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FDA approves venetoclax/obinutuzumab combo for CLL
The Food and Drug Administration has approved the combination of venetoclax (Venclexta) plus obinutuzumab (Gazyva) for patients with previously untreated chronic lymphocytic leukemia (CLL) or small lymphocytic lymphoma.
The approval provides a chemotherapy-free, fixed duration treatment. The FDA based the approval on the results of the phase 3 CLL14 trial, which will be presented at the 2019 annual meeting of the American Society of Clinical Oncology.
Researchers randomized 432 patients to either a 12-month duration of venetoclax with a 6-month duration of obinutuzumab or to a 6-month duration of obinutuzumab plus chlorambucil and another 6-month duration of chlorambucil.
The newly approved combination reduced the risk of disease progression or death (progression-free survival as assessed by an independent review committee) by 67%, compared with obinutuzumab/chlorambucil (hazard ratio, 0.33; P less than .0001).
Venetoclax/obinutuzumab also had a higher rate of minimal residual disease negativity in bone marrow and peripheral blood, compared to the other combination, according to Genentech.
The most common adverse reactions of any grade reported for venetoclax/obinutuzumab were neutropenia, diarrhea, fatigue, nausea, anemia, and upper respiratory tract infection.
The Food and Drug Administration has approved the combination of venetoclax (Venclexta) plus obinutuzumab (Gazyva) for patients with previously untreated chronic lymphocytic leukemia (CLL) or small lymphocytic lymphoma.
The approval provides a chemotherapy-free, fixed duration treatment. The FDA based the approval on the results of the phase 3 CLL14 trial, which will be presented at the 2019 annual meeting of the American Society of Clinical Oncology.
Researchers randomized 432 patients to either a 12-month duration of venetoclax with a 6-month duration of obinutuzumab or to a 6-month duration of obinutuzumab plus chlorambucil and another 6-month duration of chlorambucil.
The newly approved combination reduced the risk of disease progression or death (progression-free survival as assessed by an independent review committee) by 67%, compared with obinutuzumab/chlorambucil (hazard ratio, 0.33; P less than .0001).
Venetoclax/obinutuzumab also had a higher rate of minimal residual disease negativity in bone marrow and peripheral blood, compared to the other combination, according to Genentech.
The most common adverse reactions of any grade reported for venetoclax/obinutuzumab were neutropenia, diarrhea, fatigue, nausea, anemia, and upper respiratory tract infection.
The Food and Drug Administration has approved the combination of venetoclax (Venclexta) plus obinutuzumab (Gazyva) for patients with previously untreated chronic lymphocytic leukemia (CLL) or small lymphocytic lymphoma.
The approval provides a chemotherapy-free, fixed duration treatment. The FDA based the approval on the results of the phase 3 CLL14 trial, which will be presented at the 2019 annual meeting of the American Society of Clinical Oncology.
Researchers randomized 432 patients to either a 12-month duration of venetoclax with a 6-month duration of obinutuzumab or to a 6-month duration of obinutuzumab plus chlorambucil and another 6-month duration of chlorambucil.
The newly approved combination reduced the risk of disease progression or death (progression-free survival as assessed by an independent review committee) by 67%, compared with obinutuzumab/chlorambucil (hazard ratio, 0.33; P less than .0001).
Venetoclax/obinutuzumab also had a higher rate of minimal residual disease negativity in bone marrow and peripheral blood, compared to the other combination, according to Genentech.
The most common adverse reactions of any grade reported for venetoclax/obinutuzumab were neutropenia, diarrhea, fatigue, nausea, anemia, and upper respiratory tract infection.
Survey: Physicians predict increase in measles deaths
by real-time market insights technology firm InCrowd.
Among the 180 physicians with experience treating measles, 23% agreed and 44% said that they strongly agreed with the statement that measles deaths would increase, and another 18% said that they somewhat agreed. Only 9% expressed some level of disagreement, InCrowd said.
Most of those respondents also believe that summer travel will increase measles outbreaks (29% agreed and 30% strongly agreed) and that more communities will adopt requirements for measles vaccinations (26% and 36%). A majority also said that education about vaccinations will improve (26% agreed and 29% strongly agreed), but almost half of the physicians surveyed also expect vaccination misinformation to get worse (29% and 19%), InCrowd reported.
“With 44% of respondents predicting a high likelihood that deaths caused by measles will increase, the data show the imperative for physicians and patients to keep up the dialogue. … We have a long way to go before declaring victory,” said Diane Hayes, PhD, president and cofounder of InCrowd.
The InCrowd 5-minute microsurvey was conducted on April 18-19, 2019, and included 455 primary care physicians, of whom 40% said that they have treated or knew of colleagues in their facility or community who have treated patients with measles. Of those 180 respondents, 89 were pediatricians and 91 were in other primary care specialties.
by real-time market insights technology firm InCrowd.
Among the 180 physicians with experience treating measles, 23% agreed and 44% said that they strongly agreed with the statement that measles deaths would increase, and another 18% said that they somewhat agreed. Only 9% expressed some level of disagreement, InCrowd said.
Most of those respondents also believe that summer travel will increase measles outbreaks (29% agreed and 30% strongly agreed) and that more communities will adopt requirements for measles vaccinations (26% and 36%). A majority also said that education about vaccinations will improve (26% agreed and 29% strongly agreed), but almost half of the physicians surveyed also expect vaccination misinformation to get worse (29% and 19%), InCrowd reported.
“With 44% of respondents predicting a high likelihood that deaths caused by measles will increase, the data show the imperative for physicians and patients to keep up the dialogue. … We have a long way to go before declaring victory,” said Diane Hayes, PhD, president and cofounder of InCrowd.
The InCrowd 5-minute microsurvey was conducted on April 18-19, 2019, and included 455 primary care physicians, of whom 40% said that they have treated or knew of colleagues in their facility or community who have treated patients with measles. Of those 180 respondents, 89 were pediatricians and 91 were in other primary care specialties.
by real-time market insights technology firm InCrowd.
Among the 180 physicians with experience treating measles, 23% agreed and 44% said that they strongly agreed with the statement that measles deaths would increase, and another 18% said that they somewhat agreed. Only 9% expressed some level of disagreement, InCrowd said.
Most of those respondents also believe that summer travel will increase measles outbreaks (29% agreed and 30% strongly agreed) and that more communities will adopt requirements for measles vaccinations (26% and 36%). A majority also said that education about vaccinations will improve (26% agreed and 29% strongly agreed), but almost half of the physicians surveyed also expect vaccination misinformation to get worse (29% and 19%), InCrowd reported.
“With 44% of respondents predicting a high likelihood that deaths caused by measles will increase, the data show the imperative for physicians and patients to keep up the dialogue. … We have a long way to go before declaring victory,” said Diane Hayes, PhD, president and cofounder of InCrowd.
The InCrowd 5-minute microsurvey was conducted on April 18-19, 2019, and included 455 primary care physicians, of whom 40% said that they have treated or knew of colleagues in their facility or community who have treated patients with measles. Of those 180 respondents, 89 were pediatricians and 91 were in other primary care specialties.
New risk score predicts cardiac-device infection
SAN FRANCISCO – Researchers have devised a five-item scoring formula to quantify the risk for infection in patients undergoing placement, revision, or removal of a cardiac-rhythm device based on data from nearly 20,000 patients enrolled in a recent infection-prophylaxis trial.
The risk score can help identify patients who might benefit from intensified antibiotic prophylaxis, and it can also help during shared decision making with patients to better understand the risk a patient faces from infection, compared with their predicted device benefit, David H. Birnie, MD, said at the annual scientific sessions of the Heart Rhythm Society.
The new risk score produced a concordance statistic, the area under the receiver-operator characteristic curve, of 0.704. It showed that, although it could use further validation, the score as it currently stands has substantial predictive value, said Dr. Birnie, professor of medicine at the University of Ottawa and deputy chief of cardiology at the University of Ottawa Heart Institute. “It’s certainly better than anything we have now,” he said in a video interview.
Dr. Birnie and his associates used data they collected on baseline characteristics and infection outcomes of the 19,603 patients enrolled in PADIT (Prevention of Arrhythmia Device Infection Trial) who underwent a rhythm-device procedure at 1 of 28 participating Canadian centers. The primary aim of PADIT was to assess the safety and efficacy of an intensified antibiotic-prophylaxis regimen, compared with a standard regimen of a cefazolin infusion just before the procedure. The study’s primary endpoint was the incidence of hospitalization for device infection during 1-year follow-up, and while the intensified prophylactic regimen linked with a 23% relative reduction in the hospitalization rate, compared with standard treatment, the difference was not statistically significant (J Am Coll Cardiol. 2018 Dec 18;72[24]:3098-109).
