PHILADELPHIA – There are real concerns about whether today’s direct-to-consumer (DTC) genetic tests actually test the mutations they claim to test and of how well a tested DNA sequence tracks actual disease, Andrew D. Coyle, MD, said during a podium presentation at the annual meeting of the American College of Physicians.

Many patients don’t tell their doctors the results of DTC tests, and there’s a lot of potential for misinterpretation all around, said Dr. Coyle, assistant professor of medicine and medical education in the general internal medicine division at the Icahn School of Medicine at Mount Sinai, New York.

“I wouldn’t recommend to patients that they do [DTC testing], if they asked,” he said. “I think we probably do need to be better about asking our patients whether they’re doing this on their own, to make sure that we help them interpret it correctly, that it’s a change in risk – not a diagnosis, and not an assurance they won’t get that disease process.”

High false-positive rates have been seen in recent studies that sought to confirm genotyping data from DTC genetic test results, according to Dr. Coyle. In one 2018 study in Genetics and Medicine (2018;20:1515-21) of 49 patient samples tested for previously identified genetic variants found in raw DTC data, investigators found a 40% false positive rate, which they said underscored the importance of clinical confirmation testing to assure proper patient care, he noted.

To support his claim that many patients aren’t even telling their doctors about the DTC testing they are having done in the first place, Dr. Coyle mentioned results of a survey in Annals of Internal Medicine (2016;164[8]:513-22), which showed that only 19% of patients shared their DTC results with their primary care physicians.

He also pointed out a potential problem regarding the discussions between patients and their physicians about these test results, based on another finding reported in the paper. Of those who did tell their physicians they had DTC testing, 35% said they were “very satisfied” with how that discussion went, Dr. Coyle said.

“So they don’t tell us, and they aren’t very happy when they do tell us,” he told his audience.
 

The 23andMe test and the FDA

The 23andMe test, which was first directly marketed to consumers in 2006, was one of the DTC genetic tests discussed by Dr. Coyle. The Food and Drug Administration later halted the company’s Personal Genome Service in 2013 because of a lack of demonstrated clinical validity, Dr. Coyle noted.

Subsequently, the FDA classified carrier-screening tests as medical devices, allowing such services to come back, leading to what Dr. Coyle described as an explosion over the past few years of DTC evaluation of a variety of conditions, including celiac disease, Alzheimer’s disease, hemochromatosis, and then more recently, screening for cancer risk factors.

In 2018, 23andMe began offering DTC BRCA testing, but for 3 BRCA1/2 mutations seen in individuals of Ashkenazi Jewish descent, Dr. Coyle said.

“If someone did a BRCA test which is only testing three specific mutations seen mostly in Ashkenazi Jewish populations, they may be falsely reassured that the risk of breast cancer is low, when in fact they may have other BRCA mutations,” he said.

In real life, however, many people who order genetic tests online may not even act on the results. In a 2017 study in the Journal of Clinical Oncology, customers whose DTC genetic testing results showed elevated cancer risk were no more likely than were customers without elevated risk to change diet or exercise, engage in advanced planning behaviors, or get screened.

Dr. Coyle had no relevant disclosures to report.

PHILADELPHIA – There are real concerns about whether today’s direct-to-consumer (DTC) genetic tests actually test the mutations they claim to test and of how well a tested DNA sequence tracks actual disease, Andrew D. Coyle, MD, said during a podium presentation at the annual meeting of the American College of Physicians.

Many patients don’t tell their doctors the results of DTC tests, and there’s a lot of potential for misinterpretation all around, said Dr. Coyle, assistant professor of medicine and medical education in the general internal medicine division at the Icahn School of Medicine at Mount Sinai, New York.

“I wouldn’t recommend to patients that they do [DTC testing], if they asked,” he said. “I think we probably do need to be better about asking our patients whether they’re doing this on their own, to make sure that we help them interpret it correctly, that it’s a change in risk – not a diagnosis, and not an assurance they won’t get that disease process.”

High false-positive rates have been seen in recent studies that sought to confirm genotyping data from DTC genetic test results, according to Dr. Coyle. In one 2018 study in Genetics and Medicine (2018;20:1515-21) of 49 patient samples tested for previously identified genetic variants found in raw DTC data, investigators found a 40% false positive rate, which they said underscored the importance of clinical confirmation testing to assure proper patient care, he noted.

To support his claim that many patients aren’t even telling their doctors about the DTC testing they are having done in the first place, Dr. Coyle mentioned results of a survey in Annals of Internal Medicine (2016;164[8]:513-22), which showed that only 19% of patients shared their DTC results with their primary care physicians.

He also pointed out a potential problem regarding the discussions between patients and their physicians about these test results, based on another finding reported in the paper. Of those who did tell their physicians they had DTC testing, 35% said they were “very satisfied” with how that discussion went, Dr. Coyle said.

“So they don’t tell us, and they aren’t very happy when they do tell us,” he told his audience.
 

The 23andMe test and the FDA

The 23andMe test, which was first directly marketed to consumers in 2006, was one of the DTC genetic tests discussed by Dr. Coyle. The Food and Drug Administration later halted the company’s Personal Genome Service in 2013 because of a lack of demonstrated clinical validity, Dr. Coyle noted.

Subsequently, the FDA classified carrier-screening tests as medical devices, allowing such services to come back, leading to what Dr. Coyle described as an explosion over the past few years of DTC evaluation of a variety of conditions, including celiac disease, Alzheimer’s disease, hemochromatosis, and then more recently, screening for cancer risk factors.

In 2018, 23andMe began offering DTC BRCA testing, but for 3 BRCA1/2 mutations seen in individuals of Ashkenazi Jewish descent, Dr. Coyle said.

“If someone did a BRCA test which is only testing three specific mutations seen mostly in Ashkenazi Jewish populations, they may be falsely reassured that the risk of breast cancer is low, when in fact they may have other BRCA mutations,” he said.

In real life, however, many people who order genetic tests online may not even act on the results. In a 2017 study in the Journal of Clinical Oncology, customers whose DTC genetic testing results showed elevated cancer risk were no more likely than were customers without elevated risk to change diet or exercise, engage in advanced planning behaviors, or get screened.

Dr. Coyle had no relevant disclosures to report.

PHILADELPHIA – There are real concerns about whether today’s direct-to-consumer (DTC) genetic tests actually test the mutations they claim to test and of how well a tested DNA sequence tracks actual disease, Andrew D. Coyle, MD, said during a podium presentation at the annual meeting of the American College of Physicians.

Many patients don’t tell their doctors the results of DTC tests, and there’s a lot of potential for misinterpretation all around, said Dr. Coyle, assistant professor of medicine and medical education in the general internal medicine division at the Icahn School of Medicine at Mount Sinai, New York.

“I wouldn’t recommend to patients that they do [DTC testing], if they asked,” he said. “I think we probably do need to be better about asking our patients whether they’re doing this on their own, to make sure that we help them interpret it correctly, that it’s a change in risk – not a diagnosis, and not an assurance they won’t get that disease process.”

High false-positive rates have been seen in recent studies that sought to confirm genotyping data from DTC genetic test results, according to Dr. Coyle. In one 2018 study in Genetics and Medicine (2018;20:1515-21) of 49 patient samples tested for previously identified genetic variants found in raw DTC data, investigators found a 40% false positive rate, which they said underscored the importance of clinical confirmation testing to assure proper patient care, he noted.

To support his claim that many patients aren’t even telling their doctors about the DTC testing they are having done in the first place, Dr. Coyle mentioned results of a survey in Annals of Internal Medicine (2016;164[8]:513-22), which showed that only 19% of patients shared their DTC results with their primary care physicians.

He also pointed out a potential problem regarding the discussions between patients and their physicians about these test results, based on another finding reported in the paper. Of those who did tell their physicians they had DTC testing, 35% said they were “very satisfied” with how that discussion went, Dr. Coyle said.

“So they don’t tell us, and they aren’t very happy when they do tell us,” he told his audience.
 

The 23andMe test and the FDA

The 23andMe test, which was first directly marketed to consumers in 2006, was one of the DTC genetic tests discussed by Dr. Coyle. The Food and Drug Administration later halted the company’s Personal Genome Service in 2013 because of a lack of demonstrated clinical validity, Dr. Coyle noted.

Subsequently, the FDA classified carrier-screening tests as medical devices, allowing such services to come back, leading to what Dr. Coyle described as an explosion over the past few years of DTC evaluation of a variety of conditions, including celiac disease, Alzheimer’s disease, hemochromatosis, and then more recently, screening for cancer risk factors.

In 2018, 23andMe began offering DTC BRCA testing, but for 3 BRCA1/2 mutations seen in individuals of Ashkenazi Jewish descent, Dr. Coyle said.

“If someone did a BRCA test which is only testing three specific mutations seen mostly in Ashkenazi Jewish populations, they may be falsely reassured that the risk of breast cancer is low, when in fact they may have other BRCA mutations,” he said.

In real life, however, many people who order genetic tests online may not even act on the results. In a 2017 study in the Journal of Clinical Oncology, customers whose DTC genetic testing results showed elevated cancer risk were no more likely than were customers without elevated risk to change diet or exercise, engage in advanced planning behaviors, or get screened.

Dr. Coyle had no relevant disclosures to report.

ORLANDO – New ways of assessing and measuring the way the sense of self becomes distorted in patients with schizophrenia patients and those at risk of developing the disease are deepening understanding of the disorder, an expert said at annual congress of the Schizophrenia International Research Society.

Sohee Park, PhD, Gertrude Conaway Vanderbilt Professor of Psychology at Vanderbilt University, Nashville, Tenn., said a unified and continuous sense of self is essential to leading a functional life. But this sense of self is a complex assemblage, made up of explicit experiences and actions, a more internal awareness of our own body, as well as a “social, narrative self” involving our social identity and history. This coherent and continuous sense of self is formulated and tied together by working memory and by our ability to form expectations or predictions about what might happen next, Dr. Park said.

In schizophrenia, the sense of self becomes fragmented as these predictions – on issues such as how sensory input is perceived – break down.

Dr. Park said a more comprehensive approach is needed in understanding this breakdown if clinicians can be expected to help people with schizophrenia.

“Connection between biological disorder and personal illness experience is not really well articulated in our field,” she said. “But it’s a connection we must make if we are to understand this condition and to develop treatments and interventions that make sense and are meaningful to the person who experiences psychosis.”

