Walter Alexander

Patients with idiopathic pulmonary fibrosis (IPF) complete and respond to pulmonary rehabilitation at rates similar to patients with chronic obstructive pulmonary disease (COPD), according to results of a real-world study. The findings reported in an article published in the journal CHEST^® reinforce pulmonary rehabilitation’s benefits for this population.

A progressive decline in respiratory and physical function characterizes IPF, with median survival from diagnosis of 3-5 years, according to Claire Nolan, PhD, of Harefield Hospital, Middlesex, England, and colleagues. The effects of pharmacologic therapies on IPF on symptom burden and quality of life are modest, although lung function decline may be slowed. Supporting evidence for pulmonary rehabilitation benefit in IPF is more modest than it is for COPD, for which exercise capacity, dyspnea, and health-related quality of life improvement have been demonstrated.

“We did not design a randomized, controlled trial,” Dr. Nolan said in an interview, “as it was considered unethical by the local ethics committee to withhold pulmonary rehabilitation based on clinical guidance in the United Kingdom.” She pointed out that initial pulmonary rehabilitation trials in COPD included an intervention (pulmonary rehabilitation) and a control (standard medical care) arm.

The study aims were to compare the effects of pulmonary rehabilitation with real-world data between IPF and COPD with respect to magnitude of effect and survival. The authors’ hypothesis was that IPF patients would have a blunted response to pulmonary rehabilitation with reduced completion rates, compared with a matched COPD group, and with increased mortality.
 

Study details

Investigators use propensity score matching of 163 IPF patients with a control group of 163 patients with COPD referred to pulmonary rehabilitation. Completion rates, responses, and survival status were recorded for 1-year following pulmonary rehabilitation discharge. The 8-week outpatient program was composed of two supervised exercise and education sessions with additional unsupervised home-based exercise each week.

While spirometry data, as expected, showed a higher proportion of IPF patients using supplemental oxygen, pulmonary rehabilitation completion rates were similar for both groups (IPF, 69%; COPD, 63%; P = .24) and there was no between group difference in the number of sessions attended (P = .39). Medical Research Council (muscle strength) (MRC), incremental shuttle walk test (ISW), and Chronic Respiratory Questionnaire total score (CRQ-T) improved significantly in both groups, again with no significant difference between groups.

Over the study course, there was progressive, significant worsening of forced vital capacity percentage, predicted, prescription supplemental oxygen, resting peripheral oxygen saturation, exercise capacity, health-related quality of life and pulmonary rehabilitation adherence across groups of responders (n = 63; 38%), nonresponders (n = 50; 31%) and noncompleters (n = 50; 31%). Among the IPF patients, 6 died before completing pulmonary rehabilitation, with 42 (27%) dying during follow-up.
 

Benefits of rehabilitation

Multivariable analyses showed that noncompletion and nonresponse were associated with significantly higher risk of all-cause mortality at 1-year. Also, time to all-cause mortality was shorter (P = .001) for noncompleters and nonresponders, compared with completers. A trend toward higher completion rates in the IPF group, compared with the COPD group, may be explained, the researchers explained, by fewer hospitalizations over the prior 12 months in the IPF group.

“Although many programs are designed for people with COPD,” Dr. Nolan and colleagues concluded, “our study demonstrates that people with IPF have similar clinical benefits and completion rates to those with COPD. These data reinforce the importance of referral to and engagement in pulmonary rehabilitation amongst the IPF population.”

These findings, Dr. Nolan emphasized, emerged from a single center, and validation in other settings is needed.

This study was funded by a National Institute for Health Research Doctoral Research Fellowship (2014-07-089) and a Medical Research Council New Investigator Research Grant (98576).

Patients with idiopathic pulmonary fibrosis (IPF) complete and respond to pulmonary rehabilitation at rates similar to patients with chronic obstructive pulmonary disease (COPD), according to results of a real-world study. The findings reported in an article published in the journal CHEST^® reinforce pulmonary rehabilitation’s benefits for this population.

A progressive decline in respiratory and physical function characterizes IPF, with median survival from diagnosis of 3-5 years, according to Claire Nolan, PhD, of Harefield Hospital, Middlesex, England, and colleagues. The effects of pharmacologic therapies on IPF on symptom burden and quality of life are modest, although lung function decline may be slowed. Supporting evidence for pulmonary rehabilitation benefit in IPF is more modest than it is for COPD, for which exercise capacity, dyspnea, and health-related quality of life improvement have been demonstrated.

“We did not design a randomized, controlled trial,” Dr. Nolan said in an interview, “as it was considered unethical by the local ethics committee to withhold pulmonary rehabilitation based on clinical guidance in the United Kingdom.” She pointed out that initial pulmonary rehabilitation trials in COPD included an intervention (pulmonary rehabilitation) and a control (standard medical care) arm.

The study aims were to compare the effects of pulmonary rehabilitation with real-world data between IPF and COPD with respect to magnitude of effect and survival. The authors’ hypothesis was that IPF patients would have a blunted response to pulmonary rehabilitation with reduced completion rates, compared with a matched COPD group, and with increased mortality.
 

Study details

Investigators use propensity score matching of 163 IPF patients with a control group of 163 patients with COPD referred to pulmonary rehabilitation. Completion rates, responses, and survival status were recorded for 1-year following pulmonary rehabilitation discharge. The 8-week outpatient program was composed of two supervised exercise and education sessions with additional unsupervised home-based exercise each week.

While spirometry data, as expected, showed a higher proportion of IPF patients using supplemental oxygen, pulmonary rehabilitation completion rates were similar for both groups (IPF, 69%; COPD, 63%; P = .24) and there was no between group difference in the number of sessions attended (P = .39). Medical Research Council (muscle strength) (MRC), incremental shuttle walk test (ISW), and Chronic Respiratory Questionnaire total score (CRQ-T) improved significantly in both groups, again with no significant difference between groups.

Over the study course, there was progressive, significant worsening of forced vital capacity percentage, predicted, prescription supplemental oxygen, resting peripheral oxygen saturation, exercise capacity, health-related quality of life and pulmonary rehabilitation adherence across groups of responders (n = 63; 38%), nonresponders (n = 50; 31%) and noncompleters (n = 50; 31%). Among the IPF patients, 6 died before completing pulmonary rehabilitation, with 42 (27%) dying during follow-up.
 

Benefits of rehabilitation

Multivariable analyses showed that noncompletion and nonresponse were associated with significantly higher risk of all-cause mortality at 1-year. Also, time to all-cause mortality was shorter (P = .001) for noncompleters and nonresponders, compared with completers. A trend toward higher completion rates in the IPF group, compared with the COPD group, may be explained, the researchers explained, by fewer hospitalizations over the prior 12 months in the IPF group.

“Although many programs are designed for people with COPD,” Dr. Nolan and colleagues concluded, “our study demonstrates that people with IPF have similar clinical benefits and completion rates to those with COPD. These data reinforce the importance of referral to and engagement in pulmonary rehabilitation amongst the IPF population.”

These findings, Dr. Nolan emphasized, emerged from a single center, and validation in other settings is needed.

This study was funded by a National Institute for Health Research Doctoral Research Fellowship (2014-07-089) and a Medical Research Council New Investigator Research Grant (98576).

Patients with idiopathic pulmonary fibrosis (IPF) complete and respond to pulmonary rehabilitation at rates similar to patients with chronic obstructive pulmonary disease (COPD), according to results of a real-world study. The findings reported in an article published in the journal CHEST^® reinforce pulmonary rehabilitation’s benefits for this population.

A progressive decline in respiratory and physical function characterizes IPF, with median survival from diagnosis of 3-5 years, according to Claire Nolan, PhD, of Harefield Hospital, Middlesex, England, and colleagues. The effects of pharmacologic therapies on IPF on symptom burden and quality of life are modest, although lung function decline may be slowed. Supporting evidence for pulmonary rehabilitation benefit in IPF is more modest than it is for COPD, for which exercise capacity, dyspnea, and health-related quality of life improvement have been demonstrated.

“We did not design a randomized, controlled trial,” Dr. Nolan said in an interview, “as it was considered unethical by the local ethics committee to withhold pulmonary rehabilitation based on clinical guidance in the United Kingdom.” She pointed out that initial pulmonary rehabilitation trials in COPD included an intervention (pulmonary rehabilitation) and a control (standard medical care) arm.

The study aims were to compare the effects of pulmonary rehabilitation with real-world data between IPF and COPD with respect to magnitude of effect and survival. The authors’ hypothesis was that IPF patients would have a blunted response to pulmonary rehabilitation with reduced completion rates, compared with a matched COPD group, and with increased mortality.
 

Study details

Investigators use propensity score matching of 163 IPF patients with a control group of 163 patients with COPD referred to pulmonary rehabilitation. Completion rates, responses, and survival status were recorded for 1-year following pulmonary rehabilitation discharge. The 8-week outpatient program was composed of two supervised exercise and education sessions with additional unsupervised home-based exercise each week.

While spirometry data, as expected, showed a higher proportion of IPF patients using supplemental oxygen, pulmonary rehabilitation completion rates were similar for both groups (IPF, 69%; COPD, 63%; P = .24) and there was no between group difference in the number of sessions attended (P = .39). Medical Research Council (muscle strength) (MRC), incremental shuttle walk test (ISW), and Chronic Respiratory Questionnaire total score (CRQ-T) improved significantly in both groups, again with no significant difference between groups.

Over the study course, there was progressive, significant worsening of forced vital capacity percentage, predicted, prescription supplemental oxygen, resting peripheral oxygen saturation, exercise capacity, health-related quality of life and pulmonary rehabilitation adherence across groups of responders (n = 63; 38%), nonresponders (n = 50; 31%) and noncompleters (n = 50; 31%). Among the IPF patients, 6 died before completing pulmonary rehabilitation, with 42 (27%) dying during follow-up.
 

Benefits of rehabilitation

Multivariable analyses showed that noncompletion and nonresponse were associated with significantly higher risk of all-cause mortality at 1-year. Also, time to all-cause mortality was shorter (P = .001) for noncompleters and nonresponders, compared with completers. A trend toward higher completion rates in the IPF group, compared with the COPD group, may be explained, the researchers explained, by fewer hospitalizations over the prior 12 months in the IPF group.

“Although many programs are designed for people with COPD,” Dr. Nolan and colleagues concluded, “our study demonstrates that people with IPF have similar clinical benefits and completion rates to those with COPD. These data reinforce the importance of referral to and engagement in pulmonary rehabilitation amongst the IPF population.”

These findings, Dr. Nolan emphasized, emerged from a single center, and validation in other settings is needed.

This study was funded by a National Institute for Health Research Doctoral Research Fellowship (2014-07-089) and a Medical Research Council New Investigator Research Grant (98576).

The use of race/ethnicity in medicine to explain and interpret pulmonary function test (PFT) differences between individuals may contribute to biased medical care and research. Furthermore, it may perpetuate health disparities and structural racism, according to a study published in the journal CHEST®.

Current practices of PFT measurement and interpretation, are imperfect in their ability to accurately describe the relationship between function and health outcomes, according to Nirav R. Bhakta, MD, University of California,San Francisco, and colleagues.

The authors summarized arguments against using race-specific equations, while voicing genuine concerns about removing race from PFT interpretations, and described knowledge gaps and critical questions needing to be addressed for remediation of health disparities.

“Leaving out the perspectives of practicing pulmonologists and physiologists has global relevance for increasingly multicultural communities in which the range of values that represent normal lung function is uncertain,” Dr. Bhakta said in an interview.
 

A lesson in history

Tracing the history of spirometry, the authors stated that observations about vital lung capacity showing differences attributable to height, age, sex, and occupation (e.g., typesetter vs. firefighter) were then extended to include social classes and ultimately race. Whites showed greater average vital capacity for the same sex, height, and age than non-Whites.

While some investigators pointed to environmental sources (such as early life nutrition, respiratory illness, air pollution, exercise, and altitude), research into their mechanisms and magnitudes of effect was not pursued, but rather “a narrative of innate differences took hold,” Dr. Bhakta and colleagues reported.

That sort of narrative risks comparison with those used to uphold slavery and structural racism in the past. More recently, such a narrative was used to deny disability claims of Welsh versus English White miners, and was expanded to interpret algorithms designed to predict expected lung function.
 

Use of standing height questioned

The current practice of using normalized standard height for lung function comparisons misses racial and ethnic differences in the proportion of sitting height to standing height shown in multiple studies, the authors stated. These comparisons may ignore effects on standing height of early-life nutrition, genetics, lung-specific factors such as respiratory infections and exposures to indoor and outdoor pollution, physical activity, and high altitude. Using sitting height instead of standing height reduces lung volume differences up to 50% between White and Black populations, they noted, and socioeconomic variables, such as poverty and immigration status, accounted further for the differences seen. Population differences disappeared by as much as 90% when chest measurements used to estimate surface area or volume were more finely detailed.

The researchers warned, however, that, “because current clinical and policy algorithms rely so heavily on the comparison of an individual’s observed lung function to that which is expected for similar people without typical respiratory disease, an abrupt change to not using race/ethnicity, if not paired with education and a reform of existing algorithms and policies, is also expected to have risks on average to groups of non-White individuals.”

That could lead to potential challenges for some groups ranging from the ability to obtain employment in certain occupations, to being considered for potentially curative lung resections, or having access to home assisted ventilation and rehabilitation programs. “An abrupt change to not using race/ethnicity and taking a society’s overall average as the reference range also has the potential to lead to delayed care, denial of disability benefits, and higher life insurance premiums to White individuals.”
 

Evidence base is limited

“Although evidence demonstrates differences in lung function between racial/ethnic groups, the premise that dividing lung function interpretation up by racial/ethnic background is helpful in the clinical setting is not a proven one.” The authors cited some evidence that lung function interpretation without consideration of race/ethnicity has superior prognostic ability. In addition, research has shown only a weak relationship between lung function and work ability, according to the authors. More appropriate ways of assessing expected lung function for an individual in the absence of a diagnoses are under study.

Offering an alternative

As an alternative to race, Dr. Bhakta and colleagues proposed using a range of values that include individuals across many global populations while still adjusting for sex, age, and height. The resultant value would represent a diverse population average and widen the limits of normal that can be expected in otherwise-healthy people.

The approach would include PFTs with other factors for clinical decision-making, but would allow clinicians and patients to appreciate the limitations of interpretation based on comparison to reference values. However, such an approach may miss pathophysiologically reduced lung function in some individuals, in which case lifesaving therapies, such as chemotherapy, lung cancer resection, and bone marrow transplantation could be withheld. In other instances the consequence would be overtesting and diagnosis, they acknowledged.

The authors further discussed general concerns about the use of race in interpretation of PFTs, addressing limits/considerations as well as knowledge and practice gaps.

For example, one particular concern involves the fact that race does not capture acculturation and mixed ancestry. The limit/consideration is the need to discover mechanisms for differences and to suggest societal interventions, and the knowledge gap pertains to ignorance regarding mechanisms leading to differences in lung function.

For the concern that race is not a proxy for an individual’s genetics, the limit/consideration is that race captures only some genetics and the gap is the need for better genetic information. As an antidote to over reliance on lung function thresholds (without supporting data), they urged outcomes-based standards rather than comparisons with reference populations.
 

New thinking needed

Dr. Bhakta and colleagues pointed out that the forced expiratory volume in 1 second/forced vital capacity ratios important for diagnosis of obstructive lung disease are similar between racial/ethnic categories, underscoring the need for education about limitations of thresholds and reference values with regard to race, particularly as they are used to detect mild disease.

Ignoring race, on the other hand, can lead to unnecessary testing and treatment (with concomitant side effects), and anxiety.

“Reporting through race-based algorithms in the PFT laboratory risks portraying racial disparities as innate and immutable. By anchoring on the improved prediction of lung function from racial/ethnic-specific reference equations, we miss how the significant residual variation still leaves much uncertainty about the expected value for an individual,” the authors concluded. “Given their origin and historical and current use in society, these racial/ethnic labels are better used to identify the effects of structural racism on respiratory health in research and ensure adequate representation in research, rather than in clinical algorithms.”

One of the authors is a speaker for MGC Diagnostics. The others indicated that they had no relevant disclosures.

The use of race/ethnicity in medicine to explain and interpret pulmonary function test (PFT) differences between individuals may contribute to biased medical care and research. Furthermore, it may perpetuate health disparities and structural racism, according to a study published in the journal CHEST®.

Current practices of PFT measurement and interpretation, are imperfect in their ability to accurately describe the relationship between function and health outcomes, according to Nirav R. Bhakta, MD, University of California,San Francisco, and colleagues.

The authors summarized arguments against using race-specific equations, while voicing genuine concerns about removing race from PFT interpretations, and described knowledge gaps and critical questions needing to be addressed for remediation of health disparities.

“Leaving out the perspectives of practicing pulmonologists and physiologists has global relevance for increasingly multicultural communities in which the range of values that represent normal lung function is uncertain,” Dr. Bhakta said in an interview.
 

A lesson in history

Tracing the history of spirometry, the authors stated that observations about vital lung capacity showing differences attributable to height, age, sex, and occupation (e.g., typesetter vs. firefighter) were then extended to include social classes and ultimately race. Whites showed greater average vital capacity for the same sex, height, and age than non-Whites.

While some investigators pointed to environmental sources (such as early life nutrition, respiratory illness, air pollution, exercise, and altitude), research into their mechanisms and magnitudes of effect was not pursued, but rather “a narrative of innate differences took hold,” Dr. Bhakta and colleagues reported.

That sort of narrative risks comparison with those used to uphold slavery and structural racism in the past. More recently, such a narrative was used to deny disability claims of Welsh versus English White miners, and was expanded to interpret algorithms designed to predict expected lung function.
 

Use of standing height questioned

The current practice of using normalized standard height for lung function comparisons misses racial and ethnic differences in the proportion of sitting height to standing height shown in multiple studies, the authors stated. These comparisons may ignore effects on standing height of early-life nutrition, genetics, lung-specific factors such as respiratory infections and exposures to indoor and outdoor pollution, physical activity, and high altitude. Using sitting height instead of standing height reduces lung volume differences up to 50% between White and Black populations, they noted, and socioeconomic variables, such as poverty and immigration status, accounted further for the differences seen. Population differences disappeared by as much as 90% when chest measurements used to estimate surface area or volume were more finely detailed.

The researchers warned, however, that, “because current clinical and policy algorithms rely so heavily on the comparison of an individual’s observed lung function to that which is expected for similar people without typical respiratory disease, an abrupt change to not using race/ethnicity, if not paired with education and a reform of existing algorithms and policies, is also expected to have risks on average to groups of non-White individuals.”

That could lead to potential challenges for some groups ranging from the ability to obtain employment in certain occupations, to being considered for potentially curative lung resections, or having access to home assisted ventilation and rehabilitation programs. “An abrupt change to not using race/ethnicity and taking a society’s overall average as the reference range also has the potential to lead to delayed care, denial of disability benefits, and higher life insurance premiums to White individuals.”
 

Evidence base is limited

“Although evidence demonstrates differences in lung function between racial/ethnic groups, the premise that dividing lung function interpretation up by racial/ethnic background is helpful in the clinical setting is not a proven one.” The authors cited some evidence that lung function interpretation without consideration of race/ethnicity has superior prognostic ability. In addition, research has shown only a weak relationship between lung function and work ability, according to the authors. More appropriate ways of assessing expected lung function for an individual in the absence of a diagnoses are under study.