The researchers analyzed the baseline patient data and the blindly adjudicated infection outcomes and identified five factors that were independently associated with an increased infection rate. They organized the five factors and produced a formula they call the PADIT score (see chart). Those five factors are: prior procedures (the greater the number the greater the risk), age (which unexpectedly had an inverse relationship with infection incidence), depressed renal function, immuno-compromised status, and type of procedure. A patient can potentially score 0-15 points.
Among the PADIT patients a score of 0 correlated with about a 0.3% rate of hospitalization for a device-related infection during 1 year of follow-up, a score of 5 with about a 1.1% rate, a score of 6 with about a 1.8% rate, and a score of seven or more with a 3.4% infection rate over the following year. About 5% of patients had a score of 7 or more, and roughly another 5% had a score of 5 or 6, Dr. Birnie said. At his center, clinicians have begun routinely calculating scores for patients scheduled for an arrhythmia-device procedure, and they are considering routinely administering added antibiotic prophylaxis to patients with a preprocedural score of 6 or higher. They may also use the score to determine whether to use the antibacterial envelope recently reported to prevent cardiac-device infections (N Engl J Med. 2019 May 16;380[20]:1895-905).
“It’s very easy for patients to get to a PADIT score of 7 or higher,” Dr. Birnie noted. As an example, he cited a common patient, an 85-year-old with renal dysfunction who is under consideration for a second replacement of an implantable cardioverter defibrillator. The patient would score 1 point for renal insufficiency, 2 points for the type of device, and 4 points for having a prior history of two devices, and the consequent 3.4% risk for infection might counterbalance the potential benefit this elderly patient could expect from the new device. The score will be very important for targeting treatment, shared decision making, and selection of patients for future intervention trials, he concluded.
“I think this risk score will change practice by giving clinicians a better idea of a patient’s risk for infection,” commented Fred M. Kusumoto, MD, professor of medicine at the Mayo Medical School, Rochester, Minn., and director of heart rhythm services at the Mayo Clinic in Jacksonville, Fla. The PADIT score will help identify patients for whom leaving a device in place is a better option than taking it out because of their infection risk. The risk score could also help improve the cost effectiveness of preventive treatments, such as antibiotic-eluting envelopes, by targeting treatment to higher-risk patients, Dr. Kusumoto said during a press briefing.
SOURCE: Birnie DH. Heart Rhythm 2019, Absract S-LCT02-01.
I like this new infection risk score. It addresses a very clinically relevant issue. It’s important for the electrophysiology community to better understand how to best manage infections related to cardiac rhythm devices and ideally prevent them from happening.
I’m not a big fan of risk scores in general because they can sometimes detract from independent thinking about how to manage a patient. However, it is also helpful to have this type of risk-assessment information when discussing management options with a patient.
The PADIT risk score may also help identify which patients could potentially benefit the most from an antibiotic-eluting envelope when receiving an implanted cardiac-rhythm device. Recently reported results from WRAP-IT showed that routinely using envelopes cut the incidence of major infections by a relative 40%, but in absolute terms, the number needed to treat with the envelop to prevent one major infection was about 200 patients, a big number given the high cost of the envelope (N Engl J Med. 2019 May 16;380[20]:1895-905). It is therefore very interesting to think about using the PADIT risk score to better target an effective but expensive preventive measure like an antibiotic-eluting envelop to patients at the highest risk for infection.
Ulrika Birgersdotter-Green, MD , professor of medicine and director of pacemaker and ICD services at the University of California, San Diego, made these comments as a designated discussant for the report. She has been a consultant to and received honoraria from Abbott, Boston Scientific, and Medtronic.
I like this new infection risk score. It addresses a very clinically relevant issue. It’s important for the electrophysiology community to better understand how to best manage infections related to cardiac rhythm devices and ideally prevent them from happening.
I’m not a big fan of risk scores in general because they can sometimes detract from independent thinking about how to manage a patient. However, it is also helpful to have this type of risk-assessment information when discussing management options with a patient.
The PADIT risk score may also help identify which patients could potentially benefit the most from an antibiotic-eluting envelope when receiving an implanted cardiac-rhythm device. Recently reported results from WRAP-IT showed that routinely using envelopes cut the incidence of major infections by a relative 40%, but in absolute terms, the number needed to treat with the envelop to prevent one major infection was about 200 patients, a big number given the high cost of the envelope (N Engl J Med. 2019 May 16;380[20]:1895-905). It is therefore very interesting to think about using the PADIT risk score to better target an effective but expensive preventive measure like an antibiotic-eluting envelop to patients at the highest risk for infection.
Ulrika Birgersdotter-Green, MD , professor of medicine and director of pacemaker and ICD services at the University of California, San Diego, made these comments as a designated discussant for the report. She has been a consultant to and received honoraria from Abbott, Boston Scientific, and Medtronic.
I like this new infection risk score. It addresses a very clinically relevant issue. It’s important for the electrophysiology community to better understand how to best manage infections related to cardiac rhythm devices and ideally prevent them from happening.
I’m not a big fan of risk scores in general because they can sometimes detract from independent thinking about how to manage a patient. However, it is also helpful to have this type of risk-assessment information when discussing management options with a patient.
The PADIT risk score may also help identify which patients could potentially benefit the most from an antibiotic-eluting envelope when receiving an implanted cardiac-rhythm device. Recently reported results from WRAP-IT showed that routinely using envelopes cut the incidence of major infections by a relative 40%, but in absolute terms, the number needed to treat with the envelop to prevent one major infection was about 200 patients, a big number given the high cost of the envelope (N Engl J Med. 2019 May 16;380[20]:1895-905). It is therefore very interesting to think about using the PADIT risk score to better target an effective but expensive preventive measure like an antibiotic-eluting envelop to patients at the highest risk for infection.
Ulrika Birgersdotter-Green, MD , professor of medicine and director of pacemaker and ICD services at the University of California, San Diego, made these comments as a designated discussant for the report. She has been a consultant to and received honoraria from Abbott, Boston Scientific, and Medtronic.
SAN FRANCISCO – Researchers have devised a five-item scoring formula to quantify the risk for infection in patients undergoing placement, revision, or removal of a cardiac-rhythm device based on data from nearly 20,000 patients enrolled in a recent infection-prophylaxis trial.
The risk score can help identify patients who might benefit from intensified antibiotic prophylaxis, and it can also help during shared decision making with patients to better understand the risk a patient faces from infection, compared with their predicted device benefit, David H. Birnie, MD, said at the annual scientific sessions of the Heart Rhythm Society.
The new risk score produced a concordance statistic, the area under the receiver-operator characteristic curve, of 0.704. It showed that, although it could use further validation, the score as it currently stands has substantial predictive value, said Dr. Birnie, professor of medicine at the University of Ottawa and deputy chief of cardiology at the University of Ottawa Heart Institute. “It’s certainly better than anything we have now,” he said in a video interview.
Dr. Birnie and his associates used data they collected on baseline characteristics and infection outcomes of the 19,603 patients enrolled in PADIT (Prevention of Arrhythmia Device Infection Trial) who underwent a rhythm-device procedure at 1 of 28 participating Canadian centers. The primary aim of PADIT was to assess the safety and efficacy of an intensified antibiotic-prophylaxis regimen, compared with a standard regimen of a cefazolin infusion just before the procedure. The study’s primary endpoint was the incidence of hospitalization for device infection during 1-year follow-up, and while the intensified prophylactic regimen linked with a 23% relative reduction in the hospitalization rate, compared with standard treatment, the difference was not statistically significant (J Am Coll Cardiol. 2018 Dec 18;72[24]:3098-109).
The researchers analyzed the baseline patient data and the blindly adjudicated infection outcomes and identified five factors that were independently associated with an increased infection rate. They organized the five factors and produced a formula they call the PADIT score (see chart). Those five factors are: prior procedures (the greater the number the greater the risk), age (which unexpectedly had an inverse relationship with infection incidence), depressed renal function, immuno-compromised status, and type of procedure. A patient can potentially score 0-15 points.