With her colleagues, Dr. Park has developed a way to better measure these bodily “self-disturbances” that patients with schizophrenia experience, and how they persist over time. B-BODI – the Benson et al. Body Disturbances Inventory – is a kind of catalog of pictures representing experiences of self-disturbance, such as someone having an out-of-body experience or a person who feels her body parts changing. The pictures come with written statements, and are designed to elicit more information from the patients about their experiences, such as how vivid, disturbing, and frequent they are.

Researchers have found that these experiences of body and self-disturbances are correlated with the positive symptoms of schizophrenia – such as hallucinations and confused thoughts – as well as with loneliness. But those experiences are not correlated with negative symptoms, such as loss of ability to feel pleasure.

B-BODI scores tend to be elevated in young people who are at high risk, so the tool could be used to help with earlier identification and treatment, and the use of pictures could help patients better convey what they’re experiencing, Dr. Park said.

“Self-disturbances are difficult to verbalize,” she said. B-BODI can help verbalize these strange experiences that are hard to describe – especially in those who have difficulty communicating.

She and her colleagues have found that those at risk of schizophrenia have a more “flexible body boundary” than do those not at risk. They performed an assessment of the degree to which subjects experienced the “Pinocchio illusion,” in which subjects are blindfolded, touch their noses, and have their biceps stimulated to create the sensation that their arm is moving away from the nose – which is interpreted as the nose growing longer. They found that subjects who scored higher on the Prodromal Questionnaire Brief – an assessment of schizophrenia risk – had higher Pinocchio illusion scores.

These abnormalities in self-perception all feed into the difficulty with which people with schizophrenia have in interacting with others. To address this difficulty, her group has developed a virtual reality training program to help patients with these interactions.

In the program, the user is asked to choose an avatar to interact with by looking at the face of the avatar for a few seconds. Once chosen, the face of the avatar is fully revealed and a conversation takes place. Then the participant receives feedback. Negative symptoms of schizophrenia were significantly reduced after participation after just 10 sessions, Dr. Park said. The program has received favorable reviews from patients – one described the avatars as “very friendly” – and holds promise for helping schizophrenia patients with social situations.

“Virtual reality,” she said, “offers the ideal rehearsal space.”

This work was supported by the National Institute of Mental Health and NARSAD, formerly known as the National Alliance for Research on Schizophrenia and Depression. Dr. Park reported no financial disclosures.

ORLANDO – New ways of assessing and measuring the way the sense of self becomes distorted in patients with schizophrenia patients and those at risk of developing the disease are deepening understanding of the disorder, an expert said at annual congress of the Schizophrenia International Research Society.

Sohee Park, PhD, Gertrude Conaway Vanderbilt Professor of Psychology at Vanderbilt University, Nashville, Tenn., said a unified and continuous sense of self is essential to leading a functional life. But this sense of self is a complex assemblage, made up of explicit experiences and actions, a more internal awareness of our own body, as well as a “social, narrative self” involving our social identity and history. This coherent and continuous sense of self is formulated and tied together by working memory and by our ability to form expectations or predictions about what might happen next, Dr. Park said.

In schizophrenia, the sense of self becomes fragmented as these predictions – on issues such as how sensory input is perceived – break down.

Dr. Park said a more comprehensive approach is needed in understanding this breakdown if clinicians can be expected to help people with schizophrenia.

“Connection between biological disorder and personal illness experience is not really well articulated in our field,” she said. “But it’s a connection we must make if we are to understand this condition and to develop treatments and interventions that make sense and are meaningful to the person who experiences psychosis.”

With her colleagues, Dr. Park has developed a way to better measure these bodily “self-disturbances” that patients with schizophrenia experience, and how they persist over time. B-BODI – the Benson et al. Body Disturbances Inventory – is a kind of catalog of pictures representing experiences of self-disturbance, such as someone having an out-of-body experience or a person who feels her body parts changing. The pictures come with written statements, and are designed to elicit more information from the patients about their experiences, such as how vivid, disturbing, and frequent they are.

Researchers have found that these experiences of body and self-disturbances are correlated with the positive symptoms of schizophrenia – such as hallucinations and confused thoughts – as well as with loneliness. But those experiences are not correlated with negative symptoms, such as loss of ability to feel pleasure.

B-BODI scores tend to be elevated in young people who are at high risk, so the tool could be used to help with earlier identification and treatment, and the use of pictures could help patients better convey what they’re experiencing, Dr. Park said.

“Self-disturbances are difficult to verbalize,” she said. B-BODI can help verbalize these strange experiences that are hard to describe – especially in those who have difficulty communicating.

She and her colleagues have found that those at risk of schizophrenia have a more “flexible body boundary” than do those not at risk. They performed an assessment of the degree to which subjects experienced the “Pinocchio illusion,” in which subjects are blindfolded, touch their noses, and have their biceps stimulated to create the sensation that their arm is moving away from the nose – which is interpreted as the nose growing longer. They found that subjects who scored higher on the Prodromal Questionnaire Brief – an assessment of schizophrenia risk – had higher Pinocchio illusion scores.

These abnormalities in self-perception all feed into the difficulty with which people with schizophrenia have in interacting with others. To address this difficulty, her group has developed a virtual reality training program to help patients with these interactions.

In the program, the user is asked to choose an avatar to interact with by looking at the face of the avatar for a few seconds. Once chosen, the face of the avatar is fully revealed and a conversation takes place. Then the participant receives feedback. Negative symptoms of schizophrenia were significantly reduced after participation after just 10 sessions, Dr. Park said. The program has received favorable reviews from patients – one described the avatars as “very friendly” – and holds promise for helping schizophrenia patients with social situations.

“Virtual reality,” she said, “offers the ideal rehearsal space.”

This work was supported by the National Institute of Mental Health and NARSAD, formerly known as the National Alliance for Research on Schizophrenia and Depression. Dr. Park reported no financial disclosures.

ORLANDO – New ways of assessing and measuring the way the sense of self becomes distorted in patients with schizophrenia patients and those at risk of developing the disease are deepening understanding of the disorder, an expert said at annual congress of the Schizophrenia International Research Society.

Sohee Park, PhD, Gertrude Conaway Vanderbilt Professor of Psychology at Vanderbilt University, Nashville, Tenn., said a unified and continuous sense of self is essential to leading a functional life. But this sense of self is a complex assemblage, made up of explicit experiences and actions, a more internal awareness of our own body, as well as a “social, narrative self” involving our social identity and history. This coherent and continuous sense of self is formulated and tied together by working memory and by our ability to form expectations or predictions about what might happen next, Dr. Park said.

In schizophrenia, the sense of self becomes fragmented as these predictions – on issues such as how sensory input is perceived – break down.

Dr. Park said a more comprehensive approach is needed in understanding this breakdown if clinicians can be expected to help people with schizophrenia.

“Connection between biological disorder and personal illness experience is not really well articulated in our field,” she said. “But it’s a connection we must make if we are to understand this condition and to develop treatments and interventions that make sense and are meaningful to the person who experiences psychosis.”

With her colleagues, Dr. Park has developed a way to better measure these bodily “self-disturbances” that patients with schizophrenia experience, and how they persist over time. B-BODI – the Benson et al. Body Disturbances Inventory – is a kind of catalog of pictures representing experiences of self-disturbance, such as someone having an out-of-body experience or a person who feels her body parts changing. The pictures come with written statements, and are designed to elicit more information from the patients about their experiences, such as how vivid, disturbing, and frequent they are.

Researchers have found that these experiences of body and self-disturbances are correlated with the positive symptoms of schizophrenia – such as hallucinations and confused thoughts – as well as with loneliness. But those experiences are not correlated with negative symptoms, such as loss of ability to feel pleasure.

B-BODI scores tend to be elevated in young people who are at high risk, so the tool could be used to help with earlier identification and treatment, and the use of pictures could help patients better convey what they’re experiencing, Dr. Park said.

“Self-disturbances are difficult to verbalize,” she said. B-BODI can help verbalize these strange experiences that are hard to describe – especially in those who have difficulty communicating.

She and her colleagues have found that those at risk of schizophrenia have a more “flexible body boundary” than do those not at risk. They performed an assessment of the degree to which subjects experienced the “Pinocchio illusion,” in which subjects are blindfolded, touch their noses, and have their biceps stimulated to create the sensation that their arm is moving away from the nose – which is interpreted as the nose growing longer. They found that subjects who scored higher on the Prodromal Questionnaire Brief – an assessment of schizophrenia risk – had higher Pinocchio illusion scores.

These abnormalities in self-perception all feed into the difficulty with which people with schizophrenia have in interacting with others. To address this difficulty, her group has developed a virtual reality training program to help patients with these interactions.

In the program, the user is asked to choose an avatar to interact with by looking at the face of the avatar for a few seconds. Once chosen, the face of the avatar is fully revealed and a conversation takes place. Then the participant receives feedback. Negative symptoms of schizophrenia were significantly reduced after participation after just 10 sessions, Dr. Park said. The program has received favorable reviews from patients – one described the avatars as “very friendly” – and holds promise for helping schizophrenia patients with social situations.

“Virtual reality,” she said, “offers the ideal rehearsal space.”

This work was supported by the National Institute of Mental Health and NARSAD, formerly known as the National Alliance for Research on Schizophrenia and Depression. Dr. Park reported no financial disclosures.

ATLANTA – A combination of the epidermal growth factor receptor (EGFR)–targeted agent osimertinib (Tagrisso) with savolitinib, an investigational MET inhibitor, showed activity against MET-driven non–small cell lung cancer (NSCLC) in patients for whom prior lines of EGFR-targeted therapy had failed.

Neil Osterweil/MDedge News

Results of the phase 1b TATTON trial suggest that it may be possible to overcome MET-driven drug resistance to tyrosine kinase inhibitors (TKIs) by targeting MET amplification, said Lecia V. Sequist, MD, from the Massachusetts General Hospital Cancer Center in Boston.

“We’ve seen that up to 10% of patients at the time of acquired resistance progressing on first- or second-generation EGFR TKIs and up to 25% of patients progressing on third-generation TKIs will have resistance driven by MET amplification,” she said at a briefing at the annual meeting of the American Association for Cancer Research.

Preliminary analysis of next-generation sequencing of circulating tumor DNA showed that MET amplification was the most common resistance mechanism, occurring in 15% of patients treated for NSCLC with first-line osimertinib in the FLAURA trial. In the AURA3 trial, MET amplification was the mechanism of resistance to second-line osimertinib in 19% of patients, she said.

Savolitinib is a selective oral MET-targeted TKI that has shown preliminary antitumor activity in patients with resistance to EGFR TKIs caused by MET amplification.