Offering an alternative

As an alternative to race, Dr. Bhakta and colleagues proposed using a range of values that include individuals across many global populations while still adjusting for sex, age, and height. The resultant value would represent a diverse population average and widen the limits of normal that can be expected in otherwise-healthy people.

The approach would include PFTs with other factors for clinical decision-making, but would allow clinicians and patients to appreciate the limitations of interpretation based on comparison to reference values. However, such an approach may miss pathophysiologically reduced lung function in some individuals, in which case lifesaving therapies, such as chemotherapy, lung cancer resection, and bone marrow transplantation could be withheld. In other instances the consequence would be overtesting and diagnosis, they acknowledged.

The authors further discussed general concerns about the use of race in interpretation of PFTs, addressing limits/considerations as well as knowledge and practice gaps.

For example, one particular concern involves the fact that race does not capture acculturation and mixed ancestry. The limit/consideration is the need to discover mechanisms for differences and to suggest societal interventions, and the knowledge gap pertains to ignorance regarding mechanisms leading to differences in lung function.

For the concern that race is not a proxy for an individual’s genetics, the limit/consideration is that race captures only some genetics and the gap is the need for better genetic information. As an antidote to over reliance on lung function thresholds (without supporting data), they urged outcomes-based standards rather than comparisons with reference populations.
 

New thinking needed

Dr. Bhakta and colleagues pointed out that the forced expiratory volume in 1 second/forced vital capacity ratios important for diagnosis of obstructive lung disease are similar between racial/ethnic categories, underscoring the need for education about limitations of thresholds and reference values with regard to race, particularly as they are used to detect mild disease.

Ignoring race, on the other hand, can lead to unnecessary testing and treatment (with concomitant side effects), and anxiety.

“Reporting through race-based algorithms in the PFT laboratory risks portraying racial disparities as innate and immutable. By anchoring on the improved prediction of lung function from racial/ethnic-specific reference equations, we miss how the significant residual variation still leaves much uncertainty about the expected value for an individual,” the authors concluded. “Given their origin and historical and current use in society, these racial/ethnic labels are better used to identify the effects of structural racism on respiratory health in research and ensure adequate representation in research, rather than in clinical algorithms.”

One of the authors is a speaker for MGC Diagnostics. The others indicated that they had no relevant disclosures.

The use of race/ethnicity in medicine to explain and interpret pulmonary function test (PFT) differences between individuals may contribute to biased medical care and research. Furthermore, it may perpetuate health disparities and structural racism, according to a study published in the journal CHEST®.

Current practices of PFT measurement and interpretation, are imperfect in their ability to accurately describe the relationship between function and health outcomes, according to Nirav R. Bhakta, MD, University of California,San Francisco, and colleagues.

The authors summarized arguments against using race-specific equations, while voicing genuine concerns about removing race from PFT interpretations, and described knowledge gaps and critical questions needing to be addressed for remediation of health disparities.

“Leaving out the perspectives of practicing pulmonologists and physiologists has global relevance for increasingly multicultural communities in which the range of values that represent normal lung function is uncertain,” Dr. Bhakta said in an interview.
 

A lesson in history

Tracing the history of spirometry, the authors stated that observations about vital lung capacity showing differences attributable to height, age, sex, and occupation (e.g., typesetter vs. firefighter) were then extended to include social classes and ultimately race. Whites showed greater average vital capacity for the same sex, height, and age than non-Whites.

While some investigators pointed to environmental sources (such as early life nutrition, respiratory illness, air pollution, exercise, and altitude), research into their mechanisms and magnitudes of effect was not pursued, but rather “a narrative of innate differences took hold,” Dr. Bhakta and colleagues reported.

That sort of narrative risks comparison with those used to uphold slavery and structural racism in the past. More recently, such a narrative was used to deny disability claims of Welsh versus English White miners, and was expanded to interpret algorithms designed to predict expected lung function.
 

Use of standing height questioned

The current practice of using normalized standard height for lung function comparisons misses racial and ethnic differences in the proportion of sitting height to standing height shown in multiple studies, the authors stated. These comparisons may ignore effects on standing height of early-life nutrition, genetics, lung-specific factors such as respiratory infections and exposures to indoor and outdoor pollution, physical activity, and high altitude. Using sitting height instead of standing height reduces lung volume differences up to 50% between White and Black populations, they noted, and socioeconomic variables, such as poverty and immigration status, accounted further for the differences seen. Population differences disappeared by as much as 90% when chest measurements used to estimate surface area or volume were more finely detailed.

The researchers warned, however, that, “because current clinical and policy algorithms rely so heavily on the comparison of an individual’s observed lung function to that which is expected for similar people without typical respiratory disease, an abrupt change to not using race/ethnicity, if not paired with education and a reform of existing algorithms and policies, is also expected to have risks on average to groups of non-White individuals.”

That could lead to potential challenges for some groups ranging from the ability to obtain employment in certain occupations, to being considered for potentially curative lung resections, or having access to home assisted ventilation and rehabilitation programs. “An abrupt change to not using race/ethnicity and taking a society’s overall average as the reference range also has the potential to lead to delayed care, denial of disability benefits, and higher life insurance premiums to White individuals.”
 

Evidence base is limited

“Although evidence demonstrates differences in lung function between racial/ethnic groups, the premise that dividing lung function interpretation up by racial/ethnic background is helpful in the clinical setting is not a proven one.” The authors cited some evidence that lung function interpretation without consideration of race/ethnicity has superior prognostic ability. In addition, research has shown only a weak relationship between lung function and work ability, according to the authors. More appropriate ways of assessing expected lung function for an individual in the absence of a diagnoses are under study.

Offering an alternative

As an alternative to race, Dr. Bhakta and colleagues proposed using a range of values that include individuals across many global populations while still adjusting for sex, age, and height. The resultant value would represent a diverse population average and widen the limits of normal that can be expected in otherwise-healthy people.

The approach would include PFTs with other factors for clinical decision-making, but would allow clinicians and patients to appreciate the limitations of interpretation based on comparison to reference values. However, such an approach may miss pathophysiologically reduced lung function in some individuals, in which case lifesaving therapies, such as chemotherapy, lung cancer resection, and bone marrow transplantation could be withheld. In other instances the consequence would be overtesting and diagnosis, they acknowledged.

The authors further discussed general concerns about the use of race in interpretation of PFTs, addressing limits/considerations as well as knowledge and practice gaps.

For example, one particular concern involves the fact that race does not capture acculturation and mixed ancestry. The limit/consideration is the need to discover mechanisms for differences and to suggest societal interventions, and the knowledge gap pertains to ignorance regarding mechanisms leading to differences in lung function.

For the concern that race is not a proxy for an individual’s genetics, the limit/consideration is that race captures only some genetics and the gap is the need for better genetic information. As an antidote to over reliance on lung function thresholds (without supporting data), they urged outcomes-based standards rather than comparisons with reference populations.
 

New thinking needed

Dr. Bhakta and colleagues pointed out that the forced expiratory volume in 1 second/forced vital capacity ratios important for diagnosis of obstructive lung disease are similar between racial/ethnic categories, underscoring the need for education about limitations of thresholds and reference values with regard to race, particularly as they are used to detect mild disease.

Ignoring race, on the other hand, can lead to unnecessary testing and treatment (with concomitant side effects), and anxiety.

“Reporting through race-based algorithms in the PFT laboratory risks portraying racial disparities as innate and immutable. By anchoring on the improved prediction of lung function from racial/ethnic-specific reference equations, we miss how the significant residual variation still leaves much uncertainty about the expected value for an individual,” the authors concluded. “Given their origin and historical and current use in society, these racial/ethnic labels are better used to identify the effects of structural racism on respiratory health in research and ensure adequate representation in research, rather than in clinical algorithms.”

One of the authors is a speaker for MGC Diagnostics. The others indicated that they had no relevant disclosures.

In a new scientific statement on diet and lifestyle recommendations, the American Heart Association is highlighting, for the first time, structural challenges that impede the adoption of heart-healthy dietary patterns.

American Heart Association

This is in addition to stressing aspects of diet that improve cardiovascular health and reduce cardiovascular risk, with an emphasis on dietary patterns and food-based guidance beyond naming individual foods or nutrients.

The 2021 Dietary Guidance to Improve Cardiovascular Health scientific statement, developed under Alice H. Lichtenstein, DSc, chair of the AHA writing group, provides 10 evidence-based guidance recommendations to promote cardiometabolic health.

“The way to make heart-healthy choices every day,” said Dr. Lichtenstein, of the Jean Mayer USDA Human Nutrition Research Center on Aging at Tufts University in Boston, in a statement, “is to step back, look at the environment in which you eat, whether it be at home, at work, during social interaction, and then identify what the best choices are. And if there are no good choices, then think about how you can modify your environment so that there are good choices.”

The statement, published in Circulation, underscores growing evidence that nutrition-related chronic diseases have maternal-nutritional origins, and that prevention of pediatric obesity is a key to preserving and prolonging ideal cardiovascular health.

The features are as follows:

• Adjust energy intake and expenditure to achieve and maintain a healthy body weight. To counter the shift toward higher energy intake and more sedentary lifestyles over the past 3 decades, the statement recommends at least 150 minutes of moderate physical activity per week, adjusted for individual’s age, activity level, sex, and size.
• Eat plenty of fruits and vegetables; choose a wide variety. Observational and intervention studies document that dietary patterns rich in varied fruits and vegetables, with the exception of white potatoes, are linked to a lower risk of cardiovascular disease (CVD). Also, whole fruits and vegetables, which more readily provide fiber and satiety, are preferred over juices.
• Choose whole grain foods and products made mostly with whole grains rather than refined grains. Evidence from observational, interventional, and clinical studies confirm the benefits of frequent consumption of whole grains over infrequent consumption or over refined grains in terms of CVD risk, coronary heart disease (CHD), stroke, metabolic syndrome, cardiometabolic risk factors, laxation, and gut microbiota.
• Choose healthy sources of protein, mostly from plants (legumes and nuts).
• Higher intake of legumes, which are rich in protein and fiber, is associated with lower CVD risk, while higher nut intake is associated with lower risks of CVD, CHD, and stroke mortality/incidence. Replacing animal-source foods with plant-source whole foods, beyond health benefits, lowers the diet’s carbon footprint. Meat alternatives are often ultraprocessed and evidence on their short- and long-term health effects is limited. Unsaturated fats are preferred, as are lean, nonprocessed meats.
• Use liquid plant oils rather than tropical oils (coconut, palm, and palm kernel), animal fats (butter and lard), and partially hydrogenated fats. Saturated and trans fats (animal and dairy fats, and partially hydrogenated fat) should be replaced with nontropical liquid plant oils. Evidence supports cardiovascular benefits of dietary unsaturated fats, especially polyunsaturated fats primarily from plant oils (e.g. soybean, corn, safflower and sunflower oils, walnuts, and flax seeds).
• Choose minimally processed foods instead of ultraprocessed foods. Because of their proven association with adverse health outcomes, including overweight and obesity, cardiometabolic disorders (type 2 diabetes, CVD), and all-cause mortality, the consumption of many ultraprocessed foods is of concern. Ultraprocessed foods include artificial colors and flavors and preservatives that promote shelf stability, preserve texture, and increase palatability. A general principle is to emphasize unprocessed or minimally processed foods.
• Minimize intake of beverages and foods with added sugars. Added sugars (commonly glucose, dextrose, sucrose, corn syrup, honey, maple syrup, and concentrated fruit juice) are tied to elevated risk for type 2 diabetes, high cholesterol, and excess body weight. Findings from meta-analyses on body weight and metabolic outcomes for replacing added sugars with low-energy sweeteners are mixed, and the possibility of reverse causality has been raised.
• Choose and prepare foods with little or no salt. In general, the effects of sodium reduction on blood pressure tend to be higher in Black people, middle-aged and older people, and those with hypertension. In the United States, the main combined sources of sodium intake are processed foods, those prepared outside the home, packaged foods, and restaurant foods. Potassium-enriched salts are a promising alternative.
• If you don’t drink alcohol, don’t start; if you choose to drink, limit intake.
• While relationships between alcohol intake and cardiovascular outcomes are complex, the 2020 Dietary Guidelines Advisory Committee recently concluded that those who do drink should consume no more than one drink per day and should not drink alcohol in binges; the 2020 Dietary Guidelines for Americans con­tinues to recommend no more than one drink per day for women and two drinks per day for men.
• Adhere to the guidance regardless in all settings. Food-based dietary guidance applies to all foods and beverages, regardless of where prepared, procured, and consumed. Policies should be enacted that encourage healthier default options (for example, whole grains, minimized sodium and sugar content).

Recognizing impediments

The AHA/ASA scientific statement closes with the declaration: “Creating an environment that facilitates, rather than impedes, adherence to heart-healthy dietary patterns among all individuals is a public health imperative.” It points to the National Institutes of Health’s 2020-2030 Strategic Plan for National Institutes of Health Nutrition Research, which focuses on precision nutrition as a means “to determine the impact on health of not only what individuals eat, but also of why, when, and how they eat throughout the life course.”

Ultimately, precision nutrition may provide personalized diets for CVD prevention. But the “food environment,” often conditioned by “rampant nutrition misinformation” through local, state, and federal practices and policies, may impede the adoption of heart-healthy dietary patterns. Factors such as targeted food marketing (for example, of processed food and beverages in minority neighborhoods), structural racism, neighborhood segregation, unhealthy built environments, and food insecurity create environments in which unhealthy foods are the default option.”

These factors compound adverse dietary and health effects, and underscore a need to “directly combat nutrition misinformation among the public and health care professionals.” They also explain why, despite widespread knowledge of heart-healthy dietary pattern components, little progress has been made in achieving dietary goals in the United States.

Dr. Lichtenstein’s office, in response to a request regarding AHA advocacy and consumer programs, provided the following links: Voices for Healthy Kids initiative site and choosing healthier processed foods and one on fresh, frozen, and canned fruits and vegetables.

Dr. Lichtenstein had no disclosures. Disclosures for the writing group members are included in the statement.

In a new scientific statement on diet and lifestyle recommendations, the American Heart Association is highlighting, for the first time, structural challenges that impede the adoption of heart-healthy dietary patterns.

American Heart Association

This is in addition to stressing aspects of diet that improve cardiovascular health and reduce cardiovascular risk, with an emphasis on dietary patterns and food-based guidance beyond naming individual foods or nutrients.

The 2021 Dietary Guidance to Improve Cardiovascular Health scientific statement, developed under Alice H. Lichtenstein, DSc, chair of the AHA writing group, provides 10 evidence-based guidance recommendations to promote cardiometabolic health.

“The way to make heart-healthy choices every day,” said Dr. Lichtenstein, of the Jean Mayer USDA Human Nutrition Research Center on Aging at Tufts University in Boston, in a statement, “is to step back, look at the environment in which you eat, whether it be at home, at work, during social interaction, and then identify what the best choices are. And if there are no good choices, then think about how you can modify your environment so that there are good choices.”

The statement, published in Circulation, underscores growing evidence that nutrition-related chronic diseases have maternal-nutritional origins, and that prevention of pediatric obesity is a key to preserving and prolonging ideal cardiovascular health.

The features are as follows:

• Adjust energy intake and expenditure to achieve and maintain a healthy body weight. To counter the shift toward higher energy intake and more sedentary lifestyles over the past 3 decades, the statement recommends at least 150 minutes of moderate physical activity per week, adjusted for individual’s age, activity level, sex, and size.
• Eat plenty of fruits and vegetables; choose a wide variety. Observational and intervention studies document that dietary patterns rich in varied fruits and vegetables, with the exception of white potatoes, are linked to a lower risk of cardiovascular disease (CVD). Also, whole fruits and vegetables, which more readily provide fiber and satiety, are preferred over juices.
• Choose whole grain foods and products made mostly with whole grains rather than refined grains. Evidence from observational, interventional, and clinical studies confirm the benefits of frequent consumption of whole grains over infrequent consumption or over refined grains in terms of CVD risk, coronary heart disease (CHD), stroke, metabolic syndrome, cardiometabolic risk factors, laxation, and gut microbiota.
• Choose healthy sources of protein, mostly from plants (legumes and nuts).
• Higher intake of legumes, which are rich in protein and fiber, is associated with lower CVD risk, while higher nut intake is associated with lower risks of CVD, CHD, and stroke mortality/incidence. Replacing animal-source foods with plant-source whole foods, beyond health benefits, lowers the diet’s carbon footprint. Meat alternatives are often ultraprocessed and evidence on their short- and long-term health effects is limited. Unsaturated fats are preferred, as are lean, nonprocessed meats.
• Use liquid plant oils rather than tropical oils (coconut, palm, and palm kernel), animal fats (butter and lard), and partially hydrogenated fats. Saturated and trans fats (animal and dairy fats, and partially hydrogenated fat) should be replaced with nontropical liquid plant oils. Evidence supports cardiovascular benefits of dietary unsaturated fats, especially polyunsaturated fats primarily from plant oils (e.g. soybean, corn, safflower and sunflower oils, walnuts, and flax seeds).
• Choose minimally processed foods instead of ultraprocessed foods. Because of their proven association with adverse health outcomes, including overweight and obesity, cardiometabolic disorders (type 2 diabetes, CVD), and all-cause mortality, the consumption of many ultraprocessed foods is of concern. Ultraprocessed foods include artificial colors and flavors and preservatives that promote shelf stability, preserve texture, and increase palatability. A general principle is to emphasize unprocessed or minimally processed foods.
• Minimize intake of beverages and foods with added sugars. Added sugars (commonly glucose, dextrose, sucrose, corn syrup, honey, maple syrup, and concentrated fruit juice) are tied to elevated risk for type 2 diabetes, high cholesterol, and excess body weight. Findings from meta-analyses on body weight and metabolic outcomes for replacing added sugars with low-energy sweeteners are mixed, and the possibility of reverse causality has been raised.
• Choose and prepare foods with little or no salt. In general, the effects of sodium reduction on blood pressure tend to be higher in Black people, middle-aged and older people, and those with hypertension. In the United States, the main combined sources of sodium intake are processed foods, those prepared outside the home, packaged foods, and restaurant foods. Potassium-enriched salts are a promising alternative.
• If you don’t drink alcohol, don’t start; if you choose to drink, limit intake.
• While relationships between alcohol intake and cardiovascular outcomes are complex, the 2020 Dietary Guidelines Advisory Committee recently concluded that those who do drink should consume no more than one drink per day and should not drink alcohol in binges; the 2020 Dietary Guidelines for Americans con­tinues to recommend no more than one drink per day for women and two drinks per day for men.
• Adhere to the guidance regardless in all settings. Food-based dietary guidance applies to all foods and beverages, regardless of where prepared, procured, and consumed. Policies should be enacted that encourage healthier default options (for example, whole grains, minimized sodium and sugar content).

Recognizing impediments

The AHA/ASA scientific statement closes with the declaration: “Creating an environment that facilitates, rather than impedes, adherence to heart-healthy dietary patterns among all individuals is a public health imperative.” It points to the National Institutes of Health’s 2020-2030 Strategic Plan for National Institutes of Health Nutrition Research, which focuses on precision nutrition as a means “to determine the impact on health of not only what individuals eat, but also of why, when, and how they eat throughout the life course.”