Among the PADIT patients a score of 0 correlated with about a 0.3% rate of hospitalization for a device-related infection during 1 year of follow-up, a score of 5 with about a 1.1% rate, a score of 6 with about a 1.8% rate, and a score of seven or more with a 3.4% infection rate over the following year. About 5% of patients had a score of 7 or more, and roughly another 5% had a score of 5 or 6, Dr. Birnie said. At his center, clinicians have begun routinely calculating scores for patients scheduled for an arrhythmia-device procedure, and they are considering routinely administering added antibiotic prophylaxis to patients with a preprocedural score of 6 or higher. They may also use the score to determine whether to use the antibacterial envelope recently reported to prevent cardiac-device infections (N Engl J Med. 2019 May 16;380[20]:1895-905).
“It’s very easy for patients to get to a PADIT score of 7 or higher,” Dr. Birnie noted. As an example, he cited a common patient, an 85-year-old with renal dysfunction who is under consideration for a second replacement of an implantable cardioverter defibrillator. The patient would score 1 point for renal insufficiency, 2 points for the type of device, and 4 points for having a prior history of two devices, and the consequent 3.4% risk for infection might counterbalance the potential benefit this elderly patient could expect from the new device. The score will be very important for targeting treatment, shared decision making, and selection of patients for future intervention trials, he concluded.
“I think this risk score will change practice by giving clinicians a better idea of a patient’s risk for infection,” commented Fred M. Kusumoto, MD, professor of medicine at the Mayo Medical School, Rochester, Minn., and director of heart rhythm services at the Mayo Clinic in Jacksonville, Fla. The PADIT score will help identify patients for whom leaving a device in place is a better option than taking it out because of their infection risk. The risk score could also help improve the cost effectiveness of preventive treatments, such as antibiotic-eluting envelopes, by targeting treatment to higher-risk patients, Dr. Kusumoto said during a press briefing.
SOURCE: Birnie DH. Heart Rhythm 2019, Absract S-LCT02-01.
SAN FRANCISCO – Researchers have devised a five-item scoring formula to quantify the risk for infection in patients undergoing placement, revision, or removal of a cardiac-rhythm device based on data from nearly 20,000 patients enrolled in a recent infection-prophylaxis trial.
The risk score can help identify patients who might benefit from intensified antibiotic prophylaxis, and it can also help during shared decision making with patients to better understand the risk a patient faces from infection, compared with their predicted device benefit, David H. Birnie, MD, said at the annual scientific sessions of the Heart Rhythm Society.
The new risk score produced a concordance statistic, the area under the receiver-operator characteristic curve, of 0.704. It showed that, although it could use further validation, the score as it currently stands has substantial predictive value, said Dr. Birnie, professor of medicine at the University of Ottawa and deputy chief of cardiology at the University of Ottawa Heart Institute. “It’s certainly better than anything we have now,” he said in a video interview.
Dr. Birnie and his associates used data they collected on baseline characteristics and infection outcomes of the 19,603 patients enrolled in PADIT (Prevention of Arrhythmia Device Infection Trial) who underwent a rhythm-device procedure at 1 of 28 participating Canadian centers. The primary aim of PADIT was to assess the safety and efficacy of an intensified antibiotic-prophylaxis regimen, compared with a standard regimen of a cefazolin infusion just before the procedure. The study’s primary endpoint was the incidence of hospitalization for device infection during 1-year follow-up, and while the intensified prophylactic regimen linked with a 23% relative reduction in the hospitalization rate, compared with standard treatment, the difference was not statistically significant (J Am Coll Cardiol. 2018 Dec 18;72[24]:3098-109).
The researchers analyzed the baseline patient data and the blindly adjudicated infection outcomes and identified five factors that were independently associated with an increased infection rate. They organized the five factors and produced a formula they call the PADIT score (see chart). Those five factors are: prior procedures (the greater the number the greater the risk), age (which unexpectedly had an inverse relationship with infection incidence), depressed renal function, immuno-compromised status, and type of procedure. A patient can potentially score 0-15 points.
Among the PADIT patients a score of 0 correlated with about a 0.3% rate of hospitalization for a device-related infection during 1 year of follow-up, a score of 5 with about a 1.1% rate, a score of 6 with about a 1.8% rate, and a score of seven or more with a 3.4% infection rate over the following year. About 5% of patients had a score of 7 or more, and roughly another 5% had a score of 5 or 6, Dr. Birnie said. At his center, clinicians have begun routinely calculating scores for patients scheduled for an arrhythmia-device procedure, and they are considering routinely administering added antibiotic prophylaxis to patients with a preprocedural score of 6 or higher. They may also use the score to determine whether to use the antibacterial envelope recently reported to prevent cardiac-device infections (N Engl J Med. 2019 May 16;380[20]:1895-905).
“It’s very easy for patients to get to a PADIT score of 7 or higher,” Dr. Birnie noted. As an example, he cited a common patient, an 85-year-old with renal dysfunction who is under consideration for a second replacement of an implantable cardioverter defibrillator. The patient would score 1 point for renal insufficiency, 2 points for the type of device, and 4 points for having a prior history of two devices, and the consequent 3.4% risk for infection might counterbalance the potential benefit this elderly patient could expect from the new device. The score will be very important for targeting treatment, shared decision making, and selection of patients for future intervention trials, he concluded.
“I think this risk score will change practice by giving clinicians a better idea of a patient’s risk for infection,” commented Fred M. Kusumoto, MD, professor of medicine at the Mayo Medical School, Rochester, Minn., and director of heart rhythm services at the Mayo Clinic in Jacksonville, Fla. The PADIT score will help identify patients for whom leaving a device in place is a better option than taking it out because of their infection risk. The risk score could also help improve the cost effectiveness of preventive treatments, such as antibiotic-eluting envelopes, by targeting treatment to higher-risk patients, Dr. Kusumoto said during a press briefing.
SOURCE: Birnie DH. Heart Rhythm 2019, Absract S-LCT02-01.
REPORTING FROM HEART RHYTHM 2019
Key clinical point: Researchers have devised a five-item scoring formula to predict a patient’s risk for infection from an cardiac rhythm–device procedure.
Major finding: The risk score had an optimism-corrected concordance statistic of 0.704.
Study details: Investigators developed the risk score using data from PADIT, a multicenter, randomized trial with 19,603 patients.
Disclosures: PADIT received no commercial funding. Dr. Birnie had no relevant disclosures.
Source: Birnie DH. Heart Rhythm 2019, Absract S-LCT02-01.
Texting a stroke, game-show grants, and, um, The Beast
Autocorrect, or worse?
Is it just fat thumbs, or something more serious? Incoherent text messages could be the first sign of a stroke for adults, as displayed in two case reports presented at the annual meeting of the American Academy of Neurology.
It makes sense that stroke can cause dystextia: Typing on a phone involves some fine motor, language, and vision skills. Stroke can affect all these functions, leading to bizarre typos or angry political rants on Facebook.
Just kidding; those are equally as concerning but require a whole different diagnosis.
‘Research Funds’ for $11,000, Alex
In the universal struggle for research funding, many a scientist has resorted to desperate measures to keep the lab assistants paid, the JAX Mice fed, and the frontiers of medical science expanding ever outward.
Marina Simian is a biologist for Argentina’s National Scientific and Technical Research Council. She runs a research lab focused on oncology treatments for breast cancer. Faced with a national economic crisis and cuts to research funding, Simian says government funding has nearly dried up. Where did she turn instead?
Enter the local version of the TV game show “Who Wants to be a Millionaire?” Simian went on the show as a contestant, explaining that she needed money to support her cancer research. And when the camera cut away to commercials, Simian walked away with 500,000 pesos ($11,000) in winnings. Which she used to buy more lab supplies.
Admittedly, the “Slumdog Millionaire” approach may not save every cash-strapped scientist’s pet project, but it does give us an idea for game show super champ James Holzhauer’s career when he finally wears out his “Jeopardy!” buzzer: medical research funding consultant.
FDA tames THE BEAST
The LOTME staff had a meeting the other day with our editor (we think he might be the love child of Lois Lane and Ron Burgundy), who said that lately we’ve been “too juvenile” and “not medical enough” and told us to get our “dirty little minds out of the gutter.”
After we stopped crying, he offered up this item from the Food and Drug Administration:
“STIFF BOY LLC. Issues Voluntary Nationwide Recall of THE BEAST Capsules Due to Presence of Undeclared Sildenafil” (no, we did not add the all-caps).
Okay, here goes.
THE BEAST was marketed as a dietary supplement for “male enhancement” (add nonjuvenile but hilarious remark about tumescence), which would not be regulated by the FDA. The presence of Viagra’s active ingredient in the capsules, however, “renders it an unapproved drug for which safety and efficacy have not been established and, therefore, subject to recall,” the FDA said (insert comment about seemingly serious but totally fictitious side effects).