Dr. Sequist presented updated interim data on two cohorts of patients enrolled in the phase 1b trial evaluating osimertinib and savolitinib in patients with advanced or metastatic NSCLC bearing EGFR mutations following failure of one or more prior EGFR-targeted TKIs. A separate cohort of patients was treated with osimertinib and selumetinib, an investigational inhibitor of MEK1/2.

In the dose-expansion phase of the trial, enrolled patients with EGFR mutation–positive and MET-positive NSCLC, and divided them into two groups: patients who received prior therapy with a first- and/or second-generation EGFR-targeted TKI who were negative for the T790M resistance mutation and patients who had received prior treatment with a third-generation EGFR TKI, regardless of mutational status.

Of 46 patients treated with first- and/or second-generation agents, 24 had partial responses for an overall response rate of 52%. Of the remaining 22 patients, 16 (35%) had stable disease for at least 6 weeks, 3 had disease progression, and 3 were not evaluable. The median time to response was 43 days.

The most common adverse events of grade 3 or greater in this cohort were nausea (4%), fatigue (7%), vomiting (4%), peripheral edema (2%), decreased white blood cell count (2%), pain (7%), AST increase (8%), rash (4%), and decreased neutrophil count (8%).

Among 48 patients treated with the combination after disease progression on a third-generation EGFR TKI, 12 had a partial response, for an overall response rate of 25%. In addition, 21 of the 36 patients without objective responses had stable disease for at least 6 weeks, 6 had disease progression, and 9 were not evaluable. The median time to response was 46 days.

In this cohort, the most common adverse events, independent of causality, included nausea (2%), vomiting (4%), diarrhea (2%), fatigue (4%), decreased appetite (6%), and myalgia (1%). “Our data suggest that the combination of osimertinib and savolitinib could overcome MET-driven resistance, but certainly further research is needed to determine the final effectiveness of these therapies,” Dr. Sequist said.

The combination is being explored in two studies: the ongoing single-arm, phase 2 SAVANNAH trial in patients with advanced EGFR-mutant, MET-positive NSCLC who had disease progression on a prior course of osimertinib; and ORCHARD, currently in the planning stages as a phase 2 trial in patients with advanced NSCLC who had disease progression on first-line osimertinib.

The ORCHARD trial will have multiple biomarker-matched and nonmatched treatment arms to examine both targeted and nontargeted combinations.

“I would say this is impressive early data,” said Roy S. Herbst, MD, PhD, chief of medical oncology at Yale Cancer Center and Smilow Cancer Hospital in New Haven, Conn., the invited discussant in the session where Dr. Sequist presented the data.

“We need randomized trials to confirm the results, need to better define MET-selection criteria, and this could in the future be a very useful refractory EGFR therapy,” he said.

The TATTON trial is sponsored by AstraZeneca. Dr. Sequist reported serving as an advisory board member and receiving research support and honoraria from the company. Dr. Herbst reported receiving research support from AstraZeneca, Eli Lilly, and Merck, and has served as a consultant for AstraZeneca, Eli Lilly, Genentech/Roche, Merck, NextCure, and Pfizer.

SOURCES: Yu H et al. AACR 2019, Abstract CT032; Sequist LV et al. AACR 2019, Abstract CT033.

ATLANTA – A combination of the epidermal growth factor receptor (EGFR)–targeted agent osimertinib (Tagrisso) with savolitinib, an investigational MET inhibitor, showed activity against MET-driven non–small cell lung cancer (NSCLC) in patients for whom prior lines of EGFR-targeted therapy had failed.

Neil Osterweil/MDedge News

Results of the phase 1b TATTON trial suggest that it may be possible to overcome MET-driven drug resistance to tyrosine kinase inhibitors (TKIs) by targeting MET amplification, said Lecia V. Sequist, MD, from the Massachusetts General Hospital Cancer Center in Boston.

“We’ve seen that up to 10% of patients at the time of acquired resistance progressing on first- or second-generation EGFR TKIs and up to 25% of patients progressing on third-generation TKIs will have resistance driven by MET amplification,” she said at a briefing at the annual meeting of the American Association for Cancer Research.

Preliminary analysis of next-generation sequencing of circulating tumor DNA showed that MET amplification was the most common resistance mechanism, occurring in 15% of patients treated for NSCLC with first-line osimertinib in the FLAURA trial. In the AURA3 trial, MET amplification was the mechanism of resistance to second-line osimertinib in 19% of patients, she said.

Savolitinib is a selective oral MET-targeted TKI that has shown preliminary antitumor activity in patients with resistance to EGFR TKIs caused by MET amplification.

Dr. Sequist presented updated interim data on two cohorts of patients enrolled in the phase 1b trial evaluating osimertinib and savolitinib in patients with advanced or metastatic NSCLC bearing EGFR mutations following failure of one or more prior EGFR-targeted TKIs. A separate cohort of patients was treated with osimertinib and selumetinib, an investigational inhibitor of MEK1/2.

In the dose-expansion phase of the trial, enrolled patients with EGFR mutation–positive and MET-positive NSCLC, and divided them into two groups: patients who received prior therapy with a first- and/or second-generation EGFR-targeted TKI who were negative for the T790M resistance mutation and patients who had received prior treatment with a third-generation EGFR TKI, regardless of mutational status.

Of 46 patients treated with first- and/or second-generation agents, 24 had partial responses for an overall response rate of 52%. Of the remaining 22 patients, 16 (35%) had stable disease for at least 6 weeks, 3 had disease progression, and 3 were not evaluable. The median time to response was 43 days.

The most common adverse events of grade 3 or greater in this cohort were nausea (4%), fatigue (7%), vomiting (4%), peripheral edema (2%), decreased white blood cell count (2%), pain (7%), AST increase (8%), rash (4%), and decreased neutrophil count (8%).

Among 48 patients treated with the combination after disease progression on a third-generation EGFR TKI, 12 had a partial response, for an overall response rate of 25%. In addition, 21 of the 36 patients without objective responses had stable disease for at least 6 weeks, 6 had disease progression, and 9 were not evaluable. The median time to response was 46 days.

In this cohort, the most common adverse events, independent of causality, included nausea (2%), vomiting (4%), diarrhea (2%), fatigue (4%), decreased appetite (6%), and myalgia (1%). “Our data suggest that the combination of osimertinib and savolitinib could overcome MET-driven resistance, but certainly further research is needed to determine the final effectiveness of these therapies,” Dr. Sequist said.

The combination is being explored in two studies: the ongoing single-arm, phase 2 SAVANNAH trial in patients with advanced EGFR-mutant, MET-positive NSCLC who had disease progression on a prior course of osimertinib; and ORCHARD, currently in the planning stages as a phase 2 trial in patients with advanced NSCLC who had disease progression on first-line osimertinib.

The ORCHARD trial will have multiple biomarker-matched and nonmatched treatment arms to examine both targeted and nontargeted combinations.

“I would say this is impressive early data,” said Roy S. Herbst, MD, PhD, chief of medical oncology at Yale Cancer Center and Smilow Cancer Hospital in New Haven, Conn., the invited discussant in the session where Dr. Sequist presented the data.

“We need randomized trials to confirm the results, need to better define MET-selection criteria, and this could in the future be a very useful refractory EGFR therapy,” he said.

The TATTON trial is sponsored by AstraZeneca. Dr. Sequist reported serving as an advisory board member and receiving research support and honoraria from the company. Dr. Herbst reported receiving research support from AstraZeneca, Eli Lilly, and Merck, and has served as a consultant for AstraZeneca, Eli Lilly, Genentech/Roche, Merck, NextCure, and Pfizer.

SOURCES: Yu H et al. AACR 2019, Abstract CT032; Sequist LV et al. AACR 2019, Abstract CT033.

ATLANTA – A combination of the epidermal growth factor receptor (EGFR)–targeted agent osimertinib (Tagrisso) with savolitinib, an investigational MET inhibitor, showed activity against MET-driven non–small cell lung cancer (NSCLC) in patients for whom prior lines of EGFR-targeted therapy had failed.

Neil Osterweil/MDedge News

Results of the phase 1b TATTON trial suggest that it may be possible to overcome MET-driven drug resistance to tyrosine kinase inhibitors (TKIs) by targeting MET amplification, said Lecia V. Sequist, MD, from the Massachusetts General Hospital Cancer Center in Boston.

“We’ve seen that up to 10% of patients at the time of acquired resistance progressing on first- or second-generation EGFR TKIs and up to 25% of patients progressing on third-generation TKIs will have resistance driven by MET amplification,” she said at a briefing at the annual meeting of the American Association for Cancer Research.

Preliminary analysis of next-generation sequencing of circulating tumor DNA showed that MET amplification was the most common resistance mechanism, occurring in 15% of patients treated for NSCLC with first-line osimertinib in the FLAURA trial. In the AURA3 trial, MET amplification was the mechanism of resistance to second-line osimertinib in 19% of patients, she said.

Savolitinib is a selective oral MET-targeted TKI that has shown preliminary antitumor activity in patients with resistance to EGFR TKIs caused by MET amplification.

Dr. Sequist presented updated interim data on two cohorts of patients enrolled in the phase 1b trial evaluating osimertinib and savolitinib in patients with advanced or metastatic NSCLC bearing EGFR mutations following failure of one or more prior EGFR-targeted TKIs. A separate cohort of patients was treated with osimertinib and selumetinib, an investigational inhibitor of MEK1/2.

In the dose-expansion phase of the trial, enrolled patients with EGFR mutation–positive and MET-positive NSCLC, and divided them into two groups: patients who received prior therapy with a first- and/or second-generation EGFR-targeted TKI who were negative for the T790M resistance mutation and patients who had received prior treatment with a third-generation EGFR TKI, regardless of mutational status.

Of 46 patients treated with first- and/or second-generation agents, 24 had partial responses for an overall response rate of 52%. Of the remaining 22 patients, 16 (35%) had stable disease for at least 6 weeks, 3 had disease progression, and 3 were not evaluable. The median time to response was 43 days.

The most common adverse events of grade 3 or greater in this cohort were nausea (4%), fatigue (7%), vomiting (4%), peripheral edema (2%), decreased white blood cell count (2%), pain (7%), AST increase (8%), rash (4%), and decreased neutrophil count (8%).

Among 48 patients treated with the combination after disease progression on a third-generation EGFR TKI, 12 had a partial response, for an overall response rate of 25%. In addition, 21 of the 36 patients without objective responses had stable disease for at least 6 weeks, 6 had disease progression, and 9 were not evaluable. The median time to response was 46 days.