Ultimately, precision nutrition may provide personalized diets for CVD prevention. But the “food environment,” often conditioned by “rampant nutrition misinformation” through local, state, and federal practices and policies, may impede the adoption of heart-healthy dietary patterns. Factors such as targeted food marketing (for example, of processed food and beverages in minority neighborhoods), structural racism, neighborhood segregation, unhealthy built environments, and food insecurity create environments in which unhealthy foods are the default option.”

These factors compound adverse dietary and health effects, and underscore a need to “directly combat nutrition misinformation among the public and health care professionals.” They also explain why, despite widespread knowledge of heart-healthy dietary pattern components, little progress has been made in achieving dietary goals in the United States.

Dr. Lichtenstein’s office, in response to a request regarding AHA advocacy and consumer programs, provided the following links: Voices for Healthy Kids initiative site and choosing healthier processed foods and one on fresh, frozen, and canned fruits and vegetables.

Dr. Lichtenstein had no disclosures. Disclosures for the writing group members are included in the statement.

In a new scientific statement on diet and lifestyle recommendations, the American Heart Association is highlighting, for the first time, structural challenges that impede the adoption of heart-healthy dietary patterns.

American Heart Association

This is in addition to stressing aspects of diet that improve cardiovascular health and reduce cardiovascular risk, with an emphasis on dietary patterns and food-based guidance beyond naming individual foods or nutrients.

The 2021 Dietary Guidance to Improve Cardiovascular Health scientific statement, developed under Alice H. Lichtenstein, DSc, chair of the AHA writing group, provides 10 evidence-based guidance recommendations to promote cardiometabolic health.

“The way to make heart-healthy choices every day,” said Dr. Lichtenstein, of the Jean Mayer USDA Human Nutrition Research Center on Aging at Tufts University in Boston, in a statement, “is to step back, look at the environment in which you eat, whether it be at home, at work, during social interaction, and then identify what the best choices are. And if there are no good choices, then think about how you can modify your environment so that there are good choices.”

The statement, published in Circulation, underscores growing evidence that nutrition-related chronic diseases have maternal-nutritional origins, and that prevention of pediatric obesity is a key to preserving and prolonging ideal cardiovascular health.

The features are as follows:

• Adjust energy intake and expenditure to achieve and maintain a healthy body weight. To counter the shift toward higher energy intake and more sedentary lifestyles over the past 3 decades, the statement recommends at least 150 minutes of moderate physical activity per week, adjusted for individual’s age, activity level, sex, and size.
• Eat plenty of fruits and vegetables; choose a wide variety. Observational and intervention studies document that dietary patterns rich in varied fruits and vegetables, with the exception of white potatoes, are linked to a lower risk of cardiovascular disease (CVD). Also, whole fruits and vegetables, which more readily provide fiber and satiety, are preferred over juices.
• Choose whole grain foods and products made mostly with whole grains rather than refined grains. Evidence from observational, interventional, and clinical studies confirm the benefits of frequent consumption of whole grains over infrequent consumption or over refined grains in terms of CVD risk, coronary heart disease (CHD), stroke, metabolic syndrome, cardiometabolic risk factors, laxation, and gut microbiota.
• Choose healthy sources of protein, mostly from plants (legumes and nuts).
• Higher intake of legumes, which are rich in protein and fiber, is associated with lower CVD risk, while higher nut intake is associated with lower risks of CVD, CHD, and stroke mortality/incidence. Replacing animal-source foods with plant-source whole foods, beyond health benefits, lowers the diet’s carbon footprint. Meat alternatives are often ultraprocessed and evidence on their short- and long-term health effects is limited. Unsaturated fats are preferred, as are lean, nonprocessed meats.
• Use liquid plant oils rather than tropical oils (coconut, palm, and palm kernel), animal fats (butter and lard), and partially hydrogenated fats. Saturated and trans fats (animal and dairy fats, and partially hydrogenated fat) should be replaced with nontropical liquid plant oils. Evidence supports cardiovascular benefits of dietary unsaturated fats, especially polyunsaturated fats primarily from plant oils (e.g. soybean, corn, safflower and sunflower oils, walnuts, and flax seeds).
• Choose minimally processed foods instead of ultraprocessed foods. Because of their proven association with adverse health outcomes, including overweight and obesity, cardiometabolic disorders (type 2 diabetes, CVD), and all-cause mortality, the consumption of many ultraprocessed foods is of concern. Ultraprocessed foods include artificial colors and flavors and preservatives that promote shelf stability, preserve texture, and increase palatability. A general principle is to emphasize unprocessed or minimally processed foods.
• Minimize intake of beverages and foods with added sugars. Added sugars (commonly glucose, dextrose, sucrose, corn syrup, honey, maple syrup, and concentrated fruit juice) are tied to elevated risk for type 2 diabetes, high cholesterol, and excess body weight. Findings from meta-analyses on body weight and metabolic outcomes for replacing added sugars with low-energy sweeteners are mixed, and the possibility of reverse causality has been raised.
• Choose and prepare foods with little or no salt. In general, the effects of sodium reduction on blood pressure tend to be higher in Black people, middle-aged and older people, and those with hypertension. In the United States, the main combined sources of sodium intake are processed foods, those prepared outside the home, packaged foods, and restaurant foods. Potassium-enriched salts are a promising alternative.
• If you don’t drink alcohol, don’t start; if you choose to drink, limit intake.
• While relationships between alcohol intake and cardiovascular outcomes are complex, the 2020 Dietary Guidelines Advisory Committee recently concluded that those who do drink should consume no more than one drink per day and should not drink alcohol in binges; the 2020 Dietary Guidelines for Americans con­tinues to recommend no more than one drink per day for women and two drinks per day for men.
• Adhere to the guidance regardless in all settings. Food-based dietary guidance applies to all foods and beverages, regardless of where prepared, procured, and consumed. Policies should be enacted that encourage healthier default options (for example, whole grains, minimized sodium and sugar content).

Recognizing impediments

The AHA/ASA scientific statement closes with the declaration: “Creating an environment that facilitates, rather than impedes, adherence to heart-healthy dietary patterns among all individuals is a public health imperative.” It points to the National Institutes of Health’s 2020-2030 Strategic Plan for National Institutes of Health Nutrition Research, which focuses on precision nutrition as a means “to determine the impact on health of not only what individuals eat, but also of why, when, and how they eat throughout the life course.”

Ultimately, precision nutrition may provide personalized diets for CVD prevention. But the “food environment,” often conditioned by “rampant nutrition misinformation” through local, state, and federal practices and policies, may impede the adoption of heart-healthy dietary patterns. Factors such as targeted food marketing (for example, of processed food and beverages in minority neighborhoods), structural racism, neighborhood segregation, unhealthy built environments, and food insecurity create environments in which unhealthy foods are the default option.”

These factors compound adverse dietary and health effects, and underscore a need to “directly combat nutrition misinformation among the public and health care professionals.” They also explain why, despite widespread knowledge of heart-healthy dietary pattern components, little progress has been made in achieving dietary goals in the United States.

Dr. Lichtenstein’s office, in response to a request regarding AHA advocacy and consumer programs, provided the following links: Voices for Healthy Kids initiative site and choosing healthier processed foods and one on fresh, frozen, and canned fruits and vegetables.

Dr. Lichtenstein had no disclosures. Disclosures for the writing group members are included in the statement.

Placebo treatment was found to be superior to treatment with risankizumab with respect to time to first asthma worsening and annualized rate of asthma worsening for adults with severe persistent asthma in a phase 2a clinical trial.

The randomized, double-blind, 24-week, parallel group, multicenter trial assessed risankizumab efficacy and safety in 214 adults with severe persistent asthma. The results were reported in The New England Journal of Medicine.

Risankizumab is a humanized, monoclonal antibody directed against subunit p19 of interleukin-23. It is approved for the treatment of moderate to severe psoriasis.

Interleukin-23 has been implicated in airway inflammation mediated by type 2 and type 17 cytokines. Noting that inhibition of interleukin-23 is effective in the treatment of psoriasis and Crohn’s disease, Christopher E. Brightling, MD, and colleagues investigated whether targeting interleukin-23 in asthma patients would improve disease control and reduce airway inflammation.
 

Study details

Patients received either 90 mg of risankizumab (subcutaneous) (n = 105) or placebo (n = 109) once every 4 weeks. Time to first asthma worsening was the primary endpoint. Worsening was defined as decline from baseline on 2 or more consecutive days. Deterioration was defined as a decrease of at least 30% in the morning peak expiratory flow or an increase from baseline of at least 50% in rescue medication puffs over 24 hours. In addition, a severe asthma exacerbation or an increase of 0.75 or more points on the five-item Asthma Control Questionnaire (scores range from 0 to 6, with higher scores indicating less control) were considered to be evidence of worsening. Annualized rate of asthma worsening was a secondary endpoint.

The mean age of the patients was 53 years; 66.5% of the patients were women.
 

Disappointing results

In the risankizumab group, median time to first asthma worsening was 40 days, significantly worse than the 86 days reported for the placebo group (hazard ratio, 1.46; 95% confidence interval, 1.05-2.04; P = .03). For annualized asthma worsening, the rate ratio for the comparison of risankizumab with placebo was 1.49 (95% CI, 1.12-1.99).

Among key secondary endpoints, the adjusted mean change in trough forced expiratory volume in 1 second (FEV₁₎ from baseline to week 24 was –0.05 L in the risankizumab group and –0.01 L in the placebo group. The adjusted mean change in FEV₁ after bronchodilator use from baseline to week 24 was –0.10 L in the risankizumab group and –0.03 L in the placebo group. Sputum transcriptomic pathway analysis showed that genes involved in the activation of natural killer cells and cytotoxic T cells and the activation of type 1 helper T and type 17 helper T transcription factors were downregulated by risankizumab. Rates of adverse events were similar among patients receiving risankizumab and those taking placebo.
 

Further trials unwarranted

“The findings not only failed to show benefit for any outcome but also showed asthma worsening occurred earlier and more frequently in those treated with risankizumab versus placebo,” Dr. Brightling, professor in the department of respiratory sciences at University of Leicester, England, said in an interview. “This study does not support any further trials for anti-IL23 in asthma.” Dr. Brightling speculated on the cause of accelerated asthma worsening with risankizumab.

“We found that the gene expression of key molecules involved in our response to infection was decreased in airway samples in those treated with risankizumab versus placebo. It is possible that the increased asthma worsening following risankizumab was related to this suppression of antimicrobial immunity,” he said.

He noted that risankizumab did not affect type-2/eosinophilic inflammation, which is the target for current asthma biologics, or gene expression of T2 molecules. “That suggests that this type of inflammation would have continued in the asthma patients during the trial irrespective of receiving risankizumab or placebo,” he said.
 

Caution with investigating biologicals

Downstream biologic responses to risankizumab were detectable, Philip G. Bardin, PhD, and Paul S. Foster, DSc, observed in an accompanying editorial, but there was no discernible clinical benefit, implying attenuation of apposite pathways. Current understanding of the basic science relevant to asthma, they stated, offers clues to the failure of risankizumab to benefit these patients with severe asthma. Although targeting the interleukin-23 and Th17 axis with risankizumab can reduce development of pathogenic Th17 cells, interleukin-23 is not critical for the development of Th17 cells.

“In contrast to pathways operated by interleukin-5 and interleukin-4R alpha, interleukin-23 has only a limited auxiliary role in amplifying type 2 responses. It is possible that the trial conducted by Brightling and colleagues failed because signaling through alternative disease pathways nullified inhibition of inter-leukin-23,” the editorialists wrote.

Dr. Bardin and Dr. Foster further speculate that because interleukin-23 is vital for effective mucosal immunity, risankizumab may have conferred to patients a predisposition to more severe or more frequent virus-induced exacerbations. They stated that generally, however, the reasons for risankizumab’s poorer outcomes compared to placebo are unclear. “Overall, these findings support a cautious approach in future research investigating biologic therapies in asthma,” they concluded.

The clinical trial was sponsored and funded by BI/AbbVie.

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

Placebo treatment was found to be superior to treatment with risankizumab with respect to time to first asthma worsening and annualized rate of asthma worsening for adults with severe persistent asthma in a phase 2a clinical trial.

The randomized, double-blind, 24-week, parallel group, multicenter trial assessed risankizumab efficacy and safety in 214 adults with severe persistent asthma. The results were reported in The New England Journal of Medicine.

Risankizumab is a humanized, monoclonal antibody directed against subunit p19 of interleukin-23. It is approved for the treatment of moderate to severe psoriasis.

Interleukin-23 has been implicated in airway inflammation mediated by type 2 and type 17 cytokines. Noting that inhibition of interleukin-23 is effective in the treatment of psoriasis and Crohn’s disease, Christopher E. Brightling, MD, and colleagues investigated whether targeting interleukin-23 in asthma patients would improve disease control and reduce airway inflammation.
 

Study details

Patients received either 90 mg of risankizumab (subcutaneous) (n = 105) or placebo (n = 109) once every 4 weeks. Time to first asthma worsening was the primary endpoint. Worsening was defined as decline from baseline on 2 or more consecutive days. Deterioration was defined as a decrease of at least 30% in the morning peak expiratory flow or an increase from baseline of at least 50% in rescue medication puffs over 24 hours. In addition, a severe asthma exacerbation or an increase of 0.75 or more points on the five-item Asthma Control Questionnaire (scores range from 0 to 6, with higher scores indicating less control) were considered to be evidence of worsening. Annualized rate of asthma worsening was a secondary endpoint.

The mean age of the patients was 53 years; 66.5% of the patients were women.
 

Disappointing results

In the risankizumab group, median time to first asthma worsening was 40 days, significantly worse than the 86 days reported for the placebo group (hazard ratio, 1.46; 95% confidence interval, 1.05-2.04; P = .03). For annualized asthma worsening, the rate ratio for the comparison of risankizumab with placebo was 1.49 (95% CI, 1.12-1.99).

Among key secondary endpoints, the adjusted mean change in trough forced expiratory volume in 1 second (FEV₁₎ from baseline to week 24 was –0.05 L in the risankizumab group and –0.01 L in the placebo group. The adjusted mean change in FEV₁ after bronchodilator use from baseline to week 24 was –0.10 L in the risankizumab group and –0.03 L in the placebo group. Sputum transcriptomic pathway analysis showed that genes involved in the activation of natural killer cells and cytotoxic T cells and the activation of type 1 helper T and type 17 helper T transcription factors were downregulated by risankizumab. Rates of adverse events were similar among patients receiving risankizumab and those taking placebo.
 

Further trials unwarranted

“The findings not only failed to show benefit for any outcome but also showed asthma worsening occurred earlier and more frequently in those treated with risankizumab versus placebo,” Dr. Brightling, professor in the department of respiratory sciences at University of Leicester, England, said in an interview. “This study does not support any further trials for anti-IL23 in asthma.” Dr. Brightling speculated on the cause of accelerated asthma worsening with risankizumab.

“We found that the gene expression of key molecules involved in our response to infection was decreased in airway samples in those treated with risankizumab versus placebo. It is possible that the increased asthma worsening following risankizumab was related to this suppression of antimicrobial immunity,” he said.

He noted that risankizumab did not affect type-2/eosinophilic inflammation, which is the target for current asthma biologics, or gene expression of T2 molecules. “That suggests that this type of inflammation would have continued in the asthma patients during the trial irrespective of receiving risankizumab or placebo,” he said.
 

Caution with investigating biologicals

Downstream biologic responses to risankizumab were detectable, Philip G. Bardin, PhD, and Paul S. Foster, DSc, observed in an accompanying editorial, but there was no discernible clinical benefit, implying attenuation of apposite pathways. Current understanding of the basic science relevant to asthma, they stated, offers clues to the failure of risankizumab to benefit these patients with severe asthma. Although targeting the interleukin-23 and Th17 axis with risankizumab can reduce development of pathogenic Th17 cells, interleukin-23 is not critical for the development of Th17 cells.

“In contrast to pathways operated by interleukin-5 and interleukin-4R alpha, interleukin-23 has only a limited auxiliary role in amplifying type 2 responses. It is possible that the trial conducted by Brightling and colleagues failed because signaling through alternative disease pathways nullified inhibition of inter-leukin-23,” the editorialists wrote.

Dr. Bardin and Dr. Foster further speculate that because interleukin-23 is vital for effective mucosal immunity, risankizumab may have conferred to patients a predisposition to more severe or more frequent virus-induced exacerbations. They stated that generally, however, the reasons for risankizumab’s poorer outcomes compared to placebo are unclear. “Overall, these findings support a cautious approach in future research investigating biologic therapies in asthma,” they concluded.

The clinical trial was sponsored and funded by BI/AbbVie.

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

Placebo treatment was found to be superior to treatment with risankizumab with respect to time to first asthma worsening and annualized rate of asthma worsening for adults with severe persistent asthma in a phase 2a clinical trial.

The randomized, double-blind, 24-week, parallel group, multicenter trial assessed risankizumab efficacy and safety in 214 adults with severe persistent asthma. The results were reported in The New England Journal of Medicine.

Risankizumab is a humanized, monoclonal antibody directed against subunit p19 of interleukin-23. It is approved for the treatment of moderate to severe psoriasis.

Interleukin-23 has been implicated in airway inflammation mediated by type 2 and type 17 cytokines. Noting that inhibition of interleukin-23 is effective in the treatment of psoriasis and Crohn’s disease, Christopher E. Brightling, MD, and colleagues investigated whether targeting interleukin-23 in asthma patients would improve disease control and reduce airway inflammation.
 

Study details

Patients received either 90 mg of risankizumab (subcutaneous) (n = 105) or placebo (n = 109) once every 4 weeks. Time to first asthma worsening was the primary endpoint. Worsening was defined as decline from baseline on 2 or more consecutive days. Deterioration was defined as a decrease of at least 30% in the morning peak expiratory flow or an increase from baseline of at least 50% in rescue medication puffs over 24 hours. In addition, a severe asthma exacerbation or an increase of 0.75 or more points on the five-item Asthma Control Questionnaire (scores range from 0 to 6, with higher scores indicating less control) were considered to be evidence of worsening. Annualized rate of asthma worsening was a secondary endpoint.

The mean age of the patients was 53 years; 66.5% of the patients were women.
 

Disappointing results

In the risankizumab group, median time to first asthma worsening was 40 days, significantly worse than the 86 days reported for the placebo group (hazard ratio, 1.46; 95% confidence interval, 1.05-2.04; P = .03). For annualized asthma worsening, the rate ratio for the comparison of risankizumab with placebo was 1.49 (95% CI, 1.12-1.99).

Among key secondary endpoints, the adjusted mean change in trough forced expiratory volume in 1 second (FEV₁₎ from baseline to week 24 was –0.05 L in the risankizumab group and –0.01 L in the placebo group. The adjusted mean change in FEV₁ after bronchodilator use from baseline to week 24 was –0.10 L in the risankizumab group and –0.03 L in the placebo group. Sputum transcriptomic pathway analysis showed that genes involved in the activation of natural killer cells and cytotoxic T cells and the activation of type 1 helper T and type 17 helper T transcription factors were downregulated by risankizumab. Rates of adverse events were similar among patients receiving risankizumab and those taking placebo.
 

