patient with triple-negative breast cancer had a partial response.

The combination of RO7198457 with atezolizumab was generally well tolerated, and the maximum tolerated dose was not reached, Dr. Lopez said. Most adverse events were grade 1/2, and immune-mediated adverse events were rare.
 

Implications and next steps

This study furthers earlier observations from neoantigen vaccine studies by linking dosing of the vaccine to dosing with immune checkpoint inhibitor, rather than giving the vaccine in the period leading up to immune checkpoint inhibitor administration, according to former AACR President Elaine R. Mardis, PhD, of Nationwide Children’s Hospital and The Ohio State University College of Medicine, both in Columbus.

That said, the implications for clinical practice remain unclear, according to Dr. Mardis.

“This combination did elicit an immune response that was highly specific for the neoantigen vaccine, but most patients did not receive a clinical benefit of disease response,” Dr. Mardis said in an interview. “This tells us the combination approach used was, overall, not quite right, and we need to continue to innovate in this area.”

The low clinical response rate in the study was likely caused in part by the fact that patients had very advanced disease and were heavily pretreated, according to Dr. Lopez

Randomized phase 2 studies of RO7198457 are now underway, Dr. Lopez said. One is a study of RO7198457 plus atezolizumab as adjuvant treatment for non–small cell lung cancer (NCT04267237). Another is testing RO7198457 in combination with pembrolizumab as first-line treatment for melanoma (NCT03815058).

The current study was funded by Genentech and BioNTech. Dr. Lopez reported disclosures related to Roche/Genentech, Basilea Pharmaceutica, and Genmab. Dr. Mardis reported disclosures related to Quiagen NV, PACT Pharma, Kiadis Pharma NV, and Interpreta.

SOURCE: Lopez J et al. AACR 2020, Abstract CT301.

A model created by the National Cancer Institute predicts that tens of thousands of excess cancer deaths will occur over the next decade as a result of missed screenings, delays in diagnosis, and reductions in oncology care caused by the COVID-19 pandemic.

“As director of NCI, I am deeply concerned about the potential impacts of delayed diagnoses and deferred or modified treatment plans on cancer incidence and mortality,” said Norman “Ned” Sharpless, MD.

“In the past 3 decades, we have seen steady and strong progress against death and suffering from cancer, thanks to improvements in prevention, screening, diagnosis, and treatment. I worry that the SARS-CoV-2 pandemic has put those decades of steady progress at risk and may precipitate reversals of these trends.”

In an editorial published June 19 in Science, Dr. Sharpless highlighted modeling performed by the NCI that predicts an excess of 10,000 deaths from breast and colorectal cancer over the next 10 years.

The number of excess deaths per year would peak in the next year or 2, likely sooner for colorectal than for breast cancer, but “for both cancer types, we believe the pandemic will influence cancer deaths for at least a decade.”

In an interview, Dr. Sharpless pointed out that this analysis is conservative because the researchers only evaluated two types of cancer. They chose breast and colorectal cancer because these are common cancers (accounting for about one-sixth of all cancers) with relatively high screening rates.

“We didn’t model other cancer types, but we have no reason to think that we’re not going to see the same thing with other types of malignancies,” he said. “That is a significant amount of excess mortality.”
 

Delayed diagnosis, modified therapy

One of the effects of the pandemic has been to cause delays in cancer diagnosis. “Routine screening has plummeted and is running at less than 90% in some systems,” Dr. Sharpless said.

“Most cancers are diagnosed when people experience symptoms and go see their doctors, and those symptomatic screening events are also not happening,” he continued. “Fear of contracting the coronavirus in health care settings has dissuaded people from visits.”

In some cases, a delay in diagnosis will allow the cancer to progress to a more advanced stage. “The earlier the diagnosis, the better, and if the stages are more advanced, patients will not do as well for virtually every kind of cancer,” he said.

In addition to delays in diagnosis, treatments are being postponed or modified for patients recently diagnosed with cancer. Because of delays and reductions in curative therapies, patients may be receiving less than optimal care.

“We are seeing a lot of nonstandard care,” said Dr. Sharpless. “All of these things add up to increased cancer morbidity and mortality.”