In this cohort, the most common adverse events, independent of causality, included nausea (2%), vomiting (4%), diarrhea (2%), fatigue (4%), decreased appetite (6%), and myalgia (1%). “Our data suggest that the combination of osimertinib and savolitinib could overcome MET-driven resistance, but certainly further research is needed to determine the final effectiveness of these therapies,” Dr. Sequist said.

The combination is being explored in two studies: the ongoing single-arm, phase 2 SAVANNAH trial in patients with advanced EGFR-mutant, MET-positive NSCLC who had disease progression on a prior course of osimertinib; and ORCHARD, currently in the planning stages as a phase 2 trial in patients with advanced NSCLC who had disease progression on first-line osimertinib.

The ORCHARD trial will have multiple biomarker-matched and nonmatched treatment arms to examine both targeted and nontargeted combinations.

“I would say this is impressive early data,” said Roy S. Herbst, MD, PhD, chief of medical oncology at Yale Cancer Center and Smilow Cancer Hospital in New Haven, Conn., the invited discussant in the session where Dr. Sequist presented the data.

“We need randomized trials to confirm the results, need to better define MET-selection criteria, and this could in the future be a very useful refractory EGFR therapy,” he said.

The TATTON trial is sponsored by AstraZeneca. Dr. Sequist reported serving as an advisory board member and receiving research support and honoraria from the company. Dr. Herbst reported receiving research support from AstraZeneca, Eli Lilly, and Merck, and has served as a consultant for AstraZeneca, Eli Lilly, Genentech/Roche, Merck, NextCure, and Pfizer.

SOURCES: Yu H et al. AACR 2019, Abstract CT032; Sequist LV et al. AACR 2019, Abstract CT033.

The use of percutaneous coronary intervention after ST-segment elevation myocardial infarction is increasing in older adults, and is associated with significantly lower in-hospital mortality, new research has found.

“Our study shows that the rates of utilization of PCI in older patients with STEMI and cardiogenic shock is rising. This rise has been paralleled by an equivalent decline in unadjusted mortality rates,” Abdulla A. Damluji, MD, and his coinvestigators wrote in an analysis published in the Journal of the American College of Cardiology.

They looked at outcomes of 317,728 cases of STEMI with cardiogenic shock during 1999-2013, of which 35% occurred in individuals aged 75 years or above.

Over the study period, the proportion of adults aged 75 years and over who underwent percutaneous coronary intervention after STEMI increased from 27% in 1999 to 56% in 2013. At the same time, in-hospital mortality rates in those patients declined from 64% in 1999 to 46% in 2013. Both differences were significant at P less than 0.001.

PCI more than halved the mortality associated with STEMI in older adults, even after adjustment for propensity score, and this was seen across all four U.S. Census Bureau regions in the analysis.


However, mortality rates were slightly higher in patients who underwent percutaneous coronary intervention and had a bleeding event, compared with those who did not have a bleeding event.

There were some significant differences in the prevalence of cardiovascular risk factors and noncardiovascular diagnoses between those who underwent percutaneous coronary intervention and those who did not. There was around a 20% higher prevalence of obesity, but a lower prevalence of valvular heart disease and heart failure, in individuals who were treated with percutaneous coronary intervention than among those who were not.

Older adults who received percutaneous coronary intervention also had a significantly lower disease burden compared with older adults who did not, and were more likely to be younger, male, and not an underrepresented minority.

“Despite the improvement in survival associated with early revascularization as reported by these studies, many older adults with multiple chronic conditions, worse disease burden, and possibly limited life expectancy as assessed by interventional cardiologists do not receive early revascularization with PCI,” wrote Dr. Damluji of Sinai Hospital of Baltimore and Johns Hopkins University, and his coauthors.

“This study was aimed to address this important selection bias by implementing different methods of propensity matching to understand the influence of early revascularization adjusting for demographic, clinical, and hospital characteristics between older adults with early revascularization versus those without revascularization.”

The study was partly supported by the Jane and Stanley F. Rodbell family. Three authors declared support from the National Institute on Aging. Two authors declared funding from private industry and one declared pharmaceutical stocks. No other conflicts of interest were declared.

SOURCE: Damluji A et al. J Am Coll Cardiol. 2019 Apr;73(15):1890-900.

The use of percutaneous coronary intervention after ST-segment elevation myocardial infarction is increasing in older adults, and is associated with significantly lower in-hospital mortality, new research has found.

“Our study shows that the rates of utilization of PCI in older patients with STEMI and cardiogenic shock is rising. This rise has been paralleled by an equivalent decline in unadjusted mortality rates,” Abdulla A. Damluji, MD, and his coinvestigators wrote in an analysis published in the Journal of the American College of Cardiology.

They looked at outcomes of 317,728 cases of STEMI with cardiogenic shock during 1999-2013, of which 35% occurred in individuals aged 75 years or above.

Over the study period, the proportion of adults aged 75 years and over who underwent percutaneous coronary intervention after STEMI increased from 27% in 1999 to 56% in 2013. At the same time, in-hospital mortality rates in those patients declined from 64% in 1999 to 46% in 2013. Both differences were significant at P less than 0.001.

PCI more than halved the mortality associated with STEMI in older adults, even after adjustment for propensity score, and this was seen across all four U.S. Census Bureau regions in the analysis.


However, mortality rates were slightly higher in patients who underwent percutaneous coronary intervention and had a bleeding event, compared with those who did not have a bleeding event.

There were some significant differences in the prevalence of cardiovascular risk factors and noncardiovascular diagnoses between those who underwent percutaneous coronary intervention and those who did not. There was around a 20% higher prevalence of obesity, but a lower prevalence of valvular heart disease and heart failure, in individuals who were treated with percutaneous coronary intervention than among those who were not.

Older adults who received percutaneous coronary intervention also had a significantly lower disease burden compared with older adults who did not, and were more likely to be younger, male, and not an underrepresented minority.

“Despite the improvement in survival associated with early revascularization as reported by these studies, many older adults with multiple chronic conditions, worse disease burden, and possibly limited life expectancy as assessed by interventional cardiologists do not receive early revascularization with PCI,” wrote Dr. Damluji of Sinai Hospital of Baltimore and Johns Hopkins University, and his coauthors.

“This study was aimed to address this important selection bias by implementing different methods of propensity matching to understand the influence of early revascularization adjusting for demographic, clinical, and hospital characteristics between older adults with early revascularization versus those without revascularization.”

The study was partly supported by the Jane and Stanley F. Rodbell family. Three authors declared support from the National Institute on Aging. Two authors declared funding from private industry and one declared pharmaceutical stocks. No other conflicts of interest were declared.

SOURCE: Damluji A et al. J Am Coll Cardiol. 2019 Apr;73(15):1890-900.

The use of percutaneous coronary intervention after ST-segment elevation myocardial infarction is increasing in older adults, and is associated with significantly lower in-hospital mortality, new research has found.

“Our study shows that the rates of utilization of PCI in older patients with STEMI and cardiogenic shock is rising. This rise has been paralleled by an equivalent decline in unadjusted mortality rates,” Abdulla A. Damluji, MD, and his coinvestigators wrote in an analysis published in the Journal of the American College of Cardiology.

They looked at outcomes of 317,728 cases of STEMI with cardiogenic shock during 1999-2013, of which 35% occurred in individuals aged 75 years or above.

Over the study period, the proportion of adults aged 75 years and over who underwent percutaneous coronary intervention after STEMI increased from 27% in 1999 to 56% in 2013. At the same time, in-hospital mortality rates in those patients declined from 64% in 1999 to 46% in 2013. Both differences were significant at P less than 0.001.

PCI more than halved the mortality associated with STEMI in older adults, even after adjustment for propensity score, and this was seen across all four U.S. Census Bureau regions in the analysis.


However, mortality rates were slightly higher in patients who underwent percutaneous coronary intervention and had a bleeding event, compared with those who did not have a bleeding event.

There were some significant differences in the prevalence of cardiovascular risk factors and noncardiovascular diagnoses between those who underwent percutaneous coronary intervention and those who did not. There was around a 20% higher prevalence of obesity, but a lower prevalence of valvular heart disease and heart failure, in individuals who were treated with percutaneous coronary intervention than among those who were not.

Older adults who received percutaneous coronary intervention also had a significantly lower disease burden compared with older adults who did not, and were more likely to be younger, male, and not an underrepresented minority.

“Despite the improvement in survival associated with early revascularization as reported by these studies, many older adults with multiple chronic conditions, worse disease burden, and possibly limited life expectancy as assessed by interventional cardiologists do not receive early revascularization with PCI,” wrote Dr. Damluji of Sinai Hospital of Baltimore and Johns Hopkins University, and his coauthors.

“This study was aimed to address this important selection bias by implementing different methods of propensity matching to understand the influence of early revascularization adjusting for demographic, clinical, and hospital characteristics between older adults with early revascularization versus those without revascularization.”

The study was partly supported by the Jane and Stanley F. Rodbell family. Three authors declared support from the National Institute on Aging. Two authors declared funding from private industry and one declared pharmaceutical stocks. No other conflicts of interest were declared.

SOURCE: Damluji A et al. J Am Coll Cardiol. 2019 Apr;73(15):1890-900.

Background: Studies abound on the accelerated cost and health care activities of patients toward the end of life. Previous analyses of Medicare trends of medical care at the time of death have been compiled in 2000, 2005, 2009, and 2011; this study reexamines recent trends.

Study design: Retrospective cohort of a random sample of Medicare Fee-for-Service and Medicare Advantage decedents during 2000-2015.

Setting: Medicare patients in acute care hospitals, home/community, hospice inpatient care units, or nursing homes.

Synopsis: Approximately 1.4 million Medicare Fee-for-Service decedents and 870,000 Medicare Advantage decedents were studied in a random sample that included 20% of Medicare Fee-for-Service recipients in the years 2000, 2005, 2009, 2011, and 2015 and 100% of Medicare Advantage patients in the years 2011 and 2015. Deaths of Medicare Fee-for-Service recipients occurring in acute care hospitals and nursing homes decreased from 32.6% (95% confidence interval, 32.4%-32.8%) in 2000 to 19.8% (95% CI, 19.6%-20.0%) in 2015. Patients who died while receiving hospice services increased from 21.6% (95% CI, 21.5%-21.8%) in 2000 to 50.4% (95% CI, 50.2%-50.6%) in 2015. Review of Medicare Advantage data demonstrated similar shifts.