Further trials unwarranted

“The findings not only failed to show benefit for any outcome but also showed asthma worsening occurred earlier and more frequently in those treated with risankizumab versus placebo,” Dr. Brightling, professor in the department of respiratory sciences at University of Leicester, England, said in an interview. “This study does not support any further trials for anti-IL23 in asthma.” Dr. Brightling speculated on the cause of accelerated asthma worsening with risankizumab.

“We found that the gene expression of key molecules involved in our response to infection was decreased in airway samples in those treated with risankizumab versus placebo. It is possible that the increased asthma worsening following risankizumab was related to this suppression of antimicrobial immunity,” he said.

He noted that risankizumab did not affect type-2/eosinophilic inflammation, which is the target for current asthma biologics, or gene expression of T2 molecules. “That suggests that this type of inflammation would have continued in the asthma patients during the trial irrespective of receiving risankizumab or placebo,” he said.
 

Caution with investigating biologicals

Downstream biologic responses to risankizumab were detectable, Philip G. Bardin, PhD, and Paul S. Foster, DSc, observed in an accompanying editorial, but there was no discernible clinical benefit, implying attenuation of apposite pathways. Current understanding of the basic science relevant to asthma, they stated, offers clues to the failure of risankizumab to benefit these patients with severe asthma. Although targeting the interleukin-23 and Th17 axis with risankizumab can reduce development of pathogenic Th17 cells, interleukin-23 is not critical for the development of Th17 cells.

“In contrast to pathways operated by interleukin-5 and interleukin-4R alpha, interleukin-23 has only a limited auxiliary role in amplifying type 2 responses. It is possible that the trial conducted by Brightling and colleagues failed because signaling through alternative disease pathways nullified inhibition of inter-leukin-23,” the editorialists wrote.

Dr. Bardin and Dr. Foster further speculate that because interleukin-23 is vital for effective mucosal immunity, risankizumab may have conferred to patients a predisposition to more severe or more frequent virus-induced exacerbations. They stated that generally, however, the reasons for risankizumab’s poorer outcomes compared to placebo are unclear. “Overall, these findings support a cautious approach in future research investigating biologic therapies in asthma,” they concluded.

The clinical trial was sponsored and funded by BI/AbbVie.

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

While the use of Bruton tyrosine kinase inhibitors has significantly enhanced treatment of patients with B-cell malignancies, BTKi resistance is the “Achilles’ heel” of this otherwise effective therapeutic option, Deborah M. Stephens, DO, and John C. Byrd, MD, stated in a review article published in Blood.

Among patients with B-cell malignancies – including chronic lymphocytic leukemia (CLL), Waldenström’s macroglobulinemia (WM), mantle cell lymphoma (MCL), and marginal zone lymphoma (MZL) – BTKis have substantial efficacy. The review article focuses mainly on extremely rare primary or more common acquired BTKi resistance, particularly among patients with acquired resistance to ibrutinib (11%-38% in large studies).

Primary resistance suggests an alternative diagnosis or transformation to a more aggressive lymphoma. Acquired ibrutinib resistance manifests either as progressive CLL (typically after 2 years of therapy) or as early transformation (within the first 2 years of therapy) to more aggressive entities such as diffuse large B-cell lymphoma, Hodgkin lymphoma, or prolymphocytic leukemia. Less studied than ibrutinib, acquired resistance to acalabrutinib and zanubrutinib has been in the 12%-15% range.

Acquired resistance has meant a reduction in expected overall survival, and while the introduction of new therapies like venetoclax has extended OS, short progression-free survival (PFS) provides a rationale for research into mechanisms of resistance and alternative treatments.

Acquired resistance

Most often acquired, resistance to ibrutinib monotherapy in CLL patients has been associated with high-risk genomic features: complex karyotype, TP53 mutation, del(17)p13.1, and heavy pretreatment. In the phase 3 RESONATE trial, patients with both TP53 mutation and del(17)p13.1 had shorter PFS than those with only one or the other genomic feature. This feature may have explained the fairly good ibrutinib monotherapy outcomes in treatment-naive patients with del(17p)13.1.

Through univariable and multivariable analysis, a machine-learning program consistently identified TP53 mutation, prior CLL therapy, beta-2 microglobulin of at least5 mg/L, and lactate dehydrogenase greater than250 U/L as four risk factors associated with impaired survival. A second survival factor program comparing ibrutinib with chemoimmunotherapy identified beta-2 microglobulin levels of at least5 mg/L, lactate dehydrogenase greater than ULN, hemoglobin less than 110 g/L for women or less than120 g/L for men, and time from initiation of last therapy less than 24 months as risk factors.

While the mechanisms leading to ibrutinib resistance are not clearly known for patients with these risk factors, some research suggests that survival of TP53-mutated CLL cells is less dependent on the BCR pathway, making this CLL type more prone to ibrutinib resistance. TP53-mutated CLL cells, compared with T53–wild-type CLL cells, demonstrate a down-regulation of BCR-related genes and an up-regulation of prosurvival and antiapototic genes.
 

BTK mutations

Mutation of the active kinase domain on the BTK enzyme (C481) is the most common BTKi resistance mechanism described in CLL. A thymidine to adenine mutation (nucleotide 1634) leads to a 25-fold decrease in drug potency. Other known gene or chromosome regions affected in BTKi resistance include PLCy2, Del(8p), CARD11, TRAF2&3, BIRC3, MAP3k14, ARID2, SMARCA2, SMARCA4, MYD88, KLH14, and TNFAIP3.

Multiple mutations of PLCy2, the next most common BTKi resistance mechanism, include mutations of arginine to tryptophan, leucine to phenylalanine, serine to tyrosine, and others. When activated, these gain-of-function mutations prolong BCR signaling.

Ibrutinib resistance has also been associated with deletion of the short arm of chromosome 8 (del[8p]), with CLL cells harboring del(8p) insensitive to TRAIL-induced apoptosis, leading to continuous cell growth. Ibrutinib resistance in patients with WM has also been associated with del(8p).

CARD11 mutations, which allow for BTK-independent activation of NFkB, have been documented in ibrutinib-resistant patients with CLL and other lymphoid malignancies, as detailed in this review.
 

Novel therapies suggest promise

Survival in CLL after BTKi resistance develops is quite short, according to the authors, and they expressed hope that continued research into novel agents would prolong this population’s survival.

Venetoclax, an oral inhibitor of the antiapoptotic protein BCL2, is approved for all patients with CLL, both as monotherapy and in combination with an anti-CD20 monoclonal antibody. Data support its use after BTKi resistance has been detected. Some evidence in CLL cell lines supports use of the oral phosphoinositide 3-kinases inhibitors idelalisib and duvelisib in relapsed CLL and the BTK C481S mutation. Early response data with third-generation BTKis, such as ARQ-531 and LOXO-305, suggest promise in this setting. Also, for young and healthy patients who have progressed on both BTKi and venetoclax therapy, allogeneic hematopoietic stem cell transplantation could be considered.

In patients with heavily pretreated CLL, early clinical data support chimeric antigen receptor T-cell therapy (CAR T), a novel therapy where patients’ own T cells are extracted, engineered, and reinfused. A related immunotherapy, using a similar process of retroviral vector insertion of an anti-CD19 CAR into donor NK cells before infusion into the patient, is termed CAR-NK cell therapy. It shows promise in early data from patients with CLL who all had previously been heavily treated with ibrutinib.

More research, more hope

Despite the significant advance that BTKis represent, BTKi resistance, with shortened survival, remains a clinical problem for patients with B-cell malignancies. BTKi resistance has been associated with several genetic and clinical risk factors, with mutations in BTK and PLCy2 the most common and most thoroughly researched. “Ongoing clinical trials of third-generation noncovalent BTKis and cellular therapies, such as CAR T, provide much hope for these patients. ... Continued additional research is needed to further prolong the survival of patients with BTKi-resistant B-cell malignancies.”

Dr. Stephens has received research funding and has served on advisory boards for a variety of pharmaceutical and biotechnology companies. Dr. Byrd has received research funding and has consulted for a variety of pharmaceutical and biotechnology companies.

While the use of Bruton tyrosine kinase inhibitors has significantly enhanced treatment of patients with B-cell malignancies, BTKi resistance is the “Achilles’ heel” of this otherwise effective therapeutic option, Deborah M. Stephens, DO, and John C. Byrd, MD, stated in a review article published in Blood.

Among patients with B-cell malignancies – including chronic lymphocytic leukemia (CLL), Waldenström’s macroglobulinemia (WM), mantle cell lymphoma (MCL), and marginal zone lymphoma (MZL) – BTKis have substantial efficacy. The review article focuses mainly on extremely rare primary or more common acquired BTKi resistance, particularly among patients with acquired resistance to ibrutinib (11%-38% in large studies).

Primary resistance suggests an alternative diagnosis or transformation to a more aggressive lymphoma. Acquired ibrutinib resistance manifests either as progressive CLL (typically after 2 years of therapy) or as early transformation (within the first 2 years of therapy) to more aggressive entities such as diffuse large B-cell lymphoma, Hodgkin lymphoma, or prolymphocytic leukemia. Less studied than ibrutinib, acquired resistance to acalabrutinib and zanubrutinib has been in the 12%-15% range.

Acquired resistance has meant a reduction in expected overall survival, and while the introduction of new therapies like venetoclax has extended OS, short progression-free survival (PFS) provides a rationale for research into mechanisms of resistance and alternative treatments.

Acquired resistance

Most often acquired, resistance to ibrutinib monotherapy in CLL patients has been associated with high-risk genomic features: complex karyotype, TP53 mutation, del(17)p13.1, and heavy pretreatment. In the phase 3 RESONATE trial, patients with both TP53 mutation and del(17)p13.1 had shorter PFS than those with only one or the other genomic feature. This feature may have explained the fairly good ibrutinib monotherapy outcomes in treatment-naive patients with del(17p)13.1.

Through univariable and multivariable analysis, a machine-learning program consistently identified TP53 mutation, prior CLL therapy, beta-2 microglobulin of at least5 mg/L, and lactate dehydrogenase greater than250 U/L as four risk factors associated with impaired survival. A second survival factor program comparing ibrutinib with chemoimmunotherapy identified beta-2 microglobulin levels of at least5 mg/L, lactate dehydrogenase greater than ULN, hemoglobin less than 110 g/L for women or less than120 g/L for men, and time from initiation of last therapy less than 24 months as risk factors.

While the mechanisms leading to ibrutinib resistance are not clearly known for patients with these risk factors, some research suggests that survival of TP53-mutated CLL cells is less dependent on the BCR pathway, making this CLL type more prone to ibrutinib resistance. TP53-mutated CLL cells, compared with T53–wild-type CLL cells, demonstrate a down-regulation of BCR-related genes and an up-regulation of prosurvival and antiapototic genes.
 

BTK mutations

Mutation of the active kinase domain on the BTK enzyme (C481) is the most common BTKi resistance mechanism described in CLL. A thymidine to adenine mutation (nucleotide 1634) leads to a 25-fold decrease in drug potency. Other known gene or chromosome regions affected in BTKi resistance include PLCy2, Del(8p), CARD11, TRAF2&3, BIRC3, MAP3k14, ARID2, SMARCA2, SMARCA4, MYD88, KLH14, and TNFAIP3.

Multiple mutations of PLCy2, the next most common BTKi resistance mechanism, include mutations of arginine to tryptophan, leucine to phenylalanine, serine to tyrosine, and others. When activated, these gain-of-function mutations prolong BCR signaling.

Ibrutinib resistance has also been associated with deletion of the short arm of chromosome 8 (del[8p]), with CLL cells harboring del(8p) insensitive to TRAIL-induced apoptosis, leading to continuous cell growth. Ibrutinib resistance in patients with WM has also been associated with del(8p).

CARD11 mutations, which allow for BTK-independent activation of NFkB, have been documented in ibrutinib-resistant patients with CLL and other lymphoid malignancies, as detailed in this review.
 

Novel therapies suggest promise

Survival in CLL after BTKi resistance develops is quite short, according to the authors, and they expressed hope that continued research into novel agents would prolong this population’s survival.

Venetoclax, an oral inhibitor of the antiapoptotic protein BCL2, is approved for all patients with CLL, both as monotherapy and in combination with an anti-CD20 monoclonal antibody. Data support its use after BTKi resistance has been detected. Some evidence in CLL cell lines supports use of the oral phosphoinositide 3-kinases inhibitors idelalisib and duvelisib in relapsed CLL and the BTK C481S mutation. Early response data with third-generation BTKis, such as ARQ-531 and LOXO-305, suggest promise in this setting. Also, for young and healthy patients who have progressed on both BTKi and venetoclax therapy, allogeneic hematopoietic stem cell transplantation could be considered.

In patients with heavily pretreated CLL, early clinical data support chimeric antigen receptor T-cell therapy (CAR T), a novel therapy where patients’ own T cells are extracted, engineered, and reinfused. A related immunotherapy, using a similar process of retroviral vector insertion of an anti-CD19 CAR into donor NK cells before infusion into the patient, is termed CAR-NK cell therapy. It shows promise in early data from patients with CLL who all had previously been heavily treated with ibrutinib.

More research, more hope

Despite the significant advance that BTKis represent, BTKi resistance, with shortened survival, remains a clinical problem for patients with B-cell malignancies. BTKi resistance has been associated with several genetic and clinical risk factors, with mutations in BTK and PLCy2 the most common and most thoroughly researched. “Ongoing clinical trials of third-generation noncovalent BTKis and cellular therapies, such as CAR T, provide much hope for these patients. ... Continued additional research is needed to further prolong the survival of patients with BTKi-resistant B-cell malignancies.”

Dr. Stephens has received research funding and has served on advisory boards for a variety of pharmaceutical and biotechnology companies. Dr. Byrd has received research funding and has consulted for a variety of pharmaceutical and biotechnology companies.

While the use of Bruton tyrosine kinase inhibitors has significantly enhanced treatment of patients with B-cell malignancies, BTKi resistance is the “Achilles’ heel” of this otherwise effective therapeutic option, Deborah M. Stephens, DO, and John C. Byrd, MD, stated in a review article published in Blood.

Among patients with B-cell malignancies – including chronic lymphocytic leukemia (CLL), Waldenström’s macroglobulinemia (WM), mantle cell lymphoma (MCL), and marginal zone lymphoma (MZL) – BTKis have substantial efficacy. The review article focuses mainly on extremely rare primary or more common acquired BTKi resistance, particularly among patients with acquired resistance to ibrutinib (11%-38% in large studies).

Primary resistance suggests an alternative diagnosis or transformation to a more aggressive lymphoma. Acquired ibrutinib resistance manifests either as progressive CLL (typically after 2 years of therapy) or as early transformation (within the first 2 years of therapy) to more aggressive entities such as diffuse large B-cell lymphoma, Hodgkin lymphoma, or prolymphocytic leukemia. Less studied than ibrutinib, acquired resistance to acalabrutinib and zanubrutinib has been in the 12%-15% range.

Acquired resistance has meant a reduction in expected overall survival, and while the introduction of new therapies like venetoclax has extended OS, short progression-free survival (PFS) provides a rationale for research into mechanisms of resistance and alternative treatments.

Acquired resistance

Most often acquired, resistance to ibrutinib monotherapy in CLL patients has been associated with high-risk genomic features: complex karyotype, TP53 mutation, del(17)p13.1, and heavy pretreatment. In the phase 3 RESONATE trial, patients with both TP53 mutation and del(17)p13.1 had shorter PFS than those with only one or the other genomic feature. This feature may have explained the fairly good ibrutinib monotherapy outcomes in treatment-naive patients with del(17p)13.1.

Through univariable and multivariable analysis, a machine-learning program consistently identified TP53 mutation, prior CLL therapy, beta-2 microglobulin of at least5 mg/L, and lactate dehydrogenase greater than250 U/L as four risk factors associated with impaired survival. A second survival factor program comparing ibrutinib with chemoimmunotherapy identified beta-2 microglobulin levels of at least5 mg/L, lactate dehydrogenase greater than ULN, hemoglobin less than 110 g/L for women or less than120 g/L for men, and time from initiation of last therapy less than 24 months as risk factors.

While the mechanisms leading to ibrutinib resistance are not clearly known for patients with these risk factors, some research suggests that survival of TP53-mutated CLL cells is less dependent on the BCR pathway, making this CLL type more prone to ibrutinib resistance. TP53-mutated CLL cells, compared with T53–wild-type CLL cells, demonstrate a down-regulation of BCR-related genes and an up-regulation of prosurvival and antiapototic genes.
 

BTK mutations

Mutation of the active kinase domain on the BTK enzyme (C481) is the most common BTKi resistance mechanism described in CLL. A thymidine to adenine mutation (nucleotide 1634) leads to a 25-fold decrease in drug potency. Other known gene or chromosome regions affected in BTKi resistance include PLCy2, Del(8p), CARD11, TRAF2&3, BIRC3, MAP3k14, ARID2, SMARCA2, SMARCA4, MYD88, KLH14, and TNFAIP3.

Multiple mutations of PLCy2, the next most common BTKi resistance mechanism, include mutations of arginine to tryptophan, leucine to phenylalanine, serine to tyrosine, and others. When activated, these gain-of-function mutations prolong BCR signaling.

Ibrutinib resistance has also been associated with deletion of the short arm of chromosome 8 (del[8p]), with CLL cells harboring del(8p) insensitive to TRAIL-induced apoptosis, leading to continuous cell growth. Ibrutinib resistance in patients with WM has also been associated with del(8p).

CARD11 mutations, which allow for BTK-independent activation of NFkB, have been documented in ibrutinib-resistant patients with CLL and other lymphoid malignancies, as detailed in this review.
 

Novel therapies suggest promise

Survival in CLL after BTKi resistance develops is quite short, according to the authors, and they expressed hope that continued research into novel agents would prolong this population’s survival.

Venetoclax, an oral inhibitor of the antiapoptotic protein BCL2, is approved for all patients with CLL, both as monotherapy and in combination with an anti-CD20 monoclonal antibody. Data support its use after BTKi resistance has been detected. Some evidence in CLL cell lines supports use of the oral phosphoinositide 3-kinases inhibitors idelalisib and duvelisib in relapsed CLL and the BTK C481S mutation. Early response data with third-generation BTKis, such as ARQ-531 and LOXO-305, suggest promise in this setting. Also, for young and healthy patients who have progressed on both BTKi and venetoclax therapy, allogeneic hematopoietic stem cell transplantation could be considered.

In patients with heavily pretreated CLL, early clinical data support chimeric antigen receptor T-cell therapy (CAR T), a novel therapy where patients’ own T cells are extracted, engineered, and reinfused. A related immunotherapy, using a similar process of retroviral vector insertion of an anti-CD19 CAR into donor NK cells before infusion into the patient, is termed CAR-NK cell therapy. It shows promise in early data from patients with CLL who all had previously been heavily treated with ibrutinib.

More research, more hope

Despite the significant advance that BTKis represent, BTKi resistance, with shortened survival, remains a clinical problem for patients with B-cell malignancies. BTKi resistance has been associated with several genetic and clinical risk factors, with mutations in BTK and PLCy2 the most common and most thoroughly researched. “Ongoing clinical trials of third-generation noncovalent BTKis and cellular therapies, such as CAR T, provide much hope for these patients. ... Continued additional research is needed to further prolong the survival of patients with BTKi-resistant B-cell malignancies.”