He also pointed out that the term “elective” is confusing and problematic. “It doesn’t mean that it’s not needed, just that it’s not an emergency and doesn’t need to be done today,” said Dr. Sharpless. “But if we’re talking about chemotherapy and surgery, we don’t think they can be delayed for too long – maybe a week, but not for several months.”

Dr. Sharpless feels that overall it is time for cancer care to resume as much as possible, because “ignoring cancer for too long is an untenable choice and may turn one public health crisis into another.”

“If we act now, we can make up for lost time,” he wrote in the editorial. “Clearly, postponing procedures and deferring care due to the pandemic was prudent at one time, but now that we have made it through the initial shock of the pandemic, I believe it is time to resume robust cancer care.”

Through their network of cancer centers, researchers with the NCI can develop innovative solutions that allow screening and treatment to move forward while maintaining safety. “We need to make patients feel safe, and we have to answer important questions quickly,” he said.
 

Impact of COVID-19 on cancer care

The COVID-19 pandemic has overwhelmed health care systems worldwide and has created major challenges for clinicians who are caring for patients with cancer.

As previously reported, hospitals reprioritized resources for an impending onslaught of COVID-19 patients. Services and procedures deemed to be nonessential were canceled or delayed, including surgeries and imaging.

In a survey conducted by the American Cancer Society Cancer Action Network, half of the 1219 respondents reported changes, delays, or disruptions to the care they were receiving. The services most frequently affected included in-person provider visits (50%), supportive services (20%), and imaging procedures to monitor tumor growth (20%).

In addition, 8% reported that their treatment, including chemotherapy and immunotherapy, had been affected by the COVID-19 pandemic.

In the United Kingdom, Cancer Research UK estimated that because of the disruption to cancer services, 2.4 million people did not undergo cancer screening or further testing or did not receive cancer treatment and that tens of thousands of cases have gone undiagnosed.

Similarly, a survey by Macmillan Cancer Support showed that almost half (45%) of cancer patients have experienced delays or cancellations of cancer treatments, or their treatments have been altered as a result of coronavirus, leaving many living in fear. Calling cancer “the forgotten C” of the pandemic, it warned of a potential cancer “time bomb” when, as the number of deaths from COVID-19 falls, cancer returns as the leading cause of death in the United Kingdom.

Last month, a report also predicted that there will be an excess of cancer deaths in both the United States and United Kingdom because of patients not accessing health care services.

The authors calculated that there will be 6270 excess deaths among cancer patients 1 year from now in England and 33,890 excess deaths among cancer patients older than 40 years in the United States.

This article first appeared on Medscape.com.

A model created by the National Cancer Institute predicts that tens of thousands of excess cancer deaths will occur over the next decade as a result of missed screenings, delays in diagnosis, and reductions in oncology care caused by the COVID-19 pandemic.

“As director of NCI, I am deeply concerned about the potential impacts of delayed diagnoses and deferred or modified treatment plans on cancer incidence and mortality,” said Norman “Ned” Sharpless, MD.

“In the past 3 decades, we have seen steady and strong progress against death and suffering from cancer, thanks to improvements in prevention, screening, diagnosis, and treatment. I worry that the SARS-CoV-2 pandemic has put those decades of steady progress at risk and may precipitate reversals of these trends.”

In an editorial published June 19 in Science, Dr. Sharpless highlighted modeling performed by the NCI that predicts an excess of 10,000 deaths from breast and colorectal cancer over the next 10 years.

The number of excess deaths per year would peak in the next year or 2, likely sooner for colorectal than for breast cancer, but “for both cancer types, we believe the pandemic will influence cancer deaths for at least a decade.”

In an interview, Dr. Sharpless pointed out that this analysis is conservative because the researchers only evaluated two types of cancer. They chose breast and colorectal cancer because these are common cancers (accounting for about one-sixth of all cancers) with relatively high screening rates.

“We didn’t model other cancer types, but we have no reason to think that we’re not going to see the same thing with other types of malignancies,” he said. “That is a significant amount of excess mortality.”
 

Delayed diagnosis, modified therapy

One of the effects of the pandemic has been to cause delays in cancer diagnosis. “Routine screening has plummeted and is running at less than 90% in some systems,” Dr. Sharpless said.