Although there are concerns about the accuracy of reported location of community deaths and these results may not be generalizable to other, non-Medicare populations, the study overall adds statistical data on death trends and suggests an improvement in the use of palliative and hospice care services.

Bottom line: Compared with previous years, fewer Medicare beneficiaries are dying in acute care settings, and more beneficiaries are receiving hospice care in other settings.

Citation: Teno J et al. Site of death, place of care, and health care transitions among U. S. Medicare beneficiaries between 2000-2015. JAMA. 2018;320(3):264-71.

Dr. Smith is an assistant professor of medicine in the division of hospital medicine at Emory University, Atlanta.

Background: Studies abound on the accelerated cost and health care activities of patients toward the end of life. Previous analyses of Medicare trends of medical care at the time of death have been compiled in 2000, 2005, 2009, and 2011; this study reexamines recent trends.

Study design: Retrospective cohort of a random sample of Medicare Fee-for-Service and Medicare Advantage decedents during 2000-2015.

Setting: Medicare patients in acute care hospitals, home/community, hospice inpatient care units, or nursing homes.

Synopsis: Approximately 1.4 million Medicare Fee-for-Service decedents and 870,000 Medicare Advantage decedents were studied in a random sample that included 20% of Medicare Fee-for-Service recipients in the years 2000, 2005, 2009, 2011, and 2015 and 100% of Medicare Advantage patients in the years 2011 and 2015. Deaths of Medicare Fee-for-Service recipients occurring in acute care hospitals and nursing homes decreased from 32.6% (95% confidence interval, 32.4%-32.8%) in 2000 to 19.8% (95% CI, 19.6%-20.0%) in 2015. Patients who died while receiving hospice services increased from 21.6% (95% CI, 21.5%-21.8%) in 2000 to 50.4% (95% CI, 50.2%-50.6%) in 2015. Review of Medicare Advantage data demonstrated similar shifts.

Although there are concerns about the accuracy of reported location of community deaths and these results may not be generalizable to other, non-Medicare populations, the study overall adds statistical data on death trends and suggests an improvement in the use of palliative and hospice care services.

Bottom line: Compared with previous years, fewer Medicare beneficiaries are dying in acute care settings, and more beneficiaries are receiving hospice care in other settings.

Citation: Teno J et al. Site of death, place of care, and health care transitions among U. S. Medicare beneficiaries between 2000-2015. JAMA. 2018;320(3):264-71.

Dr. Smith is an assistant professor of medicine in the division of hospital medicine at Emory University, Atlanta.

Background: Studies abound on the accelerated cost and health care activities of patients toward the end of life. Previous analyses of Medicare trends of medical care at the time of death have been compiled in 2000, 2005, 2009, and 2011; this study reexamines recent trends.

Study design: Retrospective cohort of a random sample of Medicare Fee-for-Service and Medicare Advantage decedents during 2000-2015.

Setting: Medicare patients in acute care hospitals, home/community, hospice inpatient care units, or nursing homes.

Synopsis: Approximately 1.4 million Medicare Fee-for-Service decedents and 870,000 Medicare Advantage decedents were studied in a random sample that included 20% of Medicare Fee-for-Service recipients in the years 2000, 2005, 2009, 2011, and 2015 and 100% of Medicare Advantage patients in the years 2011 and 2015. Deaths of Medicare Fee-for-Service recipients occurring in acute care hospitals and nursing homes decreased from 32.6% (95% confidence interval, 32.4%-32.8%) in 2000 to 19.8% (95% CI, 19.6%-20.0%) in 2015. Patients who died while receiving hospice services increased from 21.6% (95% CI, 21.5%-21.8%) in 2000 to 50.4% (95% CI, 50.2%-50.6%) in 2015. Review of Medicare Advantage data demonstrated similar shifts.

Although there are concerns about the accuracy of reported location of community deaths and these results may not be generalizable to other, non-Medicare populations, the study overall adds statistical data on death trends and suggests an improvement in the use of palliative and hospice care services.

Bottom line: Compared with previous years, fewer Medicare beneficiaries are dying in acute care settings, and more beneficiaries are receiving hospice care in other settings.

Citation: Teno J et al. Site of death, place of care, and health care transitions among U. S. Medicare beneficiaries between 2000-2015. JAMA. 2018;320(3):264-71.

Dr. Smith is an assistant professor of medicine in the division of hospital medicine at Emory University, Atlanta.

A continuously updating database of clinical and genomic details on patients with non–small cell lung cancer accurately represented correlations between genomics and outcomes, based on an analysis of more than 4,000 patients.

“Most efforts to identify clinicogenomic associations currently rely on clinical trials, single-institution series, or national registries,” wrote Gaurav Singal, MD, of Foundation Medicine in Cambridge, Mass., and colleagues in JAMA.

To explore the feasibility of a clinicogenomic database, the researchers combined clinical data from electronic health records with comprehensive genetic profiling data from 28,889 patients; 4,064 adults with non–small cell lung cancer were included in the analysis of associations among tumor genomics, patient characteristics, and clinical outcomes. The data were collected between Jan. 1, 2011, and Jan. 1, 2018, from 275 U.S. oncology practices.

The researchers examined implications of clinical and genomic features for 3,522 patients with advanced disease. Among these, the median overall survival was 10.3 months and the 5-year survival rate was 3.8%. Factors influencing a longer overall survival included never smoking and having nonsquamous pathology; the presence of mutations in genes TP53 and RB1 were associated with shorter survival.

For each patient, researchers calculated the tumor mutational burden (TMB), defined as “a measure of the number of somatic mutations identified per megabase of DNA sequenced.” TMB was significantly higher among smokers, compared with nonsmokers, and “alterations in EGFR, ALK, ROS1, and RET were associated with significantly lower TMB than wild-type cases,” the researchers wrote.

Overall, the results “replicated previously described associations between clinical and genomic characteristics, driver mutations and response to targeted therapy, and TMB and response to immunotherapy,” the researchers wrote.

The findings were limited by several factors, notably the quality and completeness of mortality data, as well as potential biases from the inclusion of comprehensive genetic profiling results and analysis of therapeutic exposures in an unrandomized trial, as well as a study population limited to patients with advanced stage disease, the researchers noted.

However, the results support data from similar studies and further show that clinicogenomic databases can be used in research to augment drug development and improve the design of clinical trials, they wrote.

The study was supported by Flatiron Health and Foundation Medicine, which are both owned by the Roche Group. Dr. Singal and several coauthors are employees of Foundation Medicine.

SOURCE: Singal G et al. JAMA. 2019;321:1391-9.

A continuously updating database of clinical and genomic details on patients with non–small cell lung cancer accurately represented correlations between genomics and outcomes, based on an analysis of more than 4,000 patients.

“Most efforts to identify clinicogenomic associations currently rely on clinical trials, single-institution series, or national registries,” wrote Gaurav Singal, MD, of Foundation Medicine in Cambridge, Mass., and colleagues in JAMA.

To explore the feasibility of a clinicogenomic database, the researchers combined clinical data from electronic health records with comprehensive genetic profiling data from 28,889 patients; 4,064 adults with non–small cell lung cancer were included in the analysis of associations among tumor genomics, patient characteristics, and clinical outcomes. The data were collected between Jan. 1, 2011, and Jan. 1, 2018, from 275 U.S. oncology practices.

The researchers examined implications of clinical and genomic features for 3,522 patients with advanced disease. Among these, the median overall survival was 10.3 months and the 5-year survival rate was 3.8%. Factors influencing a longer overall survival included never smoking and having nonsquamous pathology; the presence of mutations in genes TP53 and RB1 were associated with shorter survival.

For each patient, researchers calculated the tumor mutational burden (TMB), defined as “a measure of the number of somatic mutations identified per megabase of DNA sequenced.” TMB was significantly higher among smokers, compared with nonsmokers, and “alterations in EGFR, ALK, ROS1, and RET were associated with significantly lower TMB than wild-type cases,” the researchers wrote.

Overall, the results “replicated previously described associations between clinical and genomic characteristics, driver mutations and response to targeted therapy, and TMB and response to immunotherapy,” the researchers wrote.

The findings were limited by several factors, notably the quality and completeness of mortality data, as well as potential biases from the inclusion of comprehensive genetic profiling results and analysis of therapeutic exposures in an unrandomized trial, as well as a study population limited to patients with advanced stage disease, the researchers noted.

However, the results support data from similar studies and further show that clinicogenomic databases can be used in research to augment drug development and improve the design of clinical trials, they wrote.

The study was supported by Flatiron Health and Foundation Medicine, which are both owned by the Roche Group. Dr. Singal and several coauthors are employees of Foundation Medicine.

SOURCE: Singal G et al. JAMA. 2019;321:1391-9.

A continuously updating database of clinical and genomic details on patients with non–small cell lung cancer accurately represented correlations between genomics and outcomes, based on an analysis of more than 4,000 patients.

“Most efforts to identify clinicogenomic associations currently rely on clinical trials, single-institution series, or national registries,” wrote Gaurav Singal, MD, of Foundation Medicine in Cambridge, Mass., and colleagues in JAMA.

To explore the feasibility of a clinicogenomic database, the researchers combined clinical data from electronic health records with comprehensive genetic profiling data from 28,889 patients; 4,064 adults with non–small cell lung cancer were included in the analysis of associations among tumor genomics, patient characteristics, and clinical outcomes. The data were collected between Jan. 1, 2011, and Jan. 1, 2018, from 275 U.S. oncology practices.

The researchers examined implications of clinical and genomic features for 3,522 patients with advanced disease. Among these, the median overall survival was 10.3 months and the 5-year survival rate was 3.8%. Factors influencing a longer overall survival included never smoking and having nonsquamous pathology; the presence of mutations in genes TP53 and RB1 were associated with shorter survival.

For each patient, researchers calculated the tumor mutational burden (TMB), defined as “a measure of the number of somatic mutations identified per megabase of DNA sequenced.” TMB was significantly higher among smokers, compared with nonsmokers, and “alterations in EGFR, ALK, ROS1, and RET were associated with significantly lower TMB than wild-type cases,” the researchers wrote.

Overall, the results “replicated previously described associations between clinical and genomic characteristics, driver mutations and response to targeted therapy, and TMB and response to immunotherapy,” the researchers wrote.

The findings were limited by several factors, notably the quality and completeness of mortality data, as well as potential biases from the inclusion of comprehensive genetic profiling results and analysis of therapeutic exposures in an unrandomized trial, as well as a study population limited to patients with advanced stage disease, the researchers noted.