Although the sildenafil in THE BEAST may interact with nitrates found in some prescription drugs, STIFF BOY said that it had not received any reports of adverse events before the recall (imagine a guy working on the engine of his pickup truck).
Seek immediate medical attention if your laughter lasts for more than 4 hours after reading this.
Time flies when you’re having ‘fun’
Match Day is one of the most exciting times in any young, prospective doctor’s life. Finally, the specialty of your dreams is yours. You know the training will be stressful and the hours will be long, but how bad could it be?
It’s not like it’ll take years off your life, right?
Well, according to new research published in Biological Psychiatry, that’s almost exactly what medical residency will do to you.
The researchers took a group of medical students at the University of Michigan, Ann Arbor, entering their first year of residency and measured their telomere length both before and after their internship year, comparing it with a group of first-year undergraduates. Rapidly shrinking telomere length is a well-accepted sign of aging, and interns had their telomeres shrink at a rate six times faster than their nonmedical peers, who were apparently too busy doing upside-down kegstands to notice how stressful college can be.
Oh, don’t worry, there was most definitely an association between hours worked and increased telomere shrinkage. Those who had to work more than 80 hours a week aged most of all.
So, if you emerge from a particularly difficult internship with the sudden desire to yell at those darn kids for being on your lawn, we completely understand.
Autocorrect, or worse?
Is it just fat thumbs, or something more serious? Incoherent text messages could be the first sign of a stroke for adults, as displayed in two case reports presented at the annual meeting of the American Academy of Neurology.
It makes sense that stroke can cause dystextia: Typing on a phone involves some fine motor, language, and vision skills. Stroke can affect all these functions, leading to bizarre typos or angry political rants on Facebook.
Just kidding; those are equally as concerning but require a whole different diagnosis.
‘Research Funds’ for $11,000, Alex
In the universal struggle for research funding, many a scientist has resorted to desperate measures to keep the lab assistants paid, the JAX Mice fed, and the frontiers of medical science expanding ever outward.
Marina Simian is a biologist for Argentina’s National Scientific and Technical Research Council. She runs a research lab focused on oncology treatments for breast cancer. Faced with a national economic crisis and cuts to research funding, Simian says government funding has nearly dried up. Where did she turn instead?
Enter the local version of the TV game show “Who Wants to be a Millionaire?” Simian went on the show as a contestant, explaining that she needed money to support her cancer research. And when the camera cut away to commercials, Simian walked away with 500,000 pesos ($11,000) in winnings. Which she used to buy more lab supplies.
Admittedly, the “Slumdog Millionaire” approach may not save every cash-strapped scientist’s pet project, but it does give us an idea for game show super champ James Holzhauer’s career when he finally wears out his “Jeopardy!” buzzer: medical research funding consultant.
FDA tames THE BEAST
The LOTME staff had a meeting the other day with our editor (we think he might be the love child of Lois Lane and Ron Burgundy), who said that lately we’ve been “too juvenile” and “not medical enough” and told us to get our “dirty little minds out of the gutter.”
After we stopped crying, he offered up this item from the Food and Drug Administration:
“STIFF BOY LLC. Issues Voluntary Nationwide Recall of THE BEAST Capsules Due to Presence of Undeclared Sildenafil” (no, we did not add the all-caps).
Okay, here goes.
THE BEAST was marketed as a dietary supplement for “male enhancement” (add nonjuvenile but hilarious remark about tumescence), which would not be regulated by the FDA. The presence of Viagra’s active ingredient in the capsules, however, “renders it an unapproved drug for which safety and efficacy have not been established and, therefore, subject to recall,” the FDA said (insert comment about seemingly serious but totally fictitious side effects).
Although the sildenafil in THE BEAST may interact with nitrates found in some prescription drugs, STIFF BOY said that it had not received any reports of adverse events before the recall (imagine a guy working on the engine of his pickup truck).
Seek immediate medical attention if your laughter lasts for more than 4 hours after reading this.
Time flies when you’re having ‘fun’
Match Day is one of the most exciting times in any young, prospective doctor’s life. Finally, the specialty of your dreams is yours. You know the training will be stressful and the hours will be long, but how bad could it be?
It’s not like it’ll take years off your life, right?
Well, according to new research published in Biological Psychiatry, that’s almost exactly what medical residency will do to you.
The researchers took a group of medical students at the University of Michigan, Ann Arbor, entering their first year of residency and measured their telomere length both before and after their internship year, comparing it with a group of first-year undergraduates. Rapidly shrinking telomere length is a well-accepted sign of aging, and interns had their telomeres shrink at a rate six times faster than their nonmedical peers, who were apparently too busy doing upside-down kegstands to notice how stressful college can be.
Oh, don’t worry, there was most definitely an association between hours worked and increased telomere shrinkage. Those who had to work more than 80 hours a week aged most of all.
So, if you emerge from a particularly difficult internship with the sudden desire to yell at those darn kids for being on your lawn, we completely understand.
Autocorrect, or worse?
Is it just fat thumbs, or something more serious? Incoherent text messages could be the first sign of a stroke for adults, as displayed in two case reports presented at the annual meeting of the American Academy of Neurology.
It makes sense that stroke can cause dystextia: Typing on a phone involves some fine motor, language, and vision skills. Stroke can affect all these functions, leading to bizarre typos or angry political rants on Facebook.
Just kidding; those are equally as concerning but require a whole different diagnosis.
‘Research Funds’ for $11,000, Alex
In the universal struggle for research funding, many a scientist has resorted to desperate measures to keep the lab assistants paid, the JAX Mice fed, and the frontiers of medical science expanding ever outward.
Marina Simian is a biologist for Argentina’s National Scientific and Technical Research Council. She runs a research lab focused on oncology treatments for breast cancer. Faced with a national economic crisis and cuts to research funding, Simian says government funding has nearly dried up. Where did she turn instead?
Enter the local version of the TV game show “Who Wants to be a Millionaire?” Simian went on the show as a contestant, explaining that she needed money to support her cancer research. And when the camera cut away to commercials, Simian walked away with 500,000 pesos ($11,000) in winnings. Which she used to buy more lab supplies.
Admittedly, the “Slumdog Millionaire” approach may not save every cash-strapped scientist’s pet project, but it does give us an idea for game show super champ James Holzhauer’s career when he finally wears out his “Jeopardy!” buzzer: medical research funding consultant.
FDA tames THE BEAST
The LOTME staff had a meeting the other day with our editor (we think he might be the love child of Lois Lane and Ron Burgundy), who said that lately we’ve been “too juvenile” and “not medical enough” and told us to get our “dirty little minds out of the gutter.”
After we stopped crying, he offered up this item from the Food and Drug Administration:
“STIFF BOY LLC. Issues Voluntary Nationwide Recall of THE BEAST Capsules Due to Presence of Undeclared Sildenafil” (no, we did not add the all-caps).
Okay, here goes.
THE BEAST was marketed as a dietary supplement for “male enhancement” (add nonjuvenile but hilarious remark about tumescence), which would not be regulated by the FDA. The presence of Viagra’s active ingredient in the capsules, however, “renders it an unapproved drug for which safety and efficacy have not been established and, therefore, subject to recall,” the FDA said (insert comment about seemingly serious but totally fictitious side effects).
Although the sildenafil in THE BEAST may interact with nitrates found in some prescription drugs, STIFF BOY said that it had not received any reports of adverse events before the recall (imagine a guy working on the engine of his pickup truck).
Seek immediate medical attention if your laughter lasts for more than 4 hours after reading this.
Time flies when you’re having ‘fun’
Match Day is one of the most exciting times in any young, prospective doctor’s life. Finally, the specialty of your dreams is yours. You know the training will be stressful and the hours will be long, but how bad could it be?
It’s not like it’ll take years off your life, right?
Well, according to new research published in Biological Psychiatry, that’s almost exactly what medical residency will do to you.
The researchers took a group of medical students at the University of Michigan, Ann Arbor, entering their first year of residency and measured their telomere length both before and after their internship year, comparing it with a group of first-year undergraduates. Rapidly shrinking telomere length is a well-accepted sign of aging, and interns had their telomeres shrink at a rate six times faster than their nonmedical peers, who were apparently too busy doing upside-down kegstands to notice how stressful college can be.
Oh, don’t worry, there was most definitely an association between hours worked and increased telomere shrinkage. Those who had to work more than 80 hours a week aged most of all.