“Most cancers are diagnosed when people experience symptoms and go see their doctors, and those symptomatic screening events are also not happening,” he continued. “Fear of contracting the coronavirus in health care settings has dissuaded people from visits.”

In some cases, a delay in diagnosis will allow the cancer to progress to a more advanced stage. “The earlier the diagnosis, the better, and if the stages are more advanced, patients will not do as well for virtually every kind of cancer,” he said.

In addition to delays in diagnosis, treatments are being postponed or modified for patients recently diagnosed with cancer. Because of delays and reductions in curative therapies, patients may be receiving less than optimal care.

“We are seeing a lot of nonstandard care,” said Dr. Sharpless. “All of these things add up to increased cancer morbidity and mortality.”

He also pointed out that the term “elective” is confusing and problematic. “It doesn’t mean that it’s not needed, just that it’s not an emergency and doesn’t need to be done today,” said Dr. Sharpless. “But if we’re talking about chemotherapy and surgery, we don’t think they can be delayed for too long – maybe a week, but not for several months.”

Dr. Sharpless feels that overall it is time for cancer care to resume as much as possible, because “ignoring cancer for too long is an untenable choice and may turn one public health crisis into another.”

“If we act now, we can make up for lost time,” he wrote in the editorial. “Clearly, postponing procedures and deferring care due to the pandemic was prudent at one time, but now that we have made it through the initial shock of the pandemic, I believe it is time to resume robust cancer care.”

Through their network of cancer centers, researchers with the NCI can develop innovative solutions that allow screening and treatment to move forward while maintaining safety. “We need to make patients feel safe, and we have to answer important questions quickly,” he said.
 

Impact of COVID-19 on cancer care

The COVID-19 pandemic has overwhelmed health care systems worldwide and has created major challenges for clinicians who are caring for patients with cancer.

As previously reported, hospitals reprioritized resources for an impending onslaught of COVID-19 patients. Services and procedures deemed to be nonessential were canceled or delayed, including surgeries and imaging.

In a survey conducted by the American Cancer Society Cancer Action Network, half of the 1219 respondents reported changes, delays, or disruptions to the care they were receiving. The services most frequently affected included in-person provider visits (50%), supportive services (20%), and imaging procedures to monitor tumor growth (20%).

In addition, 8% reported that their treatment, including chemotherapy and immunotherapy, had been affected by the COVID-19 pandemic.

In the United Kingdom, Cancer Research UK estimated that because of the disruption to cancer services, 2.4 million people did not undergo cancer screening or further testing or did not receive cancer treatment and that tens of thousands of cases have gone undiagnosed.

Similarly, a survey by Macmillan Cancer Support showed that almost half (45%) of cancer patients have experienced delays or cancellations of cancer treatments, or their treatments have been altered as a result of coronavirus, leaving many living in fear. Calling cancer “the forgotten C” of the pandemic, it warned of a potential cancer “time bomb” when, as the number of deaths from COVID-19 falls, cancer returns as the leading cause of death in the United Kingdom.

Last month, a report also predicted that there will be an excess of cancer deaths in both the United States and United Kingdom because of patients not accessing health care services.

The authors calculated that there will be 6270 excess deaths among cancer patients 1 year from now in England and 33,890 excess deaths among cancer patients older than 40 years in the United States.

This article first appeared on Medscape.com.

A model created by the National Cancer Institute predicts that tens of thousands of excess cancer deaths will occur over the next decade as a result of missed screenings, delays in diagnosis, and reductions in oncology care caused by the COVID-19 pandemic.

“As director of NCI, I am deeply concerned about the potential impacts of delayed diagnoses and deferred or modified treatment plans on cancer incidence and mortality,” said Norman “Ned” Sharpless, MD.

“In the past 3 decades, we have seen steady and strong progress against death and suffering from cancer, thanks to improvements in prevention, screening, diagnosis, and treatment. I worry that the SARS-CoV-2 pandemic has put those decades of steady progress at risk and may precipitate reversals of these trends.”

In an editorial published June 19 in Science, Dr. Sharpless highlighted modeling performed by the NCI that predicts an excess of 10,000 deaths from breast and colorectal cancer over the next 10 years.