However, the results support data from similar studies and further show that clinicogenomic databases can be used in research to augment drug development and improve the design of clinical trials, they wrote.

The study was supported by Flatiron Health and Foundation Medicine, which are both owned by the Roche Group. Dr. Singal and several coauthors are employees of Foundation Medicine.

SOURCE: Singal G et al. JAMA. 2019;321:1391-9.

An international group of scientists have announced they have an image of a black hole. This feat of scientific achievement and teamwork is another giant step in humankind’s understanding of the universe. It isn’t easy to find something that isn’t there. Black holes exist and this one is about 6.5 billion times more massive than Earth’s sun. That is a lot of “there.”

In medical research, most articles are about discovering something new. Lately, it is also common to publish studies that claim that something doesn’t exist. No difference is found between treatment A and treatment B. Two decades ago those negative studies rarely were published, but there was merit in the idea that more of them should be published. However, that merit presupposed that the negative studies worthy of publication would be well designed, robust, and, most importantly, contain a power calculation showing that the methodology would have detected the phenomenon if the phenomenon were large enough to be clinically important. Alas, the literature has been flooded with negative studies finding no effect because the studies were hopelessly underpowered and never had a realistic chance of detecting anything. This fake news pollutes our medical knowledge.

To clarify, let me provide a simple example. With my myopia, at 100 yards and without my glasses, I can’t detect the difference between Lebron James and Megan Rapinoe, although I know Megan is better at corner kicks.

Now let me give a second, more complex example that obfuscates the same detection issue. Are there moons circling Jupiter? I go out each night, find Jupiter, take a picture with my trusty cell phone, and examine the picture for any evidence of an object(s) circling the planet. I do this many times. How many? Well, if I only do it three times, people will doubt my science, but doing it 1,000 times would take too long. In my experience, most negative studies seem to involve about 30-50 patients. So one picture a week for a year will produce 52 observations. That is a lot of cold nights under the stars. I will use my scientific knowledge and ability to read sky charts to locate Jupiter. (There is an app for that.) I will use my experience to distinguish Jupiter from Venus and Mars. There will be cloudy days, so maybe only 30 clear pictures will be obtained. I will have a second observer examine the photos. We will calculate a kappa statistic for inter-rater agreement. There will be pictures and tables of numbers. When I’m done, I will publish an article saying that Jupiter doesn’t have moons because I didn’t find any. Trust me, I’m a doctor.

Science doesn’t work that way. Science doesn’t care how smart I am, how dedicated I am, how expensive my cell phone is, or how much work I put into the project, science wants empiric proof. My failure to find moons does not refute their existence. A claim that something does NOT exist cannot be correctly made by simply showing that the P value is greater than .05. A statistically insignificant P value also might also mean that my experiment, despite all my time, effort, commitment, and data collection, is simply inadequate to detect the phenomenon. My cell phone has enough pixels to see Jupiter but not its moons. The phone isn’t powerful enough. My claim is a type II error.

Proving zero difference with statistics is impossible. One needs to specify the threshold size of a clinically important effect and then show that your methods and results were powerful enough to have detected something that small. Only then may you correctly publish a conclusion that there is nothing there, a donut hole in the black void of space.

I invite you to do your own survey. As you read journal articles, identify the next 10 times you read a conclusion that claims no effect was found. Scour that article carefully for any indication of the size of effect that those methods and results would have been able to detect. Look for a power calculation. Grade the article with a simple pass/fail on that point. Did the authors provide that information in a way you can understand, or do you just have to trust them? Take President Reagan’s advice, “Trust, but verify.” Most of the 10 articles will lack the calculation and many negative claims are type II errors.

Dr. Powell is a pediatric hospitalist and clinical ethics consultant living in St. Louis. Email him at pdnews@mdedge.com.

An international group of scientists have announced they have an image of a black hole. This feat of scientific achievement and teamwork is another giant step in humankind’s understanding of the universe. It isn’t easy to find something that isn’t there. Black holes exist and this one is about 6.5 billion times more massive than Earth’s sun. That is a lot of “there.”

In medical research, most articles are about discovering something new. Lately, it is also common to publish studies that claim that something doesn’t exist. No difference is found between treatment A and treatment B. Two decades ago those negative studies rarely were published, but there was merit in the idea that more of them should be published. However, that merit presupposed that the negative studies worthy of publication would be well designed, robust, and, most importantly, contain a power calculation showing that the methodology would have detected the phenomenon if the phenomenon were large enough to be clinically important. Alas, the literature has been flooded with negative studies finding no effect because the studies were hopelessly underpowered and never had a realistic chance of detecting anything. This fake news pollutes our medical knowledge.

To clarify, let me provide a simple example. With my myopia, at 100 yards and without my glasses, I can’t detect the difference between Lebron James and Megan Rapinoe, although I know Megan is better at corner kicks.

Now let me give a second, more complex example that obfuscates the same detection issue. Are there moons circling Jupiter? I go out each night, find Jupiter, take a picture with my trusty cell phone, and examine the picture for any evidence of an object(s) circling the planet. I do this many times. How many? Well, if I only do it three times, people will doubt my science, but doing it 1,000 times would take too long. In my experience, most negative studies seem to involve about 30-50 patients. So one picture a week for a year will produce 52 observations. That is a lot of cold nights under the stars. I will use my scientific knowledge and ability to read sky charts to locate Jupiter. (There is an app for that.) I will use my experience to distinguish Jupiter from Venus and Mars. There will be cloudy days, so maybe only 30 clear pictures will be obtained. I will have a second observer examine the photos. We will calculate a kappa statistic for inter-rater agreement. There will be pictures and tables of numbers. When I’m done, I will publish an article saying that Jupiter doesn’t have moons because I didn’t find any. Trust me, I’m a doctor.

Science doesn’t work that way. Science doesn’t care how smart I am, how dedicated I am, how expensive my cell phone is, or how much work I put into the project, science wants empiric proof. My failure to find moons does not refute their existence. A claim that something does NOT exist cannot be correctly made by simply showing that the P value is greater than .05. A statistically insignificant P value also might also mean that my experiment, despite all my time, effort, commitment, and data collection, is simply inadequate to detect the phenomenon. My cell phone has enough pixels to see Jupiter but not its moons. The phone isn’t powerful enough. My claim is a type II error.

Proving zero difference with statistics is impossible. One needs to specify the threshold size of a clinically important effect and then show that your methods and results were powerful enough to have detected something that small. Only then may you correctly publish a conclusion that there is nothing there, a donut hole in the black void of space.

I invite you to do your own survey. As you read journal articles, identify the next 10 times you read a conclusion that claims no effect was found. Scour that article carefully for any indication of the size of effect that those methods and results would have been able to detect. Look for a power calculation. Grade the article with a simple pass/fail on that point. Did the authors provide that information in a way you can understand, or do you just have to trust them? Take President Reagan’s advice, “Trust, but verify.” Most of the 10 articles will lack the calculation and many negative claims are type II errors.

Dr. Powell is a pediatric hospitalist and clinical ethics consultant living in St. Louis. Email him at pdnews@mdedge.com.

An international group of scientists have announced they have an image of a black hole. This feat of scientific achievement and teamwork is another giant step in humankind’s understanding of the universe. It isn’t easy to find something that isn’t there. Black holes exist and this one is about 6.5 billion times more massive than Earth’s sun. That is a lot of “there.”

In medical research, most articles are about discovering something new. Lately, it is also common to publish studies that claim that something doesn’t exist. No difference is found between treatment A and treatment B. Two decades ago those negative studies rarely were published, but there was merit in the idea that more of them should be published. However, that merit presupposed that the negative studies worthy of publication would be well designed, robust, and, most importantly, contain a power calculation showing that the methodology would have detected the phenomenon if the phenomenon were large enough to be clinically important. Alas, the literature has been flooded with negative studies finding no effect because the studies were hopelessly underpowered and never had a realistic chance of detecting anything. This fake news pollutes our medical knowledge.

To clarify, let me provide a simple example. With my myopia, at 100 yards and without my glasses, I can’t detect the difference between Lebron James and Megan Rapinoe, although I know Megan is better at corner kicks.

Now let me give a second, more complex example that obfuscates the same detection issue. Are there moons circling Jupiter? I go out each night, find Jupiter, take a picture with my trusty cell phone, and examine the picture for any evidence of an object(s) circling the planet. I do this many times. How many? Well, if I only do it three times, people will doubt my science, but doing it 1,000 times would take too long. In my experience, most negative studies seem to involve about 30-50 patients. So one picture a week for a year will produce 52 observations. That is a lot of cold nights under the stars. I will use my scientific knowledge and ability to read sky charts to locate Jupiter. (There is an app for that.) I will use my experience to distinguish Jupiter from Venus and Mars. There will be cloudy days, so maybe only 30 clear pictures will be obtained. I will have a second observer examine the photos. We will calculate a kappa statistic for inter-rater agreement. There will be pictures and tables of numbers. When I’m done, I will publish an article saying that Jupiter doesn’t have moons because I didn’t find any. Trust me, I’m a doctor.

Science doesn’t work that way. Science doesn’t care how smart I am, how dedicated I am, how expensive my cell phone is, or how much work I put into the project, science wants empiric proof. My failure to find moons does not refute their existence. A claim that something does NOT exist cannot be correctly made by simply showing that the P value is greater than .05. A statistically insignificant P value also might also mean that my experiment, despite all my time, effort, commitment, and data collection, is simply inadequate to detect the phenomenon. My cell phone has enough pixels to see Jupiter but not its moons. The phone isn’t powerful enough. My claim is a type II error.

Proving zero difference with statistics is impossible. One needs to specify the threshold size of a clinically important effect and then show that your methods and results were powerful enough to have detected something that small. Only then may you correctly publish a conclusion that there is nothing there, a donut hole in the black void of space.

I invite you to do your own survey. As you read journal articles, identify the next 10 times you read a conclusion that claims no effect was found. Scour that article carefully for any indication of the size of effect that those methods and results would have been able to detect. Look for a power calculation. Grade the article with a simple pass/fail on that point. Did the authors provide that information in a way you can understand, or do you just have to trust them? Take President Reagan’s advice, “Trust, but verify.” Most of the 10 articles will lack the calculation and many negative claims are type II errors.

Dr. Powell is a pediatric hospitalist and clinical ethics consultant living in St. Louis. Email him at pdnews@mdedge.com.

More and better research is needed to guide primary care clinicians in screening asymptomatic young children and asymptomatic pregnant women for lead exposure, according to a recommendation from the U.S. Preventive Services Task Force.