Dr. Stephens has received research funding and has served on advisory boards for a variety of pharmaceutical and biotechnology companies. Dr. Byrd has received research funding and has consulted for a variety of pharmaceutical and biotechnology companies.

Patients with a baseline DLCO (diffusing capacity for carbon monoxide) of < 60% of predicted have more severe disease clinical expression with higher mortality risk, according to a long-term observational study of Global Initiative for Obstructive Lung Disease (GOLD) I chronic obstructive pulmonary disease (COPD) patients. Clarifying mechanisms of low DLCO may help clinicians direct interventions toward ameliorating the low capacity, Juan Pablo de Torres, MD, and colleagues wrote in the journal CHEST^®.

Defining increased risk

“Can a DLCO threshold help define an increased risk of death and a different clinical presentation in GOLD I patients?” the researchers questioned. For evaluation of COPD, the GOLD does not currently promote the use of DLCO, and the clinical and prognostic utility of a low DLCO has not been studied, the authors noted.

Several COPD studies, however, have shown associations between low DLCO values and reduced exercise capacity, increased symptoms, risk of severe exacerbations, and mortality. The patients included in these studies, however, have generally had moderate to severe airflow limitation, and have not had postbronchodilator forced expiratory volume in 1 second/forced vital capacity (FEV₁/FVC) < 0.70 and an FEV₁ ≥ 80%, defined by GOLD as COPD spirometric stage I. These mild obstruction GOLD I patients, in large epidemiological studies, do have increased risk of death. But it is often assumed, Dr. de Torres and colleagues noted, that “mild” suggests a good prognosis. They propose that a simple DLCO measurement could help identify those GOLD I patients with “worse overall COPD compromise and an increased risk of death.” Importantly, GOLD I represents the largest percentage of patients with airflow limitation that epidemiological studies have identified.

The researchers enrolled 360 GOLD stage I COPD patients, recording their age, sex, pack-years’ history, body mass index, dyspnea, lung function measurements, exercise capacity, BODE (body mass index, airflow obstruction, dyspnea, and exercise capacity) index, and history of exacerbations, and followed them for a mean of 109 months. They identified a cutoff DLCO value for all-cause mortality, compared the clinical and physiological characteristics of patients above and below the threshold, and explored the predictive power of that cutoff value.
 

All-cause mortality difference

The mean age in the overall population studied was 63 years (31% were women), with 43% active smokers, and pack-years history of 45. Overall mortality was 11% during the follow-up period. The predominantly male population was mildly overweight, had few comorbidities, normal FEV₁ values, mild dyspnea, normal 6-minute walk distance, and very few exacerbations.

Analysis showed a DLCO cutoff value of < 60% was associated with a significant all-cause mortality differential (DLCO ≥ 60%: 9% vs. DLCO < 60%: 23%, P = .01). At a same FEV₁% predicted and Charlson score, patients with DLCO < 60% had lower BMI, more dyspnea, lower inspiratory capacity (IC)/total lung capacity (TLC) ratio, lower 6-minute walk distance, and higher BODE index. Adjusted Cox multiple regression analysis confirmed that a DLCO < 60% was associated with an all-cause mortality hazard ratio [HR] of 3.37, (95% confidence interval, 1.35-8.39; P = .009).
 

Multiorgan loss of tissue

The researchers found that patients with baseline DLCO < 60% were more likely to be women (46% versus 28%), and to have a lower BMI (25 vs. 27), higher pack-year history (54 vs. 43), the same spirometric values but lower IC/TLC ratio (.37 vs. .40), a lower walk distance (443 vs. 485 meters), higher dyspnea (MRC score 1.1 vs. .7), similar exacerbation rate, higher BODE index (.5 vs. .2) and higher mortality than patients with higher DLCO % predicted values. This group, Dr. de Torres and colleagues suggest, represents a multiorgan loss of tissue, a phenotype associated with worse clinical outcomes and prognosis.

“Low DLCO in these patients,” Dr. de Torres said in an interview, “could mainly be secondary to coexistent emphysema, which is the most common cause of low DLCO in this population. Also possible, but less likely, is coexistent pulmonary hypertension.” He noted further that “This study opens the door to research specifically testing if such is the case, and if it is, for clinicians to use available therapies to prevent adverse outcomes.”
 

Comorbidity burden

Patients with GOLD I COPD die more often of cardiovascular disease instead of underlying lung disease, according to Richard H. Zou, MD, and Jessica Bon, MD, of the University of Pittsburgh, in an accompanying editorial in the journal CHEST.

Increased mortality rates, they suggest, may be related to higher comorbidity burden, particularly comorbidities associated with cardiovascular-related health. Subclinical cardiovascular disease is a common comorbidity in COPD, and concomitant endothelial dysfunction has been associated with both cardiovascular disease and early emphysema in smokers. They may have disproportionately reduced DLCO levels because of parenchymal destruction.

“This study suggests that DLCO can be used to identify patients with GOLD I COPD at increased death risk and that individuals with mild airflow obstruction with DLCO <60% predicted are a clinical phenotype distinct from those with higher DLCO levels,” Dr. Zhou and Dr. Bon concluded.

The researchers and the editorialists declared that they had no disclosures. One of the three cohorts assessed in the current study (CHAIN cohort in Spain) received funding from AstraZeneca.

Patients with a baseline DLCO (diffusing capacity for carbon monoxide) of < 60% of predicted have more severe disease clinical expression with higher mortality risk, according to a long-term observational study of Global Initiative for Obstructive Lung Disease (GOLD) I chronic obstructive pulmonary disease (COPD) patients. Clarifying mechanisms of low DLCO may help clinicians direct interventions toward ameliorating the low capacity, Juan Pablo de Torres, MD, and colleagues wrote in the journal CHEST^®.

Defining increased risk

“Can a DLCO threshold help define an increased risk of death and a different clinical presentation in GOLD I patients?” the researchers questioned. For evaluation of COPD, the GOLD does not currently promote the use of DLCO, and the clinical and prognostic utility of a low DLCO has not been studied, the authors noted.

Several COPD studies, however, have shown associations between low DLCO values and reduced exercise capacity, increased symptoms, risk of severe exacerbations, and mortality. The patients included in these studies, however, have generally had moderate to severe airflow limitation, and have not had postbronchodilator forced expiratory volume in 1 second/forced vital capacity (FEV₁/FVC) < 0.70 and an FEV₁ ≥ 80%, defined by GOLD as COPD spirometric stage I. These mild obstruction GOLD I patients, in large epidemiological studies, do have increased risk of death. But it is often assumed, Dr. de Torres and colleagues noted, that “mild” suggests a good prognosis. They propose that a simple DLCO measurement could help identify those GOLD I patients with “worse overall COPD compromise and an increased risk of death.” Importantly, GOLD I represents the largest percentage of patients with airflow limitation that epidemiological studies have identified.

The researchers enrolled 360 GOLD stage I COPD patients, recording their age, sex, pack-years’ history, body mass index, dyspnea, lung function measurements, exercise capacity, BODE (body mass index, airflow obstruction, dyspnea, and exercise capacity) index, and history of exacerbations, and followed them for a mean of 109 months. They identified a cutoff DLCO value for all-cause mortality, compared the clinical and physiological characteristics of patients above and below the threshold, and explored the predictive power of that cutoff value.
 

All-cause mortality difference

The mean age in the overall population studied was 63 years (31% were women), with 43% active smokers, and pack-years history of 45. Overall mortality was 11% during the follow-up period. The predominantly male population was mildly overweight, had few comorbidities, normal FEV₁ values, mild dyspnea, normal 6-minute walk distance, and very few exacerbations.

Analysis showed a DLCO cutoff value of < 60% was associated with a significant all-cause mortality differential (DLCO ≥ 60%: 9% vs. DLCO < 60%: 23%, P = .01). At a same FEV₁% predicted and Charlson score, patients with DLCO < 60% had lower BMI, more dyspnea, lower inspiratory capacity (IC)/total lung capacity (TLC) ratio, lower 6-minute walk distance, and higher BODE index. Adjusted Cox multiple regression analysis confirmed that a DLCO < 60% was associated with an all-cause mortality hazard ratio [HR] of 3.37, (95% confidence interval, 1.35-8.39; P = .009).
 

Multiorgan loss of tissue

The researchers found that patients with baseline DLCO < 60% were more likely to be women (46% versus 28%), and to have a lower BMI (25 vs. 27), higher pack-year history (54 vs. 43), the same spirometric values but lower IC/TLC ratio (.37 vs. .40), a lower walk distance (443 vs. 485 meters), higher dyspnea (MRC score 1.1 vs. .7), similar exacerbation rate, higher BODE index (.5 vs. .2) and higher mortality than patients with higher DLCO % predicted values. This group, Dr. de Torres and colleagues suggest, represents a multiorgan loss of tissue, a phenotype associated with worse clinical outcomes and prognosis.

“Low DLCO in these patients,” Dr. de Torres said in an interview, “could mainly be secondary to coexistent emphysema, which is the most common cause of low DLCO in this population. Also possible, but less likely, is coexistent pulmonary hypertension.” He noted further that “This study opens the door to research specifically testing if such is the case, and if it is, for clinicians to use available therapies to prevent adverse outcomes.”
 

Comorbidity burden

Patients with GOLD I COPD die more often of cardiovascular disease instead of underlying lung disease, according to Richard H. Zou, MD, and Jessica Bon, MD, of the University of Pittsburgh, in an accompanying editorial in the journal CHEST.

Increased mortality rates, they suggest, may be related to higher comorbidity burden, particularly comorbidities associated with cardiovascular-related health. Subclinical cardiovascular disease is a common comorbidity in COPD, and concomitant endothelial dysfunction has been associated with both cardiovascular disease and early emphysema in smokers. They may have disproportionately reduced DLCO levels because of parenchymal destruction.

“This study suggests that DLCO can be used to identify patients with GOLD I COPD at increased death risk and that individuals with mild airflow obstruction with DLCO <60% predicted are a clinical phenotype distinct from those with higher DLCO levels,” Dr. Zhou and Dr. Bon concluded.

The researchers and the editorialists declared that they had no disclosures. One of the three cohorts assessed in the current study (CHAIN cohort in Spain) received funding from AstraZeneca.

Patients with a baseline DLCO (diffusing capacity for carbon monoxide) of < 60% of predicted have more severe disease clinical expression with higher mortality risk, according to a long-term observational study of Global Initiative for Obstructive Lung Disease (GOLD) I chronic obstructive pulmonary disease (COPD) patients. Clarifying mechanisms of low DLCO may help clinicians direct interventions toward ameliorating the low capacity, Juan Pablo de Torres, MD, and colleagues wrote in the journal CHEST^®.

Defining increased risk

“Can a DLCO threshold help define an increased risk of death and a different clinical presentation in GOLD I patients?” the researchers questioned. For evaluation of COPD, the GOLD does not currently promote the use of DLCO, and the clinical and prognostic utility of a low DLCO has not been studied, the authors noted.

Several COPD studies, however, have shown associations between low DLCO values and reduced exercise capacity, increased symptoms, risk of severe exacerbations, and mortality. The patients included in these studies, however, have generally had moderate to severe airflow limitation, and have not had postbronchodilator forced expiratory volume in 1 second/forced vital capacity (FEV₁/FVC) < 0.70 and an FEV₁ ≥ 80%, defined by GOLD as COPD spirometric stage I. These mild obstruction GOLD I patients, in large epidemiological studies, do have increased risk of death. But it is often assumed, Dr. de Torres and colleagues noted, that “mild” suggests a good prognosis. They propose that a simple DLCO measurement could help identify those GOLD I patients with “worse overall COPD compromise and an increased risk of death.” Importantly, GOLD I represents the largest percentage of patients with airflow limitation that epidemiological studies have identified.

The researchers enrolled 360 GOLD stage I COPD patients, recording their age, sex, pack-years’ history, body mass index, dyspnea, lung function measurements, exercise capacity, BODE (body mass index, airflow obstruction, dyspnea, and exercise capacity) index, and history of exacerbations, and followed them for a mean of 109 months. They identified a cutoff DLCO value for all-cause mortality, compared the clinical and physiological characteristics of patients above and below the threshold, and explored the predictive power of that cutoff value.
 

All-cause mortality difference

The mean age in the overall population studied was 63 years (31% were women), with 43% active smokers, and pack-years history of 45. Overall mortality was 11% during the follow-up period. The predominantly male population was mildly overweight, had few comorbidities, normal FEV₁ values, mild dyspnea, normal 6-minute walk distance, and very few exacerbations.

Analysis showed a DLCO cutoff value of < 60% was associated with a significant all-cause mortality differential (DLCO ≥ 60%: 9% vs. DLCO < 60%: 23%, P = .01). At a same FEV₁% predicted and Charlson score, patients with DLCO < 60% had lower BMI, more dyspnea, lower inspiratory capacity (IC)/total lung capacity (TLC) ratio, lower 6-minute walk distance, and higher BODE index. Adjusted Cox multiple regression analysis confirmed that a DLCO < 60% was associated with an all-cause mortality hazard ratio [HR] of 3.37, (95% confidence interval, 1.35-8.39; P = .009).
 

Multiorgan loss of tissue

The researchers found that patients with baseline DLCO < 60% were more likely to be women (46% versus 28%), and to have a lower BMI (25 vs. 27), higher pack-year history (54 vs. 43), the same spirometric values but lower IC/TLC ratio (.37 vs. .40), a lower walk distance (443 vs. 485 meters), higher dyspnea (MRC score 1.1 vs. .7), similar exacerbation rate, higher BODE index (.5 vs. .2) and higher mortality than patients with higher DLCO % predicted values. This group, Dr. de Torres and colleagues suggest, represents a multiorgan loss of tissue, a phenotype associated with worse clinical outcomes and prognosis.

“Low DLCO in these patients,” Dr. de Torres said in an interview, “could mainly be secondary to coexistent emphysema, which is the most common cause of low DLCO in this population. Also possible, but less likely, is coexistent pulmonary hypertension.” He noted further that “This study opens the door to research specifically testing if such is the case, and if it is, for clinicians to use available therapies to prevent adverse outcomes.”
 

Comorbidity burden

Patients with GOLD I COPD die more often of cardiovascular disease instead of underlying lung disease, according to Richard H. Zou, MD, and Jessica Bon, MD, of the University of Pittsburgh, in an accompanying editorial in the journal CHEST.

Increased mortality rates, they suggest, may be related to higher comorbidity burden, particularly comorbidities associated with cardiovascular-related health. Subclinical cardiovascular disease is a common comorbidity in COPD, and concomitant endothelial dysfunction has been associated with both cardiovascular disease and early emphysema in smokers. They may have disproportionately reduced DLCO levels because of parenchymal destruction.

“This study suggests that DLCO can be used to identify patients with GOLD I COPD at increased death risk and that individuals with mild airflow obstruction with DLCO <60% predicted are a clinical phenotype distinct from those with higher DLCO levels,” Dr. Zhou and Dr. Bon concluded.

The researchers and the editorialists declared that they had no disclosures. One of the three cohorts assessed in the current study (CHAIN cohort in Spain) received funding from AstraZeneca.

A comparison of long-term survival between patients who either did or did not undergo permanent pacemaker implantation (PPI) after transcatheter aortic valve replacement (TAVR) revealed no differences, according to results of the SWEDEHEART observational study.

The nationwide population-based cohort study included all patients who underwent transfemoral TAVR in Sweden from 2008 to 2018.
 

Most frequent complications

While newer-generation aortic valve prostheses are less likely to necessitate PPI, the need for PPI is higher after TAVR than after surgical aortic valve replacement (SAVR), and the need for PPI remains the most frequent complication after TAVR, the study authors noted. Use of self-expandable valves, deep prosthetic valve implantation, preprocedural conduction disturbances, older age, and a high number of comorbidities are among the risk factors for PPI following TAVR.

With prior studies producing conflicting results, the authors stated, the impact of PPI after TAVR remains unknown. Expanding use of TAVR to include younger and low-risk patients with a long life expectancy underscores the importance of gaining greater understand of the impact of PPI after TAVR. Accordingly, the study was conducted to investigate long-term, clinically important outcomes in this post-TAVR population.

Out of 4,750 patients who underwent TAVR in the study period, 3,420 patients in SWEDEHEART met study criteria, with 481 (14.1%) undergoing PPI within 30 days after TAVR, and 2,939 not receiving a pacemaker. PPI exposure was defined as implantation of a permanent pacemaker or implantable cardioverter-defibrillator. The study primary outcome was all-cause mortality, with cardiovascular death, heart failure, and endocarditis as secondary outcomes. It was reported in JACC: Cardiovascular Interventions.
 

Similar survival

Mean patient age was 81.3 years (50.4% female). The rate for all-cause mortality in those with no pacemaker was 11.4 per 100 patient years and 13.1 for those with a pacemaker (hazard ratio, 1.04; 95% confidence interval, 0.89-1.23). The cardiovascular death rate in the no-pacemaker group was 6.0 per 100 patient years and 7.1 per 100 patient years in the pacemaker group (HR, 0.96; 95% CI, 0.75-1.23). For heart failure the rates were 4.5 per 100 patient years in the no pacemaker group and 6.3 in the pacemaker group (HR, 1.22; 95% CI, 0.93-1.672). Endocarditis rates were 1.2 and 1.1 per 100 patient years in the no pacemaker and pacemaker groups, respectively (HR, 0.93; 95% CI, 0.51-1.71).

The authors pointed out that their prior study had found PPI after SAVR in almost 25,000 patients to be associated with increased all-cause mortality and heart failure rates. Patients who undergo TAVR, however, are older and have more comorbidities than patients who undergo SAVR.

It is thus likely that patients who undergo TAVR die of other causes before the negative effects of their pacemaker become clinically evident.

Also, the incidence of conduction abnormalities increases with age, making it more likely that beneficial effects of pacemakers occur in older patients rather than younger ones, counterbalancing the detrimental effects to a larger extent.
 

Reduce PPI rates after TAVR

The study authors also observed that, although they did not find increased mortality or heart failure in patients who underwent PPI, PPI is associated with risks, including lead- and pocket-related complications, other traumatic complications, longer hospital stays and higher societal costs. These factors justify the search for strategies to reduce PPI rates after TAVR.

“Our study adds important information about the prognosis in patients who received a permanent pacemaker implantation following TAVR,” study author Natalie Glaser, MD, PhD, said in an interview. “Increased knowledge about prognosis after TAVR in different patient populations has important implications for preoperative risk stratification and can help to optimize postoperative follow-up and treatment for these patients.” Future studies, Dr. Glaser added, should include younger and low-risk patients with longer follow-up to confirm the present findings. 
 

Balancing factors

In an accompanying editorial, Antonio J. Muñoz-García, MD, PhD, and Erika Muñoz-García, MD also noted factors potentially counterbalancing and masking adverse effects of PPI, echoing some mentioned by the study authors. Among those without PPI, 10%-50% develop new-onset left bundle branch block (LBBB) after TAVR. LBBB is a known marker of low long-term survival in TAVR populations, producing intraventricular dyssynchrony leading potentially to left ventricular dysfunction or development of complete atrioventricular block with higher mortality risk in those without pacemakers. PPI, as well, can be protective against unexpected death in those with advanced conduction disorders. Still, they point out, PPI can entail lead dysfunction, need for generator replacement, infection, and tricuspid valve regurgitation.