The number of excess deaths per year would peak in the next year or 2, likely sooner for colorectal than for breast cancer, but “for both cancer types, we believe the pandemic will influence cancer deaths for at least a decade.”

In an interview, Dr. Sharpless pointed out that this analysis is conservative because the researchers only evaluated two types of cancer. They chose breast and colorectal cancer because these are common cancers (accounting for about one-sixth of all cancers) with relatively high screening rates.

“We didn’t model other cancer types, but we have no reason to think that we’re not going to see the same thing with other types of malignancies,” he said. “That is a significant amount of excess mortality.”
 

Delayed diagnosis, modified therapy

One of the effects of the pandemic has been to cause delays in cancer diagnosis. “Routine screening has plummeted and is running at less than 90% in some systems,” Dr. Sharpless said.

“Most cancers are diagnosed when people experience symptoms and go see their doctors, and those symptomatic screening events are also not happening,” he continued. “Fear of contracting the coronavirus in health care settings has dissuaded people from visits.”

In some cases, a delay in diagnosis will allow the cancer to progress to a more advanced stage. “The earlier the diagnosis, the better, and if the stages are more advanced, patients will not do as well for virtually every kind of cancer,” he said.

In addition to delays in diagnosis, treatments are being postponed or modified for patients recently diagnosed with cancer. Because of delays and reductions in curative therapies, patients may be receiving less than optimal care.

“We are seeing a lot of nonstandard care,” said Dr. Sharpless. “All of these things add up to increased cancer morbidity and mortality.”

He also pointed out that the term “elective” is confusing and problematic. “It doesn’t mean that it’s not needed, just that it’s not an emergency and doesn’t need to be done today,” said Dr. Sharpless. “But if we’re talking about chemotherapy and surgery, we don’t think they can be delayed for too long – maybe a week, but not for several months.”

Dr. Sharpless feels that overall it is time for cancer care to resume as much as possible, because “ignoring cancer for too long is an untenable choice and may turn one public health crisis into another.”

“If we act now, we can make up for lost time,” he wrote in the editorial. “Clearly, postponing procedures and deferring care due to the pandemic was prudent at one time, but now that we have made it through the initial shock of the pandemic, I believe it is time to resume robust cancer care.”

Through their network of cancer centers, researchers with the NCI can develop innovative solutions that allow screening and treatment to move forward while maintaining safety. “We need to make patients feel safe, and we have to answer important questions quickly,” he said.
 

Impact of COVID-19 on cancer care

The COVID-19 pandemic has overwhelmed health care systems worldwide and has created major challenges for clinicians who are caring for patients with cancer.

As previously reported, hospitals reprioritized resources for an impending onslaught of COVID-19 patients. Services and procedures deemed to be nonessential were canceled or delayed, including surgeries and imaging.

In a survey conducted by the American Cancer Society Cancer Action Network, half of the 1219 respondents reported changes, delays, or disruptions to the care they were receiving. The services most frequently affected included in-person provider visits (50%), supportive services (20%), and imaging procedures to monitor tumor growth (20%).

In addition, 8% reported that their treatment, including chemotherapy and immunotherapy, had been affected by the COVID-19 pandemic.

In the United Kingdom, Cancer Research UK estimated that because of the disruption to cancer services, 2.4 million people did not undergo cancer screening or further testing or did not receive cancer treatment and that tens of thousands of cases have gone undiagnosed.

Similarly, a survey by Macmillan Cancer Support showed that almost half (45%) of cancer patients have experienced delays or cancellations of cancer treatments, or their treatments have been altered as a result of coronavirus, leaving many living in fear. Calling cancer “the forgotten C” of the pandemic, it warned of a potential cancer “time bomb” when, as the number of deaths from COVID-19 falls, cancer returns as the leading cause of death in the United Kingdom.

Last month, a report also predicted that there will be an excess of cancer deaths in both the United States and United Kingdom because of patients not accessing health care services.

The authors calculated that there will be 6270 excess deaths among cancer patients 1 year from now in England and 33,890 excess deaths among cancer patients older than 40 years in the United States.

This article first appeared on Medscape.com.