KatarzynaBialasiewicz/Thinkstock

Elevated blood lead levels are associated with potentially irreversible neurologic problems in children and with organ system impairment and adverse perinatal effects in pregnant women, according to the statement.

“Thus, the primary benefit of screening may be in preventing future exposures or exposure of others to environmental sources,” the task force members wrote in JAMA Pediatrics.

However, the task force issued I statements, meaning that “the current evidence is insufficient to assess the balance of benefits and harms of screening for elevated blood lead levels” in asymptomatic children aged 5 years and younger and in asymptomatic pregnant women.

The task force cited evidence that questionnaires and other clinical prediction tools are inaccurate at identifying elevated blood lead levels in asymptomatic children and pregnant women. In addition, the task force found adequate evidence that capillary blood testing identified elevated blood lead levels in children, but found inadequate evidence that treating elevated blood lead levels was effective in asymptomatic children aged 5 years and younger or in pregnant women.

In the evidence report accompanying the recommendation statement in JAMA Pediatrics, Amy G. Cantor, MD, MPH, of Oregon Health & Science University, Portland, and her colleagues reviewed data from a total of 24 studies including 11,433 individuals.

None of the studies evaluated the risks or benefits of blood lead screening in children. However, in three of four studies, capillary blood lead testing showed sensitivities ranging from 87% to 91% and specificities from 92% to 99%, based on a blood lead level cutoff of 10 mcg/dL or less.

“Evidence indicates that capillary sampling is slightly less sensitive than venous sampling, with comparable specificity,” Dr. Cantor and her colleagues wrote. “Both methods require confirmation.”

There is only limited evidence on whether intervening when children present with elevated blood lead levels results in better neurodevelopmental outcomes. One trial showed beneficial effects of dimercaptosuccinic acid chelation of lowering elevated blood lead levels (20-44 mcg/dL) at 1 year versus placebo, but no clear effect on longer term blood lead levels or neurodevelopmental outcomes, they reported.

For residential interventions, again evidence is limited and blood lead concentrations were not clearly affected. Evidence on calcium and iron interventions was poor quality and insufficient to tell if there was an effect on blood lead levels or clinical outcomes, Dr. Cantor and her colleagues wrote.

No studies of screening for elevated lead levels in pregnant women were identified, nor were studies of health outcomes after interventions to reduce blood lead levels in asymptomatic pregnant women, they noted.

Studies involving pregnant women were limited, and included data on the diagnostic accuracy of a clinical questionnaire and the effects of nutritional intervention during pregnancy, Dr. Cantor and her colleagues wrote.

“This update confirms there are no clear effects of interventions for lowering elevated blood levels in affected children or to improve neurodevelopmental outcomes,” they concluded. “Evidence to determine benefits and harms of screening or treating elevated lead levels during pregnancy remains extremely limited.”

The recommendation updates the last version issued in 2006. The USPSTF is supported by the Agency for Healthcare Research and Quality. The researchers for both articles reported no relevant financial disclosures.

SOURCE: Curry SJ et al. JAMA Pediatr. 2019 Apr 16. doi: 10.1001/jama.2019.3326; Cantor AG et al. JAMA Pediatr. 2019 Apr 16. doi: 10.1001/jama.2019.1004.

More and better research is needed to guide primary care clinicians in screening asymptomatic young children and asymptomatic pregnant women for lead exposure, according to a recommendation from the U.S. Preventive Services Task Force.

KatarzynaBialasiewicz/Thinkstock

Elevated blood lead levels are associated with potentially irreversible neurologic problems in children and with organ system impairment and adverse perinatal effects in pregnant women, according to the statement.

“Thus, the primary benefit of screening may be in preventing future exposures or exposure of others to environmental sources,” the task force members wrote in JAMA Pediatrics.

However, the task force issued I statements, meaning that “the current evidence is insufficient to assess the balance of benefits and harms of screening for elevated blood lead levels” in asymptomatic children aged 5 years and younger and in asymptomatic pregnant women.

The task force cited evidence that questionnaires and other clinical prediction tools are inaccurate at identifying elevated blood lead levels in asymptomatic children and pregnant women. In addition, the task force found adequate evidence that capillary blood testing identified elevated blood lead levels in children, but found inadequate evidence that treating elevated blood lead levels was effective in asymptomatic children aged 5 years and younger or in pregnant women.

In the evidence report accompanying the recommendation statement in JAMA Pediatrics, Amy G. Cantor, MD, MPH, of Oregon Health & Science University, Portland, and her colleagues reviewed data from a total of 24 studies including 11,433 individuals.

None of the studies evaluated the risks or benefits of blood lead screening in children. However, in three of four studies, capillary blood lead testing showed sensitivities ranging from 87% to 91% and specificities from 92% to 99%, based on a blood lead level cutoff of 10 mcg/dL or less.

“Evidence indicates that capillary sampling is slightly less sensitive than venous sampling, with comparable specificity,” Dr. Cantor and her colleagues wrote. “Both methods require confirmation.”

There is only limited evidence on whether intervening when children present with elevated blood lead levels results in better neurodevelopmental outcomes. One trial showed beneficial effects of dimercaptosuccinic acid chelation of lowering elevated blood lead levels (20-44 mcg/dL) at 1 year versus placebo, but no clear effect on longer term blood lead levels or neurodevelopmental outcomes, they reported.

For residential interventions, again evidence is limited and blood lead concentrations were not clearly affected. Evidence on calcium and iron interventions was poor quality and insufficient to tell if there was an effect on blood lead levels or clinical outcomes, Dr. Cantor and her colleagues wrote.

No studies of screening for elevated lead levels in pregnant women were identified, nor were studies of health outcomes after interventions to reduce blood lead levels in asymptomatic pregnant women, they noted.

Studies involving pregnant women were limited, and included data on the diagnostic accuracy of a clinical questionnaire and the effects of nutritional intervention during pregnancy, Dr. Cantor and her colleagues wrote.

“This update confirms there are no clear effects of interventions for lowering elevated blood levels in affected children or to improve neurodevelopmental outcomes,” they concluded. “Evidence to determine benefits and harms of screening or treating elevated lead levels during pregnancy remains extremely limited.”

The recommendation updates the last version issued in 2006. The USPSTF is supported by the Agency for Healthcare Research and Quality. The researchers for both articles reported no relevant financial disclosures.

SOURCE: Curry SJ et al. JAMA Pediatr. 2019 Apr 16. doi: 10.1001/jama.2019.3326; Cantor AG et al. JAMA Pediatr. 2019 Apr 16. doi: 10.1001/jama.2019.1004.

More and better research is needed to guide primary care clinicians in screening asymptomatic young children and asymptomatic pregnant women for lead exposure, according to a recommendation from the U.S. Preventive Services Task Force.

KatarzynaBialasiewicz/Thinkstock

Elevated blood lead levels are associated with potentially irreversible neurologic problems in children and with organ system impairment and adverse perinatal effects in pregnant women, according to the statement.

“Thus, the primary benefit of screening may be in preventing future exposures or exposure of others to environmental sources,” the task force members wrote in JAMA Pediatrics.

However, the task force issued I statements, meaning that “the current evidence is insufficient to assess the balance of benefits and harms of screening for elevated blood lead levels” in asymptomatic children aged 5 years and younger and in asymptomatic pregnant women.

The task force cited evidence that questionnaires and other clinical prediction tools are inaccurate at identifying elevated blood lead levels in asymptomatic children and pregnant women. In addition, the task force found adequate evidence that capillary blood testing identified elevated blood lead levels in children, but found inadequate evidence that treating elevated blood lead levels was effective in asymptomatic children aged 5 years and younger or in pregnant women.

In the evidence report accompanying the recommendation statement in JAMA Pediatrics, Amy G. Cantor, MD, MPH, of Oregon Health & Science University, Portland, and her colleagues reviewed data from a total of 24 studies including 11,433 individuals.

None of the studies evaluated the risks or benefits of blood lead screening in children. However, in three of four studies, capillary blood lead testing showed sensitivities ranging from 87% to 91% and specificities from 92% to 99%, based on a blood lead level cutoff of 10 mcg/dL or less.

“Evidence indicates that capillary sampling is slightly less sensitive than venous sampling, with comparable specificity,” Dr. Cantor and her colleagues wrote. “Both methods require confirmation.”

There is only limited evidence on whether intervening when children present with elevated blood lead levels results in better neurodevelopmental outcomes. One trial showed beneficial effects of dimercaptosuccinic acid chelation of lowering elevated blood lead levels (20-44 mcg/dL) at 1 year versus placebo, but no clear effect on longer term blood lead levels or neurodevelopmental outcomes, they reported.

For residential interventions, again evidence is limited and blood lead concentrations were not clearly affected. Evidence on calcium and iron interventions was poor quality and insufficient to tell if there was an effect on blood lead levels or clinical outcomes, Dr. Cantor and her colleagues wrote.

No studies of screening for elevated lead levels in pregnant women were identified, nor were studies of health outcomes after interventions to reduce blood lead levels in asymptomatic pregnant women, they noted.

Studies involving pregnant women were limited, and included data on the diagnostic accuracy of a clinical questionnaire and the effects of nutritional intervention during pregnancy, Dr. Cantor and her colleagues wrote.

“This update confirms there are no clear effects of interventions for lowering elevated blood levels in affected children or to improve neurodevelopmental outcomes,” they concluded. “Evidence to determine benefits and harms of screening or treating elevated lead levels during pregnancy remains extremely limited.”

The recommendation updates the last version issued in 2006. The USPSTF is supported by the Agency for Healthcare Research and Quality. The researchers for both articles reported no relevant financial disclosures.

SOURCE: Curry SJ et al. JAMA Pediatr. 2019 Apr 16. doi: 10.1001/jama.2019.3326; Cantor AG et al. JAMA Pediatr. 2019 Apr 16. doi: 10.1001/jama.2019.1004.

ORLANDO – The landscape for drug development in schizophrenia includes several new promising targets as the field tries to regain its footing after a series of disappointments in recent years, a group of experts said in a session preceding the annual congress of the Schizophrenia International Research Society.

However, the experts also expressed a sense of urgency that trial design and better patient selection have to be improved. Some recent trial failures are likely because of faulty design rather than choosing the wrong target, they said in a satellite session that was funded and organized by Sunovion Pharmaceuticals.

“The question is really critical, because we’ve seen too many major pharma [companies] completely withdraw from this field because of their costly failures,” said Herbert Y. Meltzer, MD, director of the translational neuropharmacology program at Northwestern University, Chicago. “We’ve got to get it right.”