Commenting in an interview that an observed trend of a greater increase in events in the group of patients with pacemakers for the first 4 years is consistent with prior studies, Dr. Antonio Muñoz-García said: “This can be explained because long-term survival in the TAVI population is conditioned by comorbidities. It is true that the presence of a pacemaker can cause left ventricular ejection fraction to deteriorate and therefore condition heart failure and increased mortality. But the involvement of the pacemaker in left ventricular function in patients with TAVI is multifactorial and depends on the indication of the pacemaker, whether prophylactic or absolute, on the time-dependent pacing, whether or not the patients prior to TAVI present with alterations in atrioventricular conduction [and therefore could benefit from the implantation of pacemakers], as well as the forms of pacing optimization [resynchronization, hisian pacing, etc]. All of these are issues to be considered in clinical practice.”

The editorialists concluded: “To date, the impact of PPI on late clinical outcomes after TAVR remains controversial; however, this study to some extent helps clarify this controversy.” In accord with the study authors, they called for reductions in PPI rates and long-term clinical follow-up.

The study was funded by several Swedish research organizations. The study investigators and editorial authors declared having no disclosures.

A comparison of long-term survival between patients who either did or did not undergo permanent pacemaker implantation (PPI) after transcatheter aortic valve replacement (TAVR) revealed no differences, according to results of the SWEDEHEART observational study.

The nationwide population-based cohort study included all patients who underwent transfemoral TAVR in Sweden from 2008 to 2018.
 

Most frequent complications

While newer-generation aortic valve prostheses are less likely to necessitate PPI, the need for PPI is higher after TAVR than after surgical aortic valve replacement (SAVR), and the need for PPI remains the most frequent complication after TAVR, the study authors noted. Use of self-expandable valves, deep prosthetic valve implantation, preprocedural conduction disturbances, older age, and a high number of comorbidities are among the risk factors for PPI following TAVR.

With prior studies producing conflicting results, the authors stated, the impact of PPI after TAVR remains unknown. Expanding use of TAVR to include younger and low-risk patients with a long life expectancy underscores the importance of gaining greater understand of the impact of PPI after TAVR. Accordingly, the study was conducted to investigate long-term, clinically important outcomes in this post-TAVR population.

Out of 4,750 patients who underwent TAVR in the study period, 3,420 patients in SWEDEHEART met study criteria, with 481 (14.1%) undergoing PPI within 30 days after TAVR, and 2,939 not receiving a pacemaker. PPI exposure was defined as implantation of a permanent pacemaker or implantable cardioverter-defibrillator. The study primary outcome was all-cause mortality, with cardiovascular death, heart failure, and endocarditis as secondary outcomes. It was reported in JACC: Cardiovascular Interventions.
 

Similar survival

Mean patient age was 81.3 years (50.4% female). The rate for all-cause mortality in those with no pacemaker was 11.4 per 100 patient years and 13.1 for those with a pacemaker (hazard ratio, 1.04; 95% confidence interval, 0.89-1.23). The cardiovascular death rate in the no-pacemaker group was 6.0 per 100 patient years and 7.1 per 100 patient years in the pacemaker group (HR, 0.96; 95% CI, 0.75-1.23). For heart failure the rates were 4.5 per 100 patient years in the no pacemaker group and 6.3 in the pacemaker group (HR, 1.22; 95% CI, 0.93-1.672). Endocarditis rates were 1.2 and 1.1 per 100 patient years in the no pacemaker and pacemaker groups, respectively (HR, 0.93; 95% CI, 0.51-1.71).

The authors pointed out that their prior study had found PPI after SAVR in almost 25,000 patients to be associated with increased all-cause mortality and heart failure rates. Patients who undergo TAVR, however, are older and have more comorbidities than patients who undergo SAVR.

It is thus likely that patients who undergo TAVR die of other causes before the negative effects of their pacemaker become clinically evident.

Also, the incidence of conduction abnormalities increases with age, making it more likely that beneficial effects of pacemakers occur in older patients rather than younger ones, counterbalancing the detrimental effects to a larger extent.
 

Reduce PPI rates after TAVR

The study authors also observed that, although they did not find increased mortality or heart failure in patients who underwent PPI, PPI is associated with risks, including lead- and pocket-related complications, other traumatic complications, longer hospital stays and higher societal costs. These factors justify the search for strategies to reduce PPI rates after TAVR.

“Our study adds important information about the prognosis in patients who received a permanent pacemaker implantation following TAVR,” study author Natalie Glaser, MD, PhD, said in an interview. “Increased knowledge about prognosis after TAVR in different patient populations has important implications for preoperative risk stratification and can help to optimize postoperative follow-up and treatment for these patients.” Future studies, Dr. Glaser added, should include younger and low-risk patients with longer follow-up to confirm the present findings. 
 

Balancing factors

In an accompanying editorial, Antonio J. Muñoz-García, MD, PhD, and Erika Muñoz-García, MD also noted factors potentially counterbalancing and masking adverse effects of PPI, echoing some mentioned by the study authors. Among those without PPI, 10%-50% develop new-onset left bundle branch block (LBBB) after TAVR. LBBB is a known marker of low long-term survival in TAVR populations, producing intraventricular dyssynchrony leading potentially to left ventricular dysfunction or development of complete atrioventricular block with higher mortality risk in those without pacemakers. PPI, as well, can be protective against unexpected death in those with advanced conduction disorders. Still, they point out, PPI can entail lead dysfunction, need for generator replacement, infection, and tricuspid valve regurgitation.

Commenting in an interview that an observed trend of a greater increase in events in the group of patients with pacemakers for the first 4 years is consistent with prior studies, Dr. Antonio Muñoz-García said: “This can be explained because long-term survival in the TAVI population is conditioned by comorbidities. It is true that the presence of a pacemaker can cause left ventricular ejection fraction to deteriorate and therefore condition heart failure and increased mortality. But the involvement of the pacemaker in left ventricular function in patients with TAVI is multifactorial and depends on the indication of the pacemaker, whether prophylactic or absolute, on the time-dependent pacing, whether or not the patients prior to TAVI present with alterations in atrioventricular conduction [and therefore could benefit from the implantation of pacemakers], as well as the forms of pacing optimization [resynchronization, hisian pacing, etc]. All of these are issues to be considered in clinical practice.”

The editorialists concluded: “To date, the impact of PPI on late clinical outcomes after TAVR remains controversial; however, this study to some extent helps clarify this controversy.” In accord with the study authors, they called for reductions in PPI rates and long-term clinical follow-up.

The study was funded by several Swedish research organizations. The study investigators and editorial authors declared having no disclosures.

A comparison of long-term survival between patients who either did or did not undergo permanent pacemaker implantation (PPI) after transcatheter aortic valve replacement (TAVR) revealed no differences, according to results of the SWEDEHEART observational study.

The nationwide population-based cohort study included all patients who underwent transfemoral TAVR in Sweden from 2008 to 2018.
 

Most frequent complications

While newer-generation aortic valve prostheses are less likely to necessitate PPI, the need for PPI is higher after TAVR than after surgical aortic valve replacement (SAVR), and the need for PPI remains the most frequent complication after TAVR, the study authors noted. Use of self-expandable valves, deep prosthetic valve implantation, preprocedural conduction disturbances, older age, and a high number of comorbidities are among the risk factors for PPI following TAVR.

With prior studies producing conflicting results, the authors stated, the impact of PPI after TAVR remains unknown. Expanding use of TAVR to include younger and low-risk patients with a long life expectancy underscores the importance of gaining greater understand of the impact of PPI after TAVR. Accordingly, the study was conducted to investigate long-term, clinically important outcomes in this post-TAVR population.

Out of 4,750 patients who underwent TAVR in the study period, 3,420 patients in SWEDEHEART met study criteria, with 481 (14.1%) undergoing PPI within 30 days after TAVR, and 2,939 not receiving a pacemaker. PPI exposure was defined as implantation of a permanent pacemaker or implantable cardioverter-defibrillator. The study primary outcome was all-cause mortality, with cardiovascular death, heart failure, and endocarditis as secondary outcomes. It was reported in JACC: Cardiovascular Interventions.
 

Similar survival

Mean patient age was 81.3 years (50.4% female). The rate for all-cause mortality in those with no pacemaker was 11.4 per 100 patient years and 13.1 for those with a pacemaker (hazard ratio, 1.04; 95% confidence interval, 0.89-1.23). The cardiovascular death rate in the no-pacemaker group was 6.0 per 100 patient years and 7.1 per 100 patient years in the pacemaker group (HR, 0.96; 95% CI, 0.75-1.23). For heart failure the rates were 4.5 per 100 patient years in the no pacemaker group and 6.3 in the pacemaker group (HR, 1.22; 95% CI, 0.93-1.672). Endocarditis rates were 1.2 and 1.1 per 100 patient years in the no pacemaker and pacemaker groups, respectively (HR, 0.93; 95% CI, 0.51-1.71).

The authors pointed out that their prior study had found PPI after SAVR in almost 25,000 patients to be associated with increased all-cause mortality and heart failure rates. Patients who undergo TAVR, however, are older and have more comorbidities than patients who undergo SAVR.

It is thus likely that patients who undergo TAVR die of other causes before the negative effects of their pacemaker become clinically evident.

Also, the incidence of conduction abnormalities increases with age, making it more likely that beneficial effects of pacemakers occur in older patients rather than younger ones, counterbalancing the detrimental effects to a larger extent.
 

Reduce PPI rates after TAVR

The study authors also observed that, although they did not find increased mortality or heart failure in patients who underwent PPI, PPI is associated with risks, including lead- and pocket-related complications, other traumatic complications, longer hospital stays and higher societal costs. These factors justify the search for strategies to reduce PPI rates after TAVR.

“Our study adds important information about the prognosis in patients who received a permanent pacemaker implantation following TAVR,” study author Natalie Glaser, MD, PhD, said in an interview. “Increased knowledge about prognosis after TAVR in different patient populations has important implications for preoperative risk stratification and can help to optimize postoperative follow-up and treatment for these patients.” Future studies, Dr. Glaser added, should include younger and low-risk patients with longer follow-up to confirm the present findings. 
 

Balancing factors

In an accompanying editorial, Antonio J. Muñoz-García, MD, PhD, and Erika Muñoz-García, MD also noted factors potentially counterbalancing and masking adverse effects of PPI, echoing some mentioned by the study authors. Among those without PPI, 10%-50% develop new-onset left bundle branch block (LBBB) after TAVR. LBBB is a known marker of low long-term survival in TAVR populations, producing intraventricular dyssynchrony leading potentially to left ventricular dysfunction or development of complete atrioventricular block with higher mortality risk in those without pacemakers. PPI, as well, can be protective against unexpected death in those with advanced conduction disorders. Still, they point out, PPI can entail lead dysfunction, need for generator replacement, infection, and tricuspid valve regurgitation.

Commenting in an interview that an observed trend of a greater increase in events in the group of patients with pacemakers for the first 4 years is consistent with prior studies, Dr. Antonio Muñoz-García said: “This can be explained because long-term survival in the TAVI population is conditioned by comorbidities. It is true that the presence of a pacemaker can cause left ventricular ejection fraction to deteriorate and therefore condition heart failure and increased mortality. But the involvement of the pacemaker in left ventricular function in patients with TAVI is multifactorial and depends on the indication of the pacemaker, whether prophylactic or absolute, on the time-dependent pacing, whether or not the patients prior to TAVI present with alterations in atrioventricular conduction [and therefore could benefit from the implantation of pacemakers], as well as the forms of pacing optimization [resynchronization, hisian pacing, etc]. All of these are issues to be considered in clinical practice.”

The editorialists concluded: “To date, the impact of PPI on late clinical outcomes after TAVR remains controversial; however, this study to some extent helps clarify this controversy.” In accord with the study authors, they called for reductions in PPI rates and long-term clinical follow-up.

The study was funded by several Swedish research organizations. The study investigators and editorial authors declared having no disclosures.

Based on significant progression-free survival (PFS) benefits shown in the phase 3 TULIP trial, trastuzumab duocarmazine (SYD985) may provide a new treatment option among HER2-positive metastatic breast cancer patients, according to Cristina Saura, MD, head of the breast cancer program at Vall d’Hebron University Hospital, Barcelona. Dr. Saura presented the results of the TULIP trial (abstract LBA15) on Sept. 19 at the 2021 European Society for Medical Oncology Congress.

Trastuzumab duocarmazine is a novel HER2-targeting antibody-drug conjugate that consists of trastuzumab and a drug containing duocarmycin. Its three-way mechanism of action includes uptake of the antibody-drug conjugate by internalization and intracellular release of duocarmycin with two bystander effects: proteolytic cleavage and subsequent release of payload in the tumor microenvironment and diffusion of active payload to neighboring tumor cells.

While one physician described the results as encouraging, another said the treatment is not nearly ready for primetime.

“It is encouraging to observe clinically meaningful and potentially practice changing progression-free survival improvements in patients receiving treatment in the third line and beyond,” said Aditya Bardia, MD, Massachusetts General Hospital, Boston. “Several agents have been approved as treatments for HER2-positive metastatic breast cancer in recent years including T-DXd, neratinib, tucatinib, and margetuximab. Trastuzumab duocarmazine could eventually be another option.”

Fatima Cardoso, MD, director of the breast cancer unit at the Breast Cancer Research Foundation, New York, said: “At this time there is only a minor 2-month difference in progression-free survival and a nonsignificant overall difference. With the high incidence of ocular toxicity and four toxic deaths, we cannot recommend this drug for clinical practice, in my opinion.”
 

Two or more prior therapies for metastatic breast cancer

TULIP investigators enrolled 437 patients from 83 sites in 11 countries with HER2-positive locally advanced or metastatic breast cancer who had received two or more therapies for metastatic disease (treatment for brain metastases allowed). They were randomized 2:1 to trastuzumab duocarmazine (1.2 mg/kg every 21 days, 291 patients) or physician’s choice (146 patients) of one of three trastuzumab-containing combinations or lapatinib plus capecitabine. Treatment was continued until progression or unacceptable toxicity. The primary endpoint was centrally assessed PFS.

Longer PFS with trastuzumab duocarmazine

Median age was 57 years, and the median number of prior metastatic breast cancer regimens was 4.7. Centrally reviewed PFS was significantly longer in the trastuzumab duocarmazine group at 7.0 months versus 4.9 months for physicians choice treatment (hazard ratio, 0.64; 95% confidence interval, 0.49-0.84; P = .002). Subgroup analysis, also centrally reviewed, revealed numerical advantage for trastuzumab duocarmazine over physician’s choice across all categories (except for Eastern Cooperative Oncology Group status 2). Analysis of PFS by investigators showed a similar benefit for trastuzumab duocarmazine (6.9 months vs. 4.6 months; HR, 0.60; P < .001).

A first look at median overall survival showed a nonsignificant advantage for trastuzumab duocarmazine (20.4 months vs. 16.3 months (HR, 0.83; 95% CI, 0.62-1.09, P = .153). The overall response rate (partial or complete response) was similar between groups at 27.8% for trastuzumab duocarmazine and 29.5% for physician’s choice with reductions in target lesion measurement at 70.2% and 32.2% for trastuzumab duocarmazine and physician’s choice, respectively. The clinical benefit rates were 38.5% for trastuzumab duocarmazine and 32.2% for physician’s choice.
 

Ocular toxicity

Most patients had at least one treatment-related adverse event (96.5% SD985, 96.4% PC), and grade 3 or higher event rates were similar between groups (52.8% SYD985, 48.2% PC). The most frequently reported adverse events for trastuzumab duocarmazine were ocular toxicity, with conjunctivitis reported in 38.2%, and keratitis in 38.2%, with fatigue at 33.3%; for physician’s choice these were diarrhea (35.8%), nausea (31.4%) and fatigue (29.9%). Interstitial lung disease pneumonitis was reported for 7.6% (5.2% grade 1-2) of patients treated with trastuzumab duocarmazine, including two grade 5 events.

Eye toxicity led to discontinuations in 20.8% of trastuzumab duocarmazine patients, dose modifications in 22.9%, with dose modifications for interstitial lung disease/pneumonitis in 5.2% of trastuzumab duocarmazine patients. Six fatalities (2.1%) were reported in the trastuzumab duocarmazine group, with four attributed to treatment. Assessment of health-related quality of life showed no significant difference between groups.

Dr. Manich outlined risk mitigation strategies. Patients with prior keratitis were excluded and patients were given prophylactic lubricating eye drops and regular eye exams by ophthalmologists. Treatment was discontinued if grade 3 or higher keratitis developed, and was delayed if grade 3 conjunctivitis developed until it reduced to grade 2. Also, patients with prior pneumonitis were excluded and CT lung scans were evaluated for lung changes. New or worsening respiratory symptoms triggered a full diagnostic workup. Treatment was discontinued for grade 2 or higher pneumonitis and delayed until resolution for grade 1 pneumonitis.

TULIP was funded by Byondis. Dr. Saura disclosed numerous financial interests including support from AstraZeneca and Daiichi Sankyo.

Based on significant progression-free survival (PFS) benefits shown in the phase 3 TULIP trial, trastuzumab duocarmazine (SYD985) may provide a new treatment option among HER2-positive metastatic breast cancer patients, according to Cristina Saura, MD, head of the breast cancer program at Vall d’Hebron University Hospital, Barcelona. Dr. Saura presented the results of the TULIP trial (abstract LBA15) on Sept. 19 at the 2021 European Society for Medical Oncology Congress.

Trastuzumab duocarmazine is a novel HER2-targeting antibody-drug conjugate that consists of trastuzumab and a drug containing duocarmycin. Its three-way mechanism of action includes uptake of the antibody-drug conjugate by internalization and intracellular release of duocarmycin with two bystander effects: proteolytic cleavage and subsequent release of payload in the tumor microenvironment and diffusion of active payload to neighboring tumor cells.

While one physician described the results as encouraging, another said the treatment is not nearly ready for primetime.

“It is encouraging to observe clinically meaningful and potentially practice changing progression-free survival improvements in patients receiving treatment in the third line and beyond,” said Aditya Bardia, MD, Massachusetts General Hospital, Boston. “Several agents have been approved as treatments for HER2-positive metastatic breast cancer in recent years including T-DXd, neratinib, tucatinib, and margetuximab. Trastuzumab duocarmazine could eventually be another option.”

Fatima Cardoso, MD, director of the breast cancer unit at the Breast Cancer Research Foundation, New York, said: “At this time there is only a minor 2-month difference in progression-free survival and a nonsignificant overall difference. With the high incidence of ocular toxicity and four toxic deaths, we cannot recommend this drug for clinical practice, in my opinion.”
 

Two or more prior therapies for metastatic breast cancer

TULIP investigators enrolled 437 patients from 83 sites in 11 countries with HER2-positive locally advanced or metastatic breast cancer who had received two or more therapies for metastatic disease (treatment for brain metastases allowed). They were randomized 2:1 to trastuzumab duocarmazine (1.2 mg/kg every 21 days, 291 patients) or physician’s choice (146 patients) of one of three trastuzumab-containing combinations or lapatinib plus capecitabine. Treatment was continued until progression or unacceptable toxicity. The primary endpoint was centrally assessed PFS.