So, if you emerge from a particularly difficult internship with the sudden desire to yell at those darn kids for being on your lawn, we completely understand.
ICYMI: Dabigatran no better than aspirin for recurrent stroke prevention
Dabigatran was slightly but not significantly superior to aspirin at the prevention of recurring stroke in patients with a recent history of embolic stroke of undetermined source over a median follow-up of 19 months (6.6% rate of recurrent stroke for dabigatran vs. 7.7% for aspirin; hazard ratio, 0.85; 95% confidence interval, 0.69-1.03; P = 0.10), according to RE-SPECT ESUS, a multicenter, randomized, double-blind trial published in the New England Journal of Medicine (2019 May 15. doi: 10.1056/NEJMoa1813959).
We first reported on the results of this trial when they were presented at the World Stroke Congress by lead investigator Hans-Christoph Diener, MD. Find our coverage at the link below.
Dabigatran was slightly but not significantly superior to aspirin at the prevention of recurring stroke in patients with a recent history of embolic stroke of undetermined source over a median follow-up of 19 months (6.6% rate of recurrent stroke for dabigatran vs. 7.7% for aspirin; hazard ratio, 0.85; 95% confidence interval, 0.69-1.03; P = 0.10), according to RE-SPECT ESUS, a multicenter, randomized, double-blind trial published in the New England Journal of Medicine (2019 May 15. doi: 10.1056/NEJMoa1813959).
We first reported on the results of this trial when they were presented at the World Stroke Congress by lead investigator Hans-Christoph Diener, MD. Find our coverage at the link below.
Dabigatran was slightly but not significantly superior to aspirin at the prevention of recurring stroke in patients with a recent history of embolic stroke of undetermined source over a median follow-up of 19 months (6.6% rate of recurrent stroke for dabigatran vs. 7.7% for aspirin; hazard ratio, 0.85; 95% confidence interval, 0.69-1.03; P = 0.10), according to RE-SPECT ESUS, a multicenter, randomized, double-blind trial published in the New England Journal of Medicine (2019 May 15. doi: 10.1056/NEJMoa1813959).
We first reported on the results of this trial when they were presented at the World Stroke Congress by lead investigator Hans-Christoph Diener, MD. Find our coverage at the link below.
FROM THE NEW ENGLAND JOURNAL OF MEDICINE
ICYMI: Alpelisib/fulvestrant combo boosts PFS in advanced breast cancer
Patients with PIK3CA-mutated, hormone receptor–positive, HER2-negative advanced breast cancer who had previously undergone endocrine therapy experienced longer progression-free survival when receiving alpelisib and fulvestrant, compared with placebo and fulvestrant (11.0 vs. 5.7 months; hazard ratio, 0.65; 95% confidence interval, 0.50-0.85; P less than .001), according to a randomized, phase 3 trial published in the New England Journal of Medicine (2019 May 15. doi: 10.1056/NEJMoa1813904).
We first reported on the results of this trial when they were presented at the European Society for Medical Oncology Congress. Find our coverage at the link below.
Patients with PIK3CA-mutated, hormone receptor–positive, HER2-negative advanced breast cancer who had previously undergone endocrine therapy experienced longer progression-free survival when receiving alpelisib and fulvestrant, compared with placebo and fulvestrant (11.0 vs. 5.7 months; hazard ratio, 0.65; 95% confidence interval, 0.50-0.85; P less than .001), according to a randomized, phase 3 trial published in the New England Journal of Medicine (2019 May 15. doi: 10.1056/NEJMoa1813904).
We first reported on the results of this trial when they were presented at the European Society for Medical Oncology Congress. Find our coverage at the link below.
Patients with PIK3CA-mutated, hormone receptor–positive, HER2-negative advanced breast cancer who had previously undergone endocrine therapy experienced longer progression-free survival when receiving alpelisib and fulvestrant, compared with placebo and fulvestrant (11.0 vs. 5.7 months; hazard ratio, 0.65; 95% confidence interval, 0.50-0.85; P less than .001), according to a randomized, phase 3 trial published in the New England Journal of Medicine (2019 May 15. doi: 10.1056/NEJMoa1813904).
We first reported on the results of this trial when they were presented at the European Society for Medical Oncology Congress. Find our coverage at the link below.
FROM THE NEW ENGLAND JOURNAL OF MEDICINE
Lonely elderly patients suffer worse health outcomes
WASHINGTON – More lonely elderly patients suffered from health symptoms and received very aggressive end of life care than nonlonely elderly patients, according to a study presented at the annual meeting of the Society of General Internal Medicine.
“Loneliness and social isolation are very common problems, especially in older Americans, and inflict about 30%-40% of older Americans. But while we know that this may have implications for their quality [of] life and may actually lead to premature death, we know very little about the end of life experience,” said Nauzley Abedini, MD, MSc, a hospitalist in internal medicine at the University of Michigan, Ann Arbor.
The study sought to determine the association between loneliness and end of life experience as measured by symptom burden, intensity of care, and advance care planning in adults. The pooled cohort study used data from the Health and Retirement Study (HRS) to analyze older Americans (aged 50 years or more) who died between 2004 and 2014. Investigators conducted postmortem “exit interviews” with the next of kin after each participant’s death. There were 2,896 participants included in the survey. Of these participants, 34% (942) were lonely; the remaining 1,954 of elderly adults were classified as nonlonely.
Loneliness was defined using the three-item Revised University of California, Los Angeles, Loneliness Scale score from a decedent’s last HRS interview prior to death. These items included feeling left out, feeling isolated, and lacking companionship. Investigators used this data to create a loneliness variable on previously established cutpoints for “lonely” and “nonlonely” participants. The data was used from the most recent survey prior to death.
Results showed more lonely older adults suffered from health symptoms in the last year of life, compared with nonlonely older adults (69.1% vs. 59.5%; odds ratio, 1.52; 95% confidence interval, 1.30-1.78). These symptoms included being troubled by pain, having difficulty breathing, experiencing severe fatigue, and having periodic confusion.
Patients with loneliness associated with intensity of health care at the end of life were more likely to die in a nursing home than at home, compared with nonlonely adults (OR, 1.68; 95% CI, 1.25-2.27). The lonely patients also were more likely to use life support during their last 2 years of life (OR, 1.41; 95% CI, 1.16-1.70).
“For clinicians, we need to identify end of life as an additional vulnerable time for people who are lonely. Currently, most of our interventions in terms of screening for loneliness are in the outpatient setting, but I would argue that working in hospitals, hospices, nursing homes, and community organizations, where these folks are living and dying, would be useful places to screen for this,” Dr. Abedini said.
The authors had no disclosures.
WASHINGTON – More lonely elderly patients suffered from health symptoms and received very aggressive end of life care than nonlonely elderly patients, according to a study presented at the annual meeting of the Society of General Internal Medicine.
“Loneliness and social isolation are very common problems, especially in older Americans, and inflict about 30%-40% of older Americans. But while we know that this may have implications for their quality [of] life and may actually lead to premature death, we know very little about the end of life experience,” said Nauzley Abedini, MD, MSc, a hospitalist in internal medicine at the University of Michigan, Ann Arbor.
The study sought to determine the association between loneliness and end of life experience as measured by symptom burden, intensity of care, and advance care planning in adults. The pooled cohort study used data from the Health and Retirement Study (HRS) to analyze older Americans (aged 50 years or more) who died between 2004 and 2014. Investigators conducted postmortem “exit interviews” with the next of kin after each participant’s death. There were 2,896 participants included in the survey. Of these participants, 34% (942) were lonely; the remaining 1,954 of elderly adults were classified as nonlonely.
Loneliness was defined using the three-item Revised University of California, Los Angeles, Loneliness Scale score from a decedent’s last HRS interview prior to death. These items included feeling left out, feeling isolated, and lacking companionship. Investigators used this data to create a loneliness variable on previously established cutpoints for “lonely” and “nonlonely” participants. The data was used from the most recent survey prior to death.
Results showed more lonely older adults suffered from health symptoms in the last year of life, compared with nonlonely older adults (69.1% vs. 59.5%; odds ratio, 1.52; 95% confidence interval, 1.30-1.78). These symptoms included being troubled by pain, having difficulty breathing, experiencing severe fatigue, and having periodic confusion.
Patients with loneliness associated with intensity of health care at the end of life were more likely to die in a nursing home than at home, compared with nonlonely adults (OR, 1.68; 95% CI, 1.25-2.27). The lonely patients also were more likely to use life support during their last 2 years of life (OR, 1.41; 95% CI, 1.16-1.70).