Some of the more prominent, recent trials that were embarked on with hope only to end with unfavorable results include pomaglumetad, a metabotropic glutamate receptor agonist that tried but failed to reduce residual positive and negative schizophrenia symptoms; bitopertin, a glycine transporter 1 inhibitor, for similar symptoms; several phosphodiesterase-10 inhibitors targeting acutely exacerbated schizophrenia symptoms; encenicline, a nicotinic receptor agonist for cognition; and Lu AF35700, a dopamine-and serotonin-receptor agonist, which the manufacturer recently announced failed to reduce positive and negative symptom scores.

Chrisoph U. Correll, MD, professor of psychiatry and molecular medicine at Hofstra University, Hempstead, N.Y., said it’s possible that the phosphodiesterase-10 inhibitors could be looked at again.

“Maybe there is an approach to treat negative symptoms,” he said, adding that some trials might not have chosen patients effectively. “They may have had the wrong patients. They might have had also the wrong prior treatment and not having washed out patients enough.”

Dr. Meltzer said it’s clear to him that the encenicline trial, in particular, involved a problem of design. “There’s no way increasing cholinergic activity through the nicotinic receptor agonist is not going to improve cognition.”

He said embracing genetics is the best way forward, saying that the “shotgun approach” of the past has siphoned money and time away from more important work. “The future of the field is in the genetics – we’re going to have to get the right people into the right trials for the right drug and design them accordingly. If we don’t get into the genetic era very quickly, we’re not going to have a lot of new successful drugs.”

Oliver Howes, MD, PhD, professor of psychiatry at King’s College London, described new areas of interest in the disease pathway, ahead of the dopamine receptor, which has long been a dominant focus of research and treatment efforts.

“How might we target these upstream factors that might regulate dopamine synthesis and release capacity?” is a key research question at the moment, he said.

A drug – called SEP-363856 – that targets the trace amine-associated receptor 1, which has a role in neurotransmission, significantly improved Positive and Negative Syndrome Scale scores in phase 2 trials. Researchers are also making progress in employing parvalbumin interneurons to dampen dopamine synthesis, Dr. Howes said.

Drugmakers halted development of a drug that targeted dopamine firing regulated by the muscarinic receptors M4 and M1 because of gastrointestinal side effects. But there is renewed hope of a more refined approach that targets only M4, rather than M1, which was thought to be responsible for the effects. Some preclinical efforts have been encouraging in this regard, Dr. Howes said.

“This more selective M4 agonist,” he said, “could manipulate the dopamine system in the way that we want.”

Dr. Meltzer, Dr. Correll, and Dr. Howes reported financial relationships with Sunovion, Alkermes, Bristol-Myers Squibb, Lundbeck, Takeda, and other companies.

ORLANDO – The landscape for drug development in schizophrenia includes several new promising targets as the field tries to regain its footing after a series of disappointments in recent years, a group of experts said in a session preceding the annual congress of the Schizophrenia International Research Society.

However, the experts also expressed a sense of urgency that trial design and better patient selection have to be improved. Some recent trial failures are likely because of faulty design rather than choosing the wrong target, they said in a satellite session that was funded and organized by Sunovion Pharmaceuticals.

“The question is really critical, because we’ve seen too many major pharma [companies] completely withdraw from this field because of their costly failures,” said Herbert Y. Meltzer, MD, director of the translational neuropharmacology program at Northwestern University, Chicago. “We’ve got to get it right.”

Some of the more prominent, recent trials that were embarked on with hope only to end with unfavorable results include pomaglumetad, a metabotropic glutamate receptor agonist that tried but failed to reduce residual positive and negative schizophrenia symptoms; bitopertin, a glycine transporter 1 inhibitor, for similar symptoms; several phosphodiesterase-10 inhibitors targeting acutely exacerbated schizophrenia symptoms; encenicline, a nicotinic receptor agonist for cognition; and Lu AF35700, a dopamine-and serotonin-receptor agonist, which the manufacturer recently announced failed to reduce positive and negative symptom scores.

Chrisoph U. Correll, MD, professor of psychiatry and molecular medicine at Hofstra University, Hempstead, N.Y., said it’s possible that the phosphodiesterase-10 inhibitors could be looked at again.

“Maybe there is an approach to treat negative symptoms,” he said, adding that some trials might not have chosen patients effectively. “They may have had the wrong patients. They might have had also the wrong prior treatment and not having washed out patients enough.”

Dr. Meltzer said it’s clear to him that the encenicline trial, in particular, involved a problem of design. “There’s no way increasing cholinergic activity through the nicotinic receptor agonist is not going to improve cognition.”

He said embracing genetics is the best way forward, saying that the “shotgun approach” of the past has siphoned money and time away from more important work. “The future of the field is in the genetics – we’re going to have to get the right people into the right trials for the right drug and design them accordingly. If we don’t get into the genetic era very quickly, we’re not going to have a lot of new successful drugs.”

Oliver Howes, MD, PhD, professor of psychiatry at King’s College London, described new areas of interest in the disease pathway, ahead of the dopamine receptor, which has long been a dominant focus of research and treatment efforts.

“How might we target these upstream factors that might regulate dopamine synthesis and release capacity?” is a key research question at the moment, he said.

A drug – called SEP-363856 – that targets the trace amine-associated receptor 1, which has a role in neurotransmission, significantly improved Positive and Negative Syndrome Scale scores in phase 2 trials. Researchers are also making progress in employing parvalbumin interneurons to dampen dopamine synthesis, Dr. Howes said.

Drugmakers halted development of a drug that targeted dopamine firing regulated by the muscarinic receptors M4 and M1 because of gastrointestinal side effects. But there is renewed hope of a more refined approach that targets only M4, rather than M1, which was thought to be responsible for the effects. Some preclinical efforts have been encouraging in this regard, Dr. Howes said.

“This more selective M4 agonist,” he said, “could manipulate the dopamine system in the way that we want.”

Dr. Meltzer, Dr. Correll, and Dr. Howes reported financial relationships with Sunovion, Alkermes, Bristol-Myers Squibb, Lundbeck, Takeda, and other companies.

ORLANDO – The landscape for drug development in schizophrenia includes several new promising targets as the field tries to regain its footing after a series of disappointments in recent years, a group of experts said in a session preceding the annual congress of the Schizophrenia International Research Society.

However, the experts also expressed a sense of urgency that trial design and better patient selection have to be improved. Some recent trial failures are likely because of faulty design rather than choosing the wrong target, they said in a satellite session that was funded and organized by Sunovion Pharmaceuticals.

“The question is really critical, because we’ve seen too many major pharma [companies] completely withdraw from this field because of their costly failures,” said Herbert Y. Meltzer, MD, director of the translational neuropharmacology program at Northwestern University, Chicago. “We’ve got to get it right.”

Some of the more prominent, recent trials that were embarked on with hope only to end with unfavorable results include pomaglumetad, a metabotropic glutamate receptor agonist that tried but failed to reduce residual positive and negative schizophrenia symptoms; bitopertin, a glycine transporter 1 inhibitor, for similar symptoms; several phosphodiesterase-10 inhibitors targeting acutely exacerbated schizophrenia symptoms; encenicline, a nicotinic receptor agonist for cognition; and Lu AF35700, a dopamine-and serotonin-receptor agonist, which the manufacturer recently announced failed to reduce positive and negative symptom scores.

Chrisoph U. Correll, MD, professor of psychiatry and molecular medicine at Hofstra University, Hempstead, N.Y., said it’s possible that the phosphodiesterase-10 inhibitors could be looked at again.

“Maybe there is an approach to treat negative symptoms,” he said, adding that some trials might not have chosen patients effectively. “They may have had the wrong patients. They might have had also the wrong prior treatment and not having washed out patients enough.”

Dr. Meltzer said it’s clear to him that the encenicline trial, in particular, involved a problem of design. “There’s no way increasing cholinergic activity through the nicotinic receptor agonist is not going to improve cognition.”

He said embracing genetics is the best way forward, saying that the “shotgun approach” of the past has siphoned money and time away from more important work. “The future of the field is in the genetics – we’re going to have to get the right people into the right trials for the right drug and design them accordingly. If we don’t get into the genetic era very quickly, we’re not going to have a lot of new successful drugs.”

Oliver Howes, MD, PhD, professor of psychiatry at King’s College London, described new areas of interest in the disease pathway, ahead of the dopamine receptor, which has long been a dominant focus of research and treatment efforts.

“How might we target these upstream factors that might regulate dopamine synthesis and release capacity?” is a key research question at the moment, he said.

A drug – called SEP-363856 – that targets the trace amine-associated receptor 1, which has a role in neurotransmission, significantly improved Positive and Negative Syndrome Scale scores in phase 2 trials. Researchers are also making progress in employing parvalbumin interneurons to dampen dopamine synthesis, Dr. Howes said.

Drugmakers halted development of a drug that targeted dopamine firing regulated by the muscarinic receptors M4 and M1 because of gastrointestinal side effects. But there is renewed hope of a more refined approach that targets only M4, rather than M1, which was thought to be responsible for the effects. Some preclinical efforts have been encouraging in this regard, Dr. Howes said.

“This more selective M4 agonist,” he said, “could manipulate the dopamine system in the way that we want.”

Dr. Meltzer, Dr. Correll, and Dr. Howes reported financial relationships with Sunovion, Alkermes, Bristol-Myers Squibb, Lundbeck, Takeda, and other companies.

Click to Read.

This CME supplement to OBG Management provides readers with an understanding of the following topics: 

• The relationship between chronic pelvic pain and endometriosis
• The limitations of laparocopy in the diagnosis of endometriosis
• The emerging role of imaging in the diagnosis of endometriosis

Click Here to read the full supplement and access a posttest and evaluation for CME credit.

Click to Read.

This CME supplement to OBG Management provides readers with an understanding of the following topics: 

• The relationship between chronic pelvic pain and endometriosis
• The limitations of laparocopy in the diagnosis of endometriosis
• The emerging role of imaging in the diagnosis of endometriosis

Click Here to read the full supplement and access a posttest and evaluation for CME credit.

Click to Read.

This CME supplement to OBG Management provides readers with an understanding of the following topics: 

• The relationship between chronic pelvic pain and endometriosis
• The limitations of laparocopy in the diagnosis of endometriosis
• The emerging role of imaging in the diagnosis of endometriosis

Click Here to read the full supplement and access a posttest and evaluation for CME credit.