Longer PFS with trastuzumab duocarmazine

Median age was 57 years, and the median number of prior metastatic breast cancer regimens was 4.7. Centrally reviewed PFS was significantly longer in the trastuzumab duocarmazine group at 7.0 months versus 4.9 months for physicians choice treatment (hazard ratio, 0.64; 95% confidence interval, 0.49-0.84; P = .002). Subgroup analysis, also centrally reviewed, revealed numerical advantage for trastuzumab duocarmazine over physician’s choice across all categories (except for Eastern Cooperative Oncology Group status 2). Analysis of PFS by investigators showed a similar benefit for trastuzumab duocarmazine (6.9 months vs. 4.6 months; HR, 0.60; P < .001).

A first look at median overall survival showed a nonsignificant advantage for trastuzumab duocarmazine (20.4 months vs. 16.3 months (HR, 0.83; 95% CI, 0.62-1.09, P = .153). The overall response rate (partial or complete response) was similar between groups at 27.8% for trastuzumab duocarmazine and 29.5% for physician’s choice with reductions in target lesion measurement at 70.2% and 32.2% for trastuzumab duocarmazine and physician’s choice, respectively. The clinical benefit rates were 38.5% for trastuzumab duocarmazine and 32.2% for physician’s choice.
 

Ocular toxicity

Most patients had at least one treatment-related adverse event (96.5% SD985, 96.4% PC), and grade 3 or higher event rates were similar between groups (52.8% SYD985, 48.2% PC). The most frequently reported adverse events for trastuzumab duocarmazine were ocular toxicity, with conjunctivitis reported in 38.2%, and keratitis in 38.2%, with fatigue at 33.3%; for physician’s choice these were diarrhea (35.8%), nausea (31.4%) and fatigue (29.9%). Interstitial lung disease pneumonitis was reported for 7.6% (5.2% grade 1-2) of patients treated with trastuzumab duocarmazine, including two grade 5 events.

Eye toxicity led to discontinuations in 20.8% of trastuzumab duocarmazine patients, dose modifications in 22.9%, with dose modifications for interstitial lung disease/pneumonitis in 5.2% of trastuzumab duocarmazine patients. Six fatalities (2.1%) were reported in the trastuzumab duocarmazine group, with four attributed to treatment. Assessment of health-related quality of life showed no significant difference between groups.

Dr. Manich outlined risk mitigation strategies. Patients with prior keratitis were excluded and patients were given prophylactic lubricating eye drops and regular eye exams by ophthalmologists. Treatment was discontinued if grade 3 or higher keratitis developed, and was delayed if grade 3 conjunctivitis developed until it reduced to grade 2. Also, patients with prior pneumonitis were excluded and CT lung scans were evaluated for lung changes. New or worsening respiratory symptoms triggered a full diagnostic workup. Treatment was discontinued for grade 2 or higher pneumonitis and delayed until resolution for grade 1 pneumonitis.

TULIP was funded by Byondis. Dr. Saura disclosed numerous financial interests including support from AstraZeneca and Daiichi Sankyo.

Based on significant progression-free survival (PFS) benefits shown in the phase 3 TULIP trial, trastuzumab duocarmazine (SYD985) may provide a new treatment option among HER2-positive metastatic breast cancer patients, according to Cristina Saura, MD, head of the breast cancer program at Vall d’Hebron University Hospital, Barcelona. Dr. Saura presented the results of the TULIP trial (abstract LBA15) on Sept. 19 at the 2021 European Society for Medical Oncology Congress.

Trastuzumab duocarmazine is a novel HER2-targeting antibody-drug conjugate that consists of trastuzumab and a drug containing duocarmycin. Its three-way mechanism of action includes uptake of the antibody-drug conjugate by internalization and intracellular release of duocarmycin with two bystander effects: proteolytic cleavage and subsequent release of payload in the tumor microenvironment and diffusion of active payload to neighboring tumor cells.

While one physician described the results as encouraging, another said the treatment is not nearly ready for primetime.

“It is encouraging to observe clinically meaningful and potentially practice changing progression-free survival improvements in patients receiving treatment in the third line and beyond,” said Aditya Bardia, MD, Massachusetts General Hospital, Boston. “Several agents have been approved as treatments for HER2-positive metastatic breast cancer in recent years including T-DXd, neratinib, tucatinib, and margetuximab. Trastuzumab duocarmazine could eventually be another option.”

Fatima Cardoso, MD, director of the breast cancer unit at the Breast Cancer Research Foundation, New York, said: “At this time there is only a minor 2-month difference in progression-free survival and a nonsignificant overall difference. With the high incidence of ocular toxicity and four toxic deaths, we cannot recommend this drug for clinical practice, in my opinion.”
 

Two or more prior therapies for metastatic breast cancer

TULIP investigators enrolled 437 patients from 83 sites in 11 countries with HER2-positive locally advanced or metastatic breast cancer who had received two or more therapies for metastatic disease (treatment for brain metastases allowed). They were randomized 2:1 to trastuzumab duocarmazine (1.2 mg/kg every 21 days, 291 patients) or physician’s choice (146 patients) of one of three trastuzumab-containing combinations or lapatinib plus capecitabine. Treatment was continued until progression or unacceptable toxicity. The primary endpoint was centrally assessed PFS.

Longer PFS with trastuzumab duocarmazine

Median age was 57 years, and the median number of prior metastatic breast cancer regimens was 4.7. Centrally reviewed PFS was significantly longer in the trastuzumab duocarmazine group at 7.0 months versus 4.9 months for physicians choice treatment (hazard ratio, 0.64; 95% confidence interval, 0.49-0.84; P = .002). Subgroup analysis, also centrally reviewed, revealed numerical advantage for trastuzumab duocarmazine over physician’s choice across all categories (except for Eastern Cooperative Oncology Group status 2). Analysis of PFS by investigators showed a similar benefit for trastuzumab duocarmazine (6.9 months vs. 4.6 months; HR, 0.60; P < .001).

A first look at median overall survival showed a nonsignificant advantage for trastuzumab duocarmazine (20.4 months vs. 16.3 months (HR, 0.83; 95% CI, 0.62-1.09, P = .153). The overall response rate (partial or complete response) was similar between groups at 27.8% for trastuzumab duocarmazine and 29.5% for physician’s choice with reductions in target lesion measurement at 70.2% and 32.2% for trastuzumab duocarmazine and physician’s choice, respectively. The clinical benefit rates were 38.5% for trastuzumab duocarmazine and 32.2% for physician’s choice.
 

Ocular toxicity

Most patients had at least one treatment-related adverse event (96.5% SD985, 96.4% PC), and grade 3 or higher event rates were similar between groups (52.8% SYD985, 48.2% PC). The most frequently reported adverse events for trastuzumab duocarmazine were ocular toxicity, with conjunctivitis reported in 38.2%, and keratitis in 38.2%, with fatigue at 33.3%; for physician’s choice these were diarrhea (35.8%), nausea (31.4%) and fatigue (29.9%). Interstitial lung disease pneumonitis was reported for 7.6% (5.2% grade 1-2) of patients treated with trastuzumab duocarmazine, including two grade 5 events.

Eye toxicity led to discontinuations in 20.8% of trastuzumab duocarmazine patients, dose modifications in 22.9%, with dose modifications for interstitial lung disease/pneumonitis in 5.2% of trastuzumab duocarmazine patients. Six fatalities (2.1%) were reported in the trastuzumab duocarmazine group, with four attributed to treatment. Assessment of health-related quality of life showed no significant difference between groups.

Dr. Manich outlined risk mitigation strategies. Patients with prior keratitis were excluded and patients were given prophylactic lubricating eye drops and regular eye exams by ophthalmologists. Treatment was discontinued if grade 3 or higher keratitis developed, and was delayed if grade 3 conjunctivitis developed until it reduced to grade 2. Also, patients with prior pneumonitis were excluded and CT lung scans were evaluated for lung changes. New or worsening respiratory symptoms triggered a full diagnostic workup. Treatment was discontinued for grade 2 or higher pneumonitis and delayed until resolution for grade 1 pneumonitis.

TULIP was funded by Byondis. Dr. Saura disclosed numerous financial interests including support from AstraZeneca and Daiichi Sankyo.

Once-daily dosing of poziotinib shows clinically meaningful efficacy for patients with treatment-naive non–small cell lung cancer (NSCLC) HER2 exon 20 mutations, according to results of the ZENITH20 trial presented at the 2021 European Society for Medical Oncology Congress. Tumor reductions, stated lead author Robin Cornelissen, PhD, MD, Erasmus University, Rotterdam, the Netherlands, were seen in 88% of patients.

EGFR and HER2 exon 20 insertion mutations are rare subsets accounting for about 10% each of all mutations and 2%-4% each in NSCLC. “There is no approved therapy for either treatment-naive or previously treated NSCLC with HER2 exon 20 mutations,” Dr. Cornelissen said in a virtual oral presentation (abstract LBA46) on Sept. 18. While chemotherapy agents with or without checkpoint inhibitors and tyrosine kinase inhibitors (TKIs) are currently utilized, none are specific to exon 20 mutations, and historical response rates from mostly small uncontrolled studies vary widely from about 6.9%-35%, with median progression-free survival (PFS) ranging from 3 to 7 months. Poziotinib is a potent oral pan-HER TKI with activity in patients with EGFR or HER2 exon 20–mutated NSCLC.

Dr. Cornelissen presented preliminary safety and efficacy data from the phase 2 ZENITH20, a seven-cohort global clinical trial, specifically from cohort 4 (daily dosing) which included 48 HER2 exon 20 insertion NSCLC patients (median age, 60.5 years; female/male, 26/22) treated first-line with oral daily poziotinib (16 mg). The majority were White (75%), female (54%), and nonsmokers (69%) with an Eastern Cooperative Oncology Group performance status of 1 (65%).The primary endpoint was objective response rate evaluated centrally by an independent image review committee using RECIST 1.1 criteria.

All patients have experienced treatment-related adverse events (TRAEs) with 10% considered serious, and permanent discontinuation in 13%. About 83% of patients had dose interruptions and 76% had dose reductions. The most common adverse events were diarrhea (any grade, 83%; grade 3, 15%), rash (any grade, 69%; grade 3, 35%), stomatitis/mucosal inflammation (any grade, 81%; grade 3, 21%), and paronychia (any grade, 46%; grade 3 8%). Pneumonitis occurred in two patients (4%), with one grade 3 (2%). No grade 4/5 TRAEs were reported.

Discontinuations in 44 patients (92%), Dr. Cornelissen said, are attributed to death (5/10%), disease progression (30/63%), adverse events (1/2%), and other (8/17%), with treatment ongoing in 4 patients (8%).

The rate for the primary endpoint of ORR was 43.8% (n = 21) (95% confidence interval, 29.5%-58.8%).Tumor reductions have been observed in 42/48 patients (88%) with a median reduction of 35%. One complete response was reported (2.1%), with partial responses in 20 (41.7%), stable disease in 15 (31.3%), progressive disease in 7 (14.6%), and 5 (10.4%) not evaluable. The disease control rate was 75.0%.

Among secondary endpoints, median duration of response (DoR) was 5.4 months (range, 2.8 to >19.1), with 42% of patients having response duration greater than6 months and 24% greater than 12 months. Median PFS was 5.6 months (range, 0 to >20.2), with progression-free survival duration greater than6 months in 42% and duration greater than12 months in 26%.

Dr. Cornelissen concluded: “Poziotinib shows clinically meaningful efficacy for treatment-naive NSCLC HER2 exon 20 mutations with [daily] dosing.” The toxicity profile, he added, is manageable and in line with previous poziotinib studies and other second-generation EGFR TKIs.

Noting that improved tolerability and antitumor activity have been observed in the cohort 5 (8 mg b.i.d.) interim analysis, Dr. Cornelissen said that cohort 4 is ongoing with patients enrolling at 8-mg b.i.d. dosing.

HER2 mutations represents 1.7%-2.2% of NSCLC, with high-sequence homology with EGFR mutation, observed ESMO-appointed discussant Daniel S.W. Tan, PhD, National Cancer Center in Singapore. He pointed out that, while HER2 antibody drug conjugates and TKIs have gained approval in other cancer types (e.g., breast, gastric), currently no HER2 therapies are approved in NSCLC. Reviewing ZENITH20 findings (risk ratio, 43.8%; DoR, 5.4 months; PFS, 5.6 months), Dr. Tan stated that poziotinib is an active agent in HER2 mutated NSCLC. “One concern that remains for me is the safety profile that will require further evaluation in order to determine optimal dosing,” he said.

Potential combinations, he added, need to be explored to improve the durability of response. “Until we can properly characterize this and other important aspects such as CNS activity, we need to be cautious about transitioning to a frontline setting. Also, we do need to give due consideration to strategies to improve HER2 testing rates in order to expand on clinical experience. This argues for the importance of broad upfront next generation sequencing testing in NSCLC.”

The study was funded by Spectrum Pharmaceuticals. Other authors associated with the research disclosed full or part-time employment with Spectrum.

Once-daily dosing of poziotinib shows clinically meaningful efficacy for patients with treatment-naive non–small cell lung cancer (NSCLC) HER2 exon 20 mutations, according to results of the ZENITH20 trial presented at the 2021 European Society for Medical Oncology Congress. Tumor reductions, stated lead author Robin Cornelissen, PhD, MD, Erasmus University, Rotterdam, the Netherlands, were seen in 88% of patients.

EGFR and HER2 exon 20 insertion mutations are rare subsets accounting for about 10% each of all mutations and 2%-4% each in NSCLC. “There is no approved therapy for either treatment-naive or previously treated NSCLC with HER2 exon 20 mutations,” Dr. Cornelissen said in a virtual oral presentation (abstract LBA46) on Sept. 18. While chemotherapy agents with or without checkpoint inhibitors and tyrosine kinase inhibitors (TKIs) are currently utilized, none are specific to exon 20 mutations, and historical response rates from mostly small uncontrolled studies vary widely from about 6.9%-35%, with median progression-free survival (PFS) ranging from 3 to 7 months. Poziotinib is a potent oral pan-HER TKI with activity in patients with EGFR or HER2 exon 20–mutated NSCLC.

Dr. Cornelissen presented preliminary safety and efficacy data from the phase 2 ZENITH20, a seven-cohort global clinical trial, specifically from cohort 4 (daily dosing) which included 48 HER2 exon 20 insertion NSCLC patients (median age, 60.5 years; female/male, 26/22) treated first-line with oral daily poziotinib (16 mg). The majority were White (75%), female (54%), and nonsmokers (69%) with an Eastern Cooperative Oncology Group performance status of 1 (65%).The primary endpoint was objective response rate evaluated centrally by an independent image review committee using RECIST 1.1 criteria.

All patients have experienced treatment-related adverse events (TRAEs) with 10% considered serious, and permanent discontinuation in 13%. About 83% of patients had dose interruptions and 76% had dose reductions. The most common adverse events were diarrhea (any grade, 83%; grade 3, 15%), rash (any grade, 69%; grade 3, 35%), stomatitis/mucosal inflammation (any grade, 81%; grade 3, 21%), and paronychia (any grade, 46%; grade 3 8%). Pneumonitis occurred in two patients (4%), with one grade 3 (2%). No grade 4/5 TRAEs were reported.

Discontinuations in 44 patients (92%), Dr. Cornelissen said, are attributed to death (5/10%), disease progression (30/63%), adverse events (1/2%), and other (8/17%), with treatment ongoing in 4 patients (8%).

The rate for the primary endpoint of ORR was 43.8% (n = 21) (95% confidence interval, 29.5%-58.8%).Tumor reductions have been observed in 42/48 patients (88%) with a median reduction of 35%. One complete response was reported (2.1%), with partial responses in 20 (41.7%), stable disease in 15 (31.3%), progressive disease in 7 (14.6%), and 5 (10.4%) not evaluable. The disease control rate was 75.0%.

Among secondary endpoints, median duration of response (DoR) was 5.4 months (range, 2.8 to >19.1), with 42% of patients having response duration greater than6 months and 24% greater than 12 months. Median PFS was 5.6 months (range, 0 to >20.2), with progression-free survival duration greater than6 months in 42% and duration greater than12 months in 26%.

Dr. Cornelissen concluded: “Poziotinib shows clinically meaningful efficacy for treatment-naive NSCLC HER2 exon 20 mutations with [daily] dosing.” The toxicity profile, he added, is manageable and in line with previous poziotinib studies and other second-generation EGFR TKIs.

Noting that improved tolerability and antitumor activity have been observed in the cohort 5 (8 mg b.i.d.) interim analysis, Dr. Cornelissen said that cohort 4 is ongoing with patients enrolling at 8-mg b.i.d. dosing.

HER2 mutations represents 1.7%-2.2% of NSCLC, with high-sequence homology with EGFR mutation, observed ESMO-appointed discussant Daniel S.W. Tan, PhD, National Cancer Center in Singapore. He pointed out that, while HER2 antibody drug conjugates and TKIs have gained approval in other cancer types (e.g., breast, gastric), currently no HER2 therapies are approved in NSCLC. Reviewing ZENITH20 findings (risk ratio, 43.8%; DoR, 5.4 months; PFS, 5.6 months), Dr. Tan stated that poziotinib is an active agent in HER2 mutated NSCLC. “One concern that remains for me is the safety profile that will require further evaluation in order to determine optimal dosing,” he said.

Potential combinations, he added, need to be explored to improve the durability of response. “Until we can properly characterize this and other important aspects such as CNS activity, we need to be cautious about transitioning to a frontline setting. Also, we do need to give due consideration to strategies to improve HER2 testing rates in order to expand on clinical experience. This argues for the importance of broad upfront next generation sequencing testing in NSCLC.”

The study was funded by Spectrum Pharmaceuticals. Other authors associated with the research disclosed full or part-time employment with Spectrum.

Once-daily dosing of poziotinib shows clinically meaningful efficacy for patients with treatment-naive non–small cell lung cancer (NSCLC) HER2 exon 20 mutations, according to results of the ZENITH20 trial presented at the 2021 European Society for Medical Oncology Congress. Tumor reductions, stated lead author Robin Cornelissen, PhD, MD, Erasmus University, Rotterdam, the Netherlands, were seen in 88% of patients.

EGFR and HER2 exon 20 insertion mutations are rare subsets accounting for about 10% each of all mutations and 2%-4% each in NSCLC. “There is no approved therapy for either treatment-naive or previously treated NSCLC with HER2 exon 20 mutations,” Dr. Cornelissen said in a virtual oral presentation (abstract LBA46) on Sept. 18. While chemotherapy agents with or without checkpoint inhibitors and tyrosine kinase inhibitors (TKIs) are currently utilized, none are specific to exon 20 mutations, and historical response rates from mostly small uncontrolled studies vary widely from about 6.9%-35%, with median progression-free survival (PFS) ranging from 3 to 7 months. Poziotinib is a potent oral pan-HER TKI with activity in patients with EGFR or HER2 exon 20–mutated NSCLC.

Dr. Cornelissen presented preliminary safety and efficacy data from the phase 2 ZENITH20, a seven-cohort global clinical trial, specifically from cohort 4 (daily dosing) which included 48 HER2 exon 20 insertion NSCLC patients (median age, 60.5 years; female/male, 26/22) treated first-line with oral daily poziotinib (16 mg). The majority were White (75%), female (54%), and nonsmokers (69%) with an Eastern Cooperative Oncology Group performance status of 1 (65%).The primary endpoint was objective response rate evaluated centrally by an independent image review committee using RECIST 1.1 criteria.