“For clinicians, we need to identify end of life as an additional vulnerable time for people who are lonely. Currently, most of our interventions in terms of screening for loneliness are in the outpatient setting, but I would argue that working in hospitals, hospices, nursing homes, and community organizations, where these folks are living and dying, would be useful places to screen for this,” Dr. Abedini said.
The authors had no disclosures.
WASHINGTON – More lonely elderly patients suffered from health symptoms and received very aggressive end of life care than nonlonely elderly patients, according to a study presented at the annual meeting of the Society of General Internal Medicine.
“Loneliness and social isolation are very common problems, especially in older Americans, and inflict about 30%-40% of older Americans. But while we know that this may have implications for their quality [of] life and may actually lead to premature death, we know very little about the end of life experience,” said Nauzley Abedini, MD, MSc, a hospitalist in internal medicine at the University of Michigan, Ann Arbor.
The study sought to determine the association between loneliness and end of life experience as measured by symptom burden, intensity of care, and advance care planning in adults. The pooled cohort study used data from the Health and Retirement Study (HRS) to analyze older Americans (aged 50 years or more) who died between 2004 and 2014. Investigators conducted postmortem “exit interviews” with the next of kin after each participant’s death. There were 2,896 participants included in the survey. Of these participants, 34% (942) were lonely; the remaining 1,954 of elderly adults were classified as nonlonely.
Loneliness was defined using the three-item Revised University of California, Los Angeles, Loneliness Scale score from a decedent’s last HRS interview prior to death. These items included feeling left out, feeling isolated, and lacking companionship. Investigators used this data to create a loneliness variable on previously established cutpoints for “lonely” and “nonlonely” participants. The data was used from the most recent survey prior to death.
Results showed more lonely older adults suffered from health symptoms in the last year of life, compared with nonlonely older adults (69.1% vs. 59.5%; odds ratio, 1.52; 95% confidence interval, 1.30-1.78). These symptoms included being troubled by pain, having difficulty breathing, experiencing severe fatigue, and having periodic confusion.
Patients with loneliness associated with intensity of health care at the end of life were more likely to die in a nursing home than at home, compared with nonlonely adults (OR, 1.68; 95% CI, 1.25-2.27). The lonely patients also were more likely to use life support during their last 2 years of life (OR, 1.41; 95% CI, 1.16-1.70).
“For clinicians, we need to identify end of life as an additional vulnerable time for people who are lonely. Currently, most of our interventions in terms of screening for loneliness are in the outpatient setting, but I would argue that working in hospitals, hospices, nursing homes, and community organizations, where these folks are living and dying, would be useful places to screen for this,” Dr. Abedini said.
The authors had no disclosures.
REPORTING FROM SGIM 2019
TVEC may improve response rates in nonmetastatic TNBC
ATLANTA – Adding intratumoral talimogene laherparepvec (TVEC) to neoadjuvant chemotherapy appears to improve response rates in patients with nonmetastatic triple-negative breast cancer, according to findings from a phase 1 trial.
The pathologic complete response rate (pCR) in nine patients aged 18-70 years with stage T2-T3NO-2 disease who were enrolled in the single-center trial was 55%, whereas the expected rate with neoadjuvant chemotherapy alone was 30%, Hatem Soliman, MD, reported at the annual meeting of the American Association for Cancer Research.
“Even in the patients with residual disease, they had almost complete obliteration of their tumors, as well,” said Dr. Soliman of Moffitt Cancer Center, Tampa, Fla., adding that preliminary analyses of T cell subtypes indicated that CD45RO+ cells, which are associated with activated memory effector phenotype cells, were found in higher percentages in tumor specimens from patients who had pCR vs. those who did not.
“This could be an emerging marker that could be associated with pCR from TVEC,” he said, stressing, however, that “this is preliminary data [that] needs to be borne out in subsequent studies.”
Of the nine participants, six had stage II disease and three had stage III disease, and tumor size was greater than 5 cm in 2 patients, and 2-5 cm in 7 patients. Three received 106 plaque-forming units (PFUs) x 5 injections (dose level 1), and 6 received 106 PFUs for the first injection then 108 PFUs for 4 additional injections. Patients also received neoadjuvant paclitaxel followed by doxorubicin/cyclophosphamide chemotherapy.
They then went on to surgery and were evaluated for pCR.
No dose-limiting toxicities occurred, therefore the maximum-tolerated dose was dose level 2, Dr. Soliman noted.
The most common toxicities due to TVEC were fevers, chills, and injection site reactions, and “these are considered expected side effects of TVEC administration and were manageable,” he said.
Two serious adverse events occurred in the trial: a pulmonary embolism and a postoperative case of severe bradycardia thought to be a vasovagal episode; there were no deaths or any sequelae from these adverse events and they completely resolved.
One latent genital wild type herpes simplex 1 virus (HSV1) reactivation event occurred and was treated with a topical agent.
Early-stage triple-negative breast cancer is associated with a higher risk of early relapse, but attaining a pCR after neoadjuvant chemotherapy is associated with improved prognosis, Dr. Soliman said.
“Historically, standard regimens used for triple-negative breast cancer include an anthracycline and a taxane, and the rates of pCR in those patients hover around 30%,” he said. “Others have looked at the relationship of increased tumor infiltrating lymphocytes (TILs] in triple-negative breast cancers and other breast cancers, and found that those tumors that did have a higher de novo TIL infiltrate, either at the beginning of treatment or acquired during treatment, seemed to have a higher rate of pCR and also seemed to have improved prognosis.”
This suggested that these TIL infiltrates may be both a predictive and prognostic biologic marker for the biology of the disease, he noted.
Further, promising prior research on the role of oncolytic viruses as a potential treatment modality for cancer led to interest in their use during neoadjuvant chemotherapy “with the idea that we could potentially improve pathologic complete response rates both through direct tumor cell lysis of treated tumors, but also through recruitment of a robust antitumor immune response caused by the viruses’ mechanism of action,” he said, adding that “this could be beneficial, particularly in those immunologically ‘cold’ tumors.”
This led to the incorporation of TVEC, a genetically engineered oncolytic HSV1 currently approved for the treatment of melanoma, in this neoadjuvant trial. TVEC preferentially lyses tumor cells over normal tissue to release tumor associated antigens, produces granulocyte-macrophage colony-stimulating factor to activate dendritic cells, and stimulates T cells to provoke an adaptive immune response, he explained.
“[This] then can not only potentially attack tumor cells at the primary site, but then may potentially spread around the body to improve host surveillance and try to eradicate micrometastatic disease, as well,” he said.
The current findings show that adding TVEC to neoadjuvant chemotherapy is feasible at the full Food and Drug Administration–approved dose and has manageable toxicity, he concluded, noting that “a phase 2 single-arm trial of this regimen is ongoing, and we are actively accruing patients to further evaluate the efficacy signal and formally test the hypothesis along with immune correlates.”
Dr. Soliman reported relationships with Eli Lilly, Pfizer, Celgene, AstraZeneca, PUMA, Novartis, Eisai, and Amgen.
SOURCE: Soliman H et al. AACR 2019, Abstract CT040.
ATLANTA – Adding intratumoral talimogene laherparepvec (TVEC) to neoadjuvant chemotherapy appears to improve response rates in patients with nonmetastatic triple-negative breast cancer, according to findings from a phase 1 trial.
The pathologic complete response rate (pCR) in nine patients aged 18-70 years with stage T2-T3NO-2 disease who were enrolled in the single-center trial was 55%, whereas the expected rate with neoadjuvant chemotherapy alone was 30%, Hatem Soliman, MD, reported at the annual meeting of the American Association for Cancer Research.
“Even in the patients with residual disease, they had almost complete obliteration of their tumors, as well,” said Dr. Soliman of Moffitt Cancer Center, Tampa, Fla., adding that preliminary analyses of T cell subtypes indicated that CD45RO+ cells, which are associated with activated memory effector phenotype cells, were found in higher percentages in tumor specimens from patients who had pCR vs. those who did not.
“This could be an emerging marker that could be associated with pCR from TVEC,” he said, stressing, however, that “this is preliminary data [that] needs to be borne out in subsequent studies.”
Of the nine participants, six had stage II disease and three had stage III disease, and tumor size was greater than 5 cm in 2 patients, and 2-5 cm in 7 patients. Three received 106 plaque-forming units (PFUs) x 5 injections (dose level 1), and 6 received 106 PFUs for the first injection then 108 PFUs for 4 additional injections. Patients also received neoadjuvant paclitaxel followed by doxorubicin/cyclophosphamide chemotherapy.
They then went on to surgery and were evaluated for pCR.
No dose-limiting toxicities occurred, therefore the maximum-tolerated dose was dose level 2, Dr. Soliman noted.
The most common toxicities due to TVEC were fevers, chills, and injection site reactions, and “these are considered expected side effects of TVEC administration and were manageable,” he said.
Two serious adverse events occurred in the trial: a pulmonary embolism and a postoperative case of severe bradycardia thought to be a vasovagal episode; there were no deaths or any sequelae from these adverse events and they completely resolved.
One latent genital wild type herpes simplex 1 virus (HSV1) reactivation event occurred and was treated with a topical agent.
Early-stage triple-negative breast cancer is associated with a higher risk of early relapse, but attaining a pCR after neoadjuvant chemotherapy is associated with improved prognosis, Dr. Soliman said.
“Historically, standard regimens used for triple-negative breast cancer include an anthracycline and a taxane, and the rates of pCR in those patients hover around 30%,” he said. “Others have looked at the relationship of increased tumor infiltrating lymphocytes (TILs] in triple-negative breast cancers and other breast cancers, and found that those tumors that did have a higher de novo TIL infiltrate, either at the beginning of treatment or acquired during treatment, seemed to have a higher rate of pCR and also seemed to have improved prognosis.”
This suggested that these TIL infiltrates may be both a predictive and prognostic biologic marker for the biology of the disease, he noted.
Further, promising prior research on the role of oncolytic viruses as a potential treatment modality for cancer led to interest in their use during neoadjuvant chemotherapy “with the idea that we could potentially improve pathologic complete response rates both through direct tumor cell lysis of treated tumors, but also through recruitment of a robust antitumor immune response caused by the viruses’ mechanism of action,” he said, adding that “this could be beneficial, particularly in those immunologically ‘cold’ tumors.”
This led to the incorporation of TVEC, a genetically engineered oncolytic HSV1 currently approved for the treatment of melanoma, in this neoadjuvant trial. TVEC preferentially lyses tumor cells over normal tissue to release tumor associated antigens, produces granulocyte-macrophage colony-stimulating factor to activate dendritic cells, and stimulates T cells to provoke an adaptive immune response, he explained.
“[This] then can not only potentially attack tumor cells at the primary site, but then may potentially spread around the body to improve host surveillance and try to eradicate micrometastatic disease, as well,” he said.
The current findings show that adding TVEC to neoadjuvant chemotherapy is feasible at the full Food and Drug Administration–approved dose and has manageable toxicity, he concluded, noting that “a phase 2 single-arm trial of this regimen is ongoing, and we are actively accruing patients to further evaluate the efficacy signal and formally test the hypothesis along with immune correlates.”
Dr. Soliman reported relationships with Eli Lilly, Pfizer, Celgene, AstraZeneca, PUMA, Novartis, Eisai, and Amgen.
SOURCE: Soliman H et al. AACR 2019, Abstract CT040.
ATLANTA – Adding intratumoral talimogene laherparepvec (TVEC) to neoadjuvant chemotherapy appears to improve response rates in patients with nonmetastatic triple-negative breast cancer, according to findings from a phase 1 trial.
The pathologic complete response rate (pCR) in nine patients aged 18-70 years with stage T2-T3NO-2 disease who were enrolled in the single-center trial was 55%, whereas the expected rate with neoadjuvant chemotherapy alone was 30%, Hatem Soliman, MD, reported at the annual meeting of the American Association for Cancer Research.
“Even in the patients with residual disease, they had almost complete obliteration of their tumors, as well,” said Dr. Soliman of Moffitt Cancer Center, Tampa, Fla., adding that preliminary analyses of T cell subtypes indicated that CD45RO+ cells, which are associated with activated memory effector phenotype cells, were found in higher percentages in tumor specimens from patients who had pCR vs. those who did not.
“This could be an emerging marker that could be associated with pCR from TVEC,” he said, stressing, however, that “this is preliminary data [that] needs to be borne out in subsequent studies.”
Of the nine participants, six had stage II disease and three had stage III disease, and tumor size was greater than 5 cm in 2 patients, and 2-5 cm in 7 patients. Three received 106 plaque-forming units (PFUs) x 5 injections (dose level 1), and 6 received 106 PFUs for the first injection then 108 PFUs for 4 additional injections. Patients also received neoadjuvant paclitaxel followed by doxorubicin/cyclophosphamide chemotherapy.
They then went on to surgery and were evaluated for pCR.
No dose-limiting toxicities occurred, therefore the maximum-tolerated dose was dose level 2, Dr. Soliman noted.
The most common toxicities due to TVEC were fevers, chills, and injection site reactions, and “these are considered expected side effects of TVEC administration and were manageable,” he said.
Two serious adverse events occurred in the trial: a pulmonary embolism and a postoperative case of severe bradycardia thought to be a vasovagal episode; there were no deaths or any sequelae from these adverse events and they completely resolved.
One latent genital wild type herpes simplex 1 virus (HSV1) reactivation event occurred and was treated with a topical agent.
Early-stage triple-negative breast cancer is associated with a higher risk of early relapse, but attaining a pCR after neoadjuvant chemotherapy is associated with improved prognosis, Dr. Soliman said.
“Historically, standard regimens used for triple-negative breast cancer include an anthracycline and a taxane, and the rates of pCR in those patients hover around 30%,” he said. “Others have looked at the relationship of increased tumor infiltrating lymphocytes (TILs] in triple-negative breast cancers and other breast cancers, and found that those tumors that did have a higher de novo TIL infiltrate, either at the beginning of treatment or acquired during treatment, seemed to have a higher rate of pCR and also seemed to have improved prognosis.”
This suggested that these TIL infiltrates may be both a predictive and prognostic biologic marker for the biology of the disease, he noted.
Further, promising prior research on the role of oncolytic viruses as a potential treatment modality for cancer led to interest in their use during neoadjuvant chemotherapy “with the idea that we could potentially improve pathologic complete response rates both through direct tumor cell lysis of treated tumors, but also through recruitment of a robust antitumor immune response caused by the viruses’ mechanism of action,” he said, adding that “this could be beneficial, particularly in those immunologically ‘cold’ tumors.”
This led to the incorporation of TVEC, a genetically engineered oncolytic HSV1 currently approved for the treatment of melanoma, in this neoadjuvant trial. TVEC preferentially lyses tumor cells over normal tissue to release tumor associated antigens, produces granulocyte-macrophage colony-stimulating factor to activate dendritic cells, and stimulates T cells to provoke an adaptive immune response, he explained.
“[This] then can not only potentially attack tumor cells at the primary site, but then may potentially spread around the body to improve host surveillance and try to eradicate micrometastatic disease, as well,” he said.
The current findings show that adding TVEC to neoadjuvant chemotherapy is feasible at the full Food and Drug Administration–approved dose and has manageable toxicity, he concluded, noting that “a phase 2 single-arm trial of this regimen is ongoing, and we are actively accruing patients to further evaluate the efficacy signal and formally test the hypothesis along with immune correlates.”
Dr. Soliman reported relationships with Eli Lilly, Pfizer, Celgene, AstraZeneca, PUMA, Novartis, Eisai, and Amgen.
SOURCE: Soliman H et al. AACR 2019, Abstract CT040.
REPORTING FROM AACR 2019
Key clinical point: Adding TVEC to neoadjuvant chemotherapy for nonmetastatic TNBC appears to improve pCR response rates.
Major finding: The pCR was 55% with TVEC compared with an expected rate of 30% without TVEC.
Study details: A phase 1 study of 9 patients.
Disclosures: Dr. Soliman reported relationships with Eli Lilly, Pfizer, Celgene, AstraZeneca, PUMA, Novartis, Eisai, and Amgen.
Source: Soliman H et al. AACR 2019, Abstract CT040.
Pexidartinib gets ODAC nod for tenosynovial giant cell tumor treatment
The Oncologic Drugs Advisory Committee (ODAC) of the Food and Drug Administration voted to support approval of the small molecule kinase inhibitor pexidartinib for the treatment of adults with symptomatic tenosynovial giant cell tumor (TGCT) associated with severe morbidity or functional limitations and is not amenable to improvement with surgery.
The drug was favored by a 12-3 margin (no abstentions), with the majority of panel members agreeing that it offers clinical benefits that outweigh significant risk for elevated liver enzymes and small but real potential for serious or even fatal liver injury.
The FDA usually follows the recommendation of advisory committees in deciding final approval. Daiichi Sankyo plans to market the drug under the trade name Turalio.
Final approval and marketing of the drug will hinge on a mandatory Risk Evaluation and Mitigation Strategy that will require certification of prescribers, patient participation in education about the need for frequent liver function testing and the signs and symptoms of liver injury, and distribution of the drug only to certified pharmacies.
Both the ODAC panel members and pexidartinib’s manufacturer, Daiichi Sankyo, agreed that the drug is effective, but opinions about the degree of clinical benefit and the risk-benefit ratio differed.
TGCT is a rare, nonmalignant, and nonlethal tumor of the synovium, bursae, or tendon sheath that can be locally aggressive, and for some patients completely disabling. Surgery is the primary mode of treatment, but less than 10% of patients have disease that is not amenable to resection; for these patients treatment options are limited, because there are no approved systemic therapies for the disease.
ENLIVEN
Evidence submitted to support the application comes from the phase 3 ENLIVEN trial, in which patients with TGCT not amenable to surgery were randomly assigned to receive pexidartinib or placebo. The trial was designed to enroll 126 patients to provide 90% power to detect a difference in objective response rate at a two-sided alpha level of 0.05, assuming an overall response rate of 10% with placebo, and 35% with pexidartinib.
The actual trial enrollment, however, fell a little short, with a total of 120 patients randomized.
The ORR at week 25 as assessed by blinded independent central reviewers, the primary endpoint, was 39% for the 61 patients in the pexidartinib group, compared with 0% for the 59 patients in the placebo group (P less than .0001).
There were also statistically significant improvements in the pexidartinib arm at week 25 in the secondary endpoints of mean change in range of motion (ROM), ORR by tumor-volume score at week 25, mean change from baseline in the Patient-Reported Outcomes Measurement Information physical function scale, and mean change in the Worst Stiffness numeric rating scale item. There were no significant differences between the groups for worst pain, however.
The FDA briefing document notes that “interpretation of the results of the secondary endpoints should be viewed with caution as there was a high proportion of missing data at week 25 for ROM, physical function, and worst stiffness (27%, 43% 43%, respectively); the proportion of patients with missing data was similar across study arms.”
Risk and benefits
The major issues before the ODAC included the validity of clinical outcome assessment given the large chunks of missing data and the major adverse event of liver injury, with a majority of patients on pexidartinib experiencing transaminase elevations. The potential for liver injury may be exacerbated by chronic use of the drug or by drugs used to treat comorbidities such as diabetes or cardiovascular disease, several panel members noted.
During the clinical development program for the drug, 2 of 768 patients who received the drug developed irreversible liver injury leading to liver transplant in 1 patient and death in the other.
Many of the panelists who voted to support approval did so with some reluctance about the adverse events. For example, Karin Anton Calis, PharmD, of the National Institutes of Health voted yes because of the efficacy of the drug in a disabling condition.
“Hopefully it will be used in a restricted system so that there can be adequate monitoring, but I’m still concerned about those patients that may have this unpredictable liver toxicity, “ he said.
Victor M. Villalobos MD, PhD, from the University of Colorado at Denver, Aurora, also voted yes.
“This is an ultra-rare disease with no good therapies available to patients and it can be highly morbid, and I feel that getting real-world data on how we can use this drug in a safe and effective manner will be really important to the academic community going forward,” he said.
Other panel members who also voted to support approval expressed concerns about the hepatotoxicity, but noted that the drug has the potential to change lives, as attested by TCGT patients who spoke during the public comment portion of the meeting.
However, panelist Doris Strader, MD, from the University of Vermont, Burlington, said that she voted no because, while she was sensitive to the potential benefits of the drug for some patients, “I was concerned about the missing data and was not convinced that there was clinically meaningful benefit. Likewise, while I understand that the hepatic injury is not liver failure, I am concerned that this may be persistent for a long time, and I worry that there is not enough to suggest that there is going to be rigorous monitoring of patients over their lifetimes.”
The Oncologic Drugs Advisory Committee (ODAC) of the Food and Drug Administration voted to support approval of the small molecule kinase inhibitor pexidartinib for the treatment of adults with symptomatic tenosynovial giant cell tumor (TGCT) associated with severe morbidity or functional limitations and is not amenable to improvement with surgery.
The drug was favored by a 12-3 margin (no abstentions), with the majority of panel members agreeing that it offers clinical benefits that outweigh significant risk for elevated liver enzymes and small but real potential for serious or even fatal liver injury.
The FDA usually follows the recommendation of advisory committees in deciding final approval. Daiichi Sankyo plans to market the drug under the trade name Turalio.
Final approval and marketing of the drug will hinge on a mandatory Risk Evaluation and Mitigation Strategy that will require certification of prescribers, patient participation in education about the need for frequent liver function testing and the signs and symptoms of liver injury, and distribution of the drug only to certified pharmacies.
Both the ODAC panel members and pexidartinib’s manufacturer, Daiichi Sankyo, agreed that the drug is effective, but opinions about the degree of clinical benefit and the risk-benefit ratio differed.
TGCT is a rare, nonmalignant, and nonlethal tumor of the synovium, bursae, or tendon sheath that can be locally aggressive, and for some patients completely disabling. Surgery is the primary mode of treatment, but less than 10% of patients have disease that is not amenable to resection; for these patients treatment options are limited, because there are no approved systemic therapies for the disease.
ENLIVEN
Evidence submitted to support the application comes from the phase 3 ENLIVEN trial, in which patients with TGCT not amenable to surgery were randomly assigned to receive pexidartinib or placebo. The trial was designed to enroll 126 patients to provide 90% power to detect a difference in objective response rate at a two-sided alpha level of 0.05, assuming an overall response rate of 10% with placebo, and 35% with pexidartinib.
The actual trial enrollment, however, fell a little short, with a total of 120 patients randomized.
The ORR at week 25 as assessed by blinded independent central reviewers, the primary endpoint, was 39% for the 61 patients in the pexidartinib group, compared with 0% for the 59 patients in the placebo group (P less than .0001).
There were also statistically significant improvements in the pexidartinib arm at week 25 in the secondary endpoints of mean change in range of motion (ROM), ORR by tumor-volume score at week 25, mean change from baseline in the Patient-Reported Outcomes Measurement Information physical function scale, and mean change in the Worst Stiffness numeric rating scale item. There were no significant differences between the groups for worst pain, however.
The FDA briefing document notes that “interpretation of the results of the secondary endpoints should be viewed with caution as there was a high proportion of missing data at week 25 for ROM, physical function, and worst stiffness (27%, 43% 43%, respectively); the proportion of patients with missing data was similar across study arms.”
Risk and benefits
The major issues before the ODAC included the validity of clinical outcome assessment given the large chunks of missing data and the major adverse event of liver injury, with a majority of patients on pexidartinib experiencing transaminase elevations. The potential for liver injury may be exacerbated by chronic use of the drug or by drugs used to treat comorbidities such as diabetes or cardiovascular disease, several panel members noted.
During the clinical development program for the drug, 2 of 768 patients who received the drug developed irreversible liver injury leading to liver transplant in 1 patient and death in the other.
Many of the panelists who voted to support approval did so with some reluctance about the adverse events. For example, Karin Anton Calis, PharmD, of the National Institutes of Health voted yes because of the efficacy of the drug in a disabling condition.
“Hopefully it will be used in a restricted system so that there can be adequate monitoring, but I’m still concerned about those patients that may have this unpredictable liver toxicity, “ he said.
Victor M. Villalobos MD, PhD, from the University of Colorado at Denver, Aurora, also voted yes.
“This is an ultra-rare disease with no good therapies available to patients and it can be highly morbid, and I feel that getting real-world data on how we can use this drug in a safe and effective manner will be really important to the academic community going forward,” he said.
Other panel members who also voted to support approval expressed concerns about the hepatotoxicity, but noted that the drug has the potential to change lives, as attested by TCGT patients who spoke during the public comment portion of the meeting.
However, panelist Doris Strader, MD, from the University of Vermont, Burlington, said that she voted no because, while she was sensitive to the potential benefits of the drug for some patients, “I was concerned about the missing data and was not convinced that there was clinically meaningful benefit. Likewise, while I understand that the hepatic injury is not liver failure, I am concerned that this may be persistent for a long time, and I worry that there is not enough to suggest that there is going to be rigorous monitoring of