All patients have experienced treatment-related adverse events (TRAEs) with 10% considered serious, and permanent discontinuation in 13%. About 83% of patients had dose interruptions and 76% had dose reductions. The most common adverse events were diarrhea (any grade, 83%; grade 3, 15%), rash (any grade, 69%; grade 3, 35%), stomatitis/mucosal inflammation (any grade, 81%; grade 3, 21%), and paronychia (any grade, 46%; grade 3 8%). Pneumonitis occurred in two patients (4%), with one grade 3 (2%). No grade 4/5 TRAEs were reported.

Discontinuations in 44 patients (92%), Dr. Cornelissen said, are attributed to death (5/10%), disease progression (30/63%), adverse events (1/2%), and other (8/17%), with treatment ongoing in 4 patients (8%).

The rate for the primary endpoint of ORR was 43.8% (n = 21) (95% confidence interval, 29.5%-58.8%).Tumor reductions have been observed in 42/48 patients (88%) with a median reduction of 35%. One complete response was reported (2.1%), with partial responses in 20 (41.7%), stable disease in 15 (31.3%), progressive disease in 7 (14.6%), and 5 (10.4%) not evaluable. The disease control rate was 75.0%.

Among secondary endpoints, median duration of response (DoR) was 5.4 months (range, 2.8 to >19.1), with 42% of patients having response duration greater than6 months and 24% greater than 12 months. Median PFS was 5.6 months (range, 0 to >20.2), with progression-free survival duration greater than6 months in 42% and duration greater than12 months in 26%.

Dr. Cornelissen concluded: “Poziotinib shows clinically meaningful efficacy for treatment-naive NSCLC HER2 exon 20 mutations with [daily] dosing.” The toxicity profile, he added, is manageable and in line with previous poziotinib studies and other second-generation EGFR TKIs.

Noting that improved tolerability and antitumor activity have been observed in the cohort 5 (8 mg b.i.d.) interim analysis, Dr. Cornelissen said that cohort 4 is ongoing with patients enrolling at 8-mg b.i.d. dosing.

HER2 mutations represents 1.7%-2.2% of NSCLC, with high-sequence homology with EGFR mutation, observed ESMO-appointed discussant Daniel S.W. Tan, PhD, National Cancer Center in Singapore. He pointed out that, while HER2 antibody drug conjugates and TKIs have gained approval in other cancer types (e.g., breast, gastric), currently no HER2 therapies are approved in NSCLC. Reviewing ZENITH20 findings (risk ratio, 43.8%; DoR, 5.4 months; PFS, 5.6 months), Dr. Tan stated that poziotinib is an active agent in HER2 mutated NSCLC. “One concern that remains for me is the safety profile that will require further evaluation in order to determine optimal dosing,” he said.

Potential combinations, he added, need to be explored to improve the durability of response. “Until we can properly characterize this and other important aspects such as CNS activity, we need to be cautious about transitioning to a frontline setting. Also, we do need to give due consideration to strategies to improve HER2 testing rates in order to expand on clinical experience. This argues for the importance of broad upfront next generation sequencing testing in NSCLC.”

The study was funded by Spectrum Pharmaceuticals. Other authors associated with the research disclosed full or part-time employment with Spectrum.

The 34% reduction in disease recurrence for adjuvant atezolizumab in PD-L1 tumor cells of at least 50% stage II-IIIA patients in the IMpower010 clinical trial, may change the standard of care for early-stage non–small cell lung cancer (NSCLC), according to Enriqueta Felip, MD, the head of thoracic and head and neck cancer unit at Vall d’Hebron Institute of Oncology, Hospital, Barcelona.

IMpower010 is the first positive randomized phase 3 study to show significant disease-free survival (DFS) improvement with adjuvant cancer immunotherapy (atezolizumab, anti–programmed death–ligand 1, and platinum-based chemotherapy) in this population, Dr. Felip said in a presentation at the 2021 European Society for Medical Oncology Congress on Sept. 20 (abstract LBA9).

High unmet need

Up to 60% of patients with stage I-III NSCLC still experience disease relapse despite having received treatment, Dr. Felip said. IMpower010 included 1,280 patients who received up to four cycles of chemotherapy (cisplatin with pemetrexed, gemcitabine, docetaxel, or vinorelbine) after completely resected stage IB-IIIA NSCLC. Patients were randomized to open label to atezolizumab (1,200 mg every 21 days for 16 cycles or best supportive care (BSC). The primary endpoint of investigator-assessed DFS in the stage II-IIIA population (n = 1,005) was stratified according to three groups: PD-L1 tumor cells of at least 1% (stage II-IIIA), all-randomized (stage II-IIIA) and intention-to-treat (stage IB-IIIA).

Median disease-free survival in PD-L1 tumor cells of at least 1% was not estimated in the atezolizumab group and was 35.3 months in the BSC group (95% CI, 29.0 to NE). In the all-randomized group, median DFS was 42.3 months in the atezolizumab group (95% CI, 36.0 to NE) and 35.3 months in the BSC group (95% CI, 30.4-46.4) with a stratified hazard ratio of 0.79 (95% CI, 0.64-0.96; P = .02). In the intent-to-treat population, median DFS was not evaluable in the atezolizumab group and 37.2 months in the BSC group (95% CI, 31.6 to NE) with a hazard ratio of 0.81 (95% CI, 0.67-0.99; P = .04).
 

DFS hazard ratio 0.43 in TC ≥50% group

Looking at DFS by PD-L1 status in the population with and without known EGFR/ALK+ disease, Dr. Felip said that the hazard ratio for the tumor cells of at least 50% group (n = 229) was 0.43 (95% CI, 0.27-0.68), as compared with 0.87 (95% CI, 0.60-1.26) for the tumor cells 1%-49% group. With EGFR/ALK+ patients excluded, the respective HRs were similar (0.43/0.82). Considering DFS events including only disease recurrence, disease incidence was 29.4%/44.7% in the atezolizumab and BSC groups, respectively for those with PD-L1 tumor cells of at least 1%. The same pattern of atezolizumab benefit persisted in the all-randomized and intent-to-treat groups.

An assessment according to regions of relapse (locoregional only, distant only, locoregional and distant, CNS only, second primary lung) revealed no differences in the three groups. Analysis of time from randomization to relapse revealed regional differences in the PD-L1 tumor cells of at least 1% group with a median time to any relapse of 17.6 months in the atezolizumab group and 10.9 months in the BSC group. Time from randomization to relapse was generally similar for atezolizumab and best supportive care in the all randomized and intent-to-treat groups (about 11-12 months).

“The greatest magnitude of disease-free survival benefit was observed in the PD-L1 tumor cell of at least 50% population with a hazard ratio of 0.43,” Dr. Felip said. In a post hoc analysis excluding patients with known EFGR/ALK with NSCLC, she said that hazard ratios were numerically improved in most PD-L1 subgroups. Postrelapse cancer immunotherapies were used at a higher rate in the BSC arm of the trial. “Longer-term follow-up is warranted and may reveal differences in relapse patterns and treatment options.
 

Playing with the immune system

Benjamin Besse, MD, director of oncology and chair of the EORTC Lung Group at Paris-Saclay University, acknowledged the disease-free survival benefit with atezolizumab in IMpower010 and underscored that adjuvant immunotherapy has been changing treatment in resected cancers across tumor types (i.e., melanoma, renal cell carcinoma, NSCLC). He voiced some concerns, including the absence of benefit in PD-L1 less than 1%, pneumonectomy and EGFRmut/ALK+ patients, and generally the potential “when you play with the immune system for there to be a dark side too.” Dr. Besse said delayed side effects in 43.2% of patients , citing a recent report of chronic, mostly grade 1-2 immune-related adverse events following (>12 weeks after discontinuation) adjuvant anti–PD-1 therapy for high-risk resected melanoma. He mentioned, however, that the rate of second primary lung tumors in the atezolizumab group (1.4%) was lower than in the BSC group (2.6%), with generally similar rates between immuno- and nonimmunotherapies in melanoma and breast cancer trials.

“IMpower 010 is the first adjuvant study establishing immune checkpoint blockade as a new standard of care. We need to cure more, not to delay relapse,” he said. The optimal population for treatment is still yet to be defined, as is the best perioperative strategy, Dr. Besse added. “If approved I would prescribe adjuvant atezolizumab ... until I see the overall survival curves.”

IMpower010 was funded by–F. Hoffmann-La Roche. Dr. Felip disclosed numerous financial interests, including having received financial support from F. Hoffmann–La Roche, AstraZeneca, Amgen, and Merck, among other pharmaceutical companies.

The 34% reduction in disease recurrence for adjuvant atezolizumab in PD-L1 tumor cells of at least 50% stage II-IIIA patients in the IMpower010 clinical trial, may change the standard of care for early-stage non–small cell lung cancer (NSCLC), according to Enriqueta Felip, MD, the head of thoracic and head and neck cancer unit at Vall d’Hebron Institute of Oncology, Hospital, Barcelona.

IMpower010 is the first positive randomized phase 3 study to show significant disease-free survival (DFS) improvement with adjuvant cancer immunotherapy (atezolizumab, anti–programmed death–ligand 1, and platinum-based chemotherapy) in this population, Dr. Felip said in a presentation at the 2021 European Society for Medical Oncology Congress on Sept. 20 (abstract LBA9).

High unmet need

Up to 60% of patients with stage I-III NSCLC still experience disease relapse despite having received treatment, Dr. Felip said. IMpower010 included 1,280 patients who received up to four cycles of chemotherapy (cisplatin with pemetrexed, gemcitabine, docetaxel, or vinorelbine) after completely resected stage IB-IIIA NSCLC. Patients were randomized to open label to atezolizumab (1,200 mg every 21 days for 16 cycles or best supportive care (BSC). The primary endpoint of investigator-assessed DFS in the stage II-IIIA population (n = 1,005) was stratified according to three groups: PD-L1 tumor cells of at least 1% (stage II-IIIA), all-randomized (stage II-IIIA) and intention-to-treat (stage IB-IIIA).

Median disease-free survival in PD-L1 tumor cells of at least 1% was not estimated in the atezolizumab group and was 35.3 months in the BSC group (95% CI, 29.0 to NE). In the all-randomized group, median DFS was 42.3 months in the atezolizumab group (95% CI, 36.0 to NE) and 35.3 months in the BSC group (95% CI, 30.4-46.4) with a stratified hazard ratio of 0.79 (95% CI, 0.64-0.96; P = .02). In the intent-to-treat population, median DFS was not evaluable in the atezolizumab group and 37.2 months in the BSC group (95% CI, 31.6 to NE) with a hazard ratio of 0.81 (95% CI, 0.67-0.99; P = .04).
 

DFS hazard ratio 0.43 in TC ≥50% group

Looking at DFS by PD-L1 status in the population with and without known EGFR/ALK+ disease, Dr. Felip said that the hazard ratio for the tumor cells of at least 50% group (n = 229) was 0.43 (95% CI, 0.27-0.68), as compared with 0.87 (95% CI, 0.60-1.26) for the tumor cells 1%-49% group. With EGFR/ALK+ patients excluded, the respective HRs were similar (0.43/0.82). Considering DFS events including only disease recurrence, disease incidence was 29.4%/44.7% in the atezolizumab and BSC groups, respectively for those with PD-L1 tumor cells of at least 1%. The same pattern of atezolizumab benefit persisted in the all-randomized and intent-to-treat groups.

An assessment according to regions of relapse (locoregional only, distant only, locoregional and distant, CNS only, second primary lung) revealed no differences in the three groups. Analysis of time from randomization to relapse revealed regional differences in the PD-L1 tumor cells of at least 1% group with a median time to any relapse of 17.6 months in the atezolizumab group and 10.9 months in the BSC group. Time from randomization to relapse was generally similar for atezolizumab and best supportive care in the all randomized and intent-to-treat groups (about 11-12 months).

“The greatest magnitude of disease-free survival benefit was observed in the PD-L1 tumor cell of at least 50% population with a hazard ratio of 0.43,” Dr. Felip said. In a post hoc analysis excluding patients with known EFGR/ALK with NSCLC, she said that hazard ratios were numerically improved in most PD-L1 subgroups. Postrelapse cancer immunotherapies were used at a higher rate in the BSC arm of the trial. “Longer-term follow-up is warranted and may reveal differences in relapse patterns and treatment options.
 

Playing with the immune system

Benjamin Besse, MD, director of oncology and chair of the EORTC Lung Group at Paris-Saclay University, acknowledged the disease-free survival benefit with atezolizumab in IMpower010 and underscored that adjuvant immunotherapy has been changing treatment in resected cancers across tumor types (i.e., melanoma, renal cell carcinoma, NSCLC). He voiced some concerns, including the absence of benefit in PD-L1 less than 1%, pneumonectomy and EGFRmut/ALK+ patients, and generally the potential “when you play with the immune system for there to be a dark side too.” Dr. Besse said delayed side effects in 43.2% of patients , citing a recent report of chronic, mostly grade 1-2 immune-related adverse events following (>12 weeks after discontinuation) adjuvant anti–PD-1 therapy for high-risk resected melanoma. He mentioned, however, that the rate of second primary lung tumors in the atezolizumab group (1.4%) was lower than in the BSC group (2.6%), with generally similar rates between immuno- and nonimmunotherapies in melanoma and breast cancer trials.

“IMpower 010 is the first adjuvant study establishing immune checkpoint blockade as a new standard of care. We need to cure more, not to delay relapse,” he said. The optimal population for treatment is still yet to be defined, as is the best perioperative strategy, Dr. Besse added. “If approved I would prescribe adjuvant atezolizumab ... until I see the overall survival curves.”

IMpower010 was funded by–F. Hoffmann-La Roche. Dr. Felip disclosed numerous financial interests, including having received financial support from F. Hoffmann–La Roche, AstraZeneca, Amgen, and Merck, among other pharmaceutical companies.

The 34% reduction in disease recurrence for adjuvant atezolizumab in PD-L1 tumor cells of at least 50% stage II-IIIA patients in the IMpower010 clinical trial, may change the standard of care for early-stage non–small cell lung cancer (NSCLC), according to Enriqueta Felip, MD, the head of thoracic and head and neck cancer unit at Vall d’Hebron Institute of Oncology, Hospital, Barcelona.

IMpower010 is the first positive randomized phase 3 study to show significant disease-free survival (DFS) improvement with adjuvant cancer immunotherapy (atezolizumab, anti–programmed death–ligand 1, and platinum-based chemotherapy) in this population, Dr. Felip said in a presentation at the 2021 European Society for Medical Oncology Congress on Sept. 20 (abstract LBA9).

High unmet need

Up to 60% of patients with stage I-III NSCLC still experience disease relapse despite having received treatment, Dr. Felip said. IMpower010 included 1,280 patients who received up to four cycles of chemotherapy (cisplatin with pemetrexed, gemcitabine, docetaxel, or vinorelbine) after completely resected stage IB-IIIA NSCLC. Patients were randomized to open label to atezolizumab (1,200 mg every 21 days for 16 cycles or best supportive care (BSC). The primary endpoint of investigator-assessed DFS in the stage II-IIIA population (n = 1,005) was stratified according to three groups: PD-L1 tumor cells of at least 1% (stage II-IIIA), all-randomized (stage II-IIIA) and intention-to-treat (stage IB-IIIA).

Median disease-free survival in PD-L1 tumor cells of at least 1% was not estimated in the atezolizumab group and was 35.3 months in the BSC group (95% CI, 29.0 to NE). In the all-randomized group, median DFS was 42.3 months in the atezolizumab group (95% CI, 36.0 to NE) and 35.3 months in the BSC group (95% CI, 30.4-46.4) with a stratified hazard ratio of 0.79 (95% CI, 0.64-0.96; P = .02). In the intent-to-treat population, median DFS was not evaluable in the atezolizumab group and 37.2 months in the BSC group (95% CI, 31.6 to NE) with a hazard ratio of 0.81 (95% CI, 0.67-0.99; P = .04).
 

DFS hazard ratio 0.43 in TC ≥50% group

Looking at DFS by PD-L1 status in the population with and without known EGFR/ALK+ disease, Dr. Felip said that the hazard ratio for the tumor cells of at least 50% group (n = 229) was 0.43 (95% CI, 0.27-0.68), as compared with 0.87 (95% CI, 0.60-1.26) for the tumor cells 1%-49% group. With EGFR/ALK+ patients excluded, the respective HRs were similar (0.43/0.82). Considering DFS events including only disease recurrence, disease incidence was 29.4%/44.7% in the atezolizumab and BSC groups, respectively for those with PD-L1 tumor cells of at least 1%. The same pattern of atezolizumab benefit persisted in the all-randomized and intent-to-treat groups.

An assessment according to regions of relapse (locoregional only, distant only, locoregional and distant, CNS only, second primary lung) revealed no differences in the three groups. Analysis of time from randomization to relapse revealed regional differences in the PD-L1 tumor cells of at least 1% group with a median time to any relapse of 17.6 months in the atezolizumab group and 10.9 months in the BSC group. Time from randomization to relapse was generally similar for atezolizumab and best supportive care in the all randomized and intent-to-treat groups (about 11-12 months).

“The greatest magnitude of disease-free survival benefit was observed in the PD-L1 tumor cell of at least 50% population with a hazard ratio of 0.43,” Dr. Felip said. In a post hoc analysis excluding patients with known EFGR/ALK with NSCLC, she said that hazard ratios were numerically improved in most PD-L1 subgroups. Postrelapse cancer immunotherapies were used at a higher rate in the BSC arm of the trial. “Longer-term follow-up is warranted and may reveal differences in relapse patterns and treatment options.
 

Playing with the immune system

Benjamin Besse, MD, director of oncology and chair of the EORTC Lung Group at Paris-Saclay University, acknowledged the disease-free survival benefit with atezolizumab in IMpower010 and underscored that adjuvant immunotherapy has been changing treatment in resected cancers across tumor types (i.e., melanoma, renal cell carcinoma, NSCLC). He voiced some concerns, including the absence of benefit in PD-L1 less than 1%, pneumonectomy and EGFRmut/ALK+ patients, and generally the potential “when you play with the immune system for there to be a dark side too.” Dr. Besse said delayed side effects in 43.2% of patients , citing a recent report of chronic, mostly grade 1-2 immune-related adverse events following (>12 weeks after discontinuation) adjuvant anti–PD-1 therapy for high-risk resected melanoma. He mentioned, however, that the rate of second primary lung tumors in the atezolizumab group (1.4%) was lower than in the BSC group (2.6%), with generally similar rates between immuno- and nonimmunotherapies in melanoma and breast cancer trials.

“IMpower 010 is the first adjuvant study establishing immune checkpoint blockade as a new standard of care. We need to cure more, not to delay relapse,” he said. The optimal population for treatment is still yet to be defined, as is the best perioperative strategy, Dr. Besse added. “If approved I would prescribe adjuvant atezolizumab ... until I see the overall survival curves.”

IMpower010 was funded by–F. Hoffmann-La Roche. Dr. Felip disclosed numerous financial interests, including having received financial support from F. Hoffmann–La Roche, AstraZeneca, Amgen, and Merck, among other pharmaceutical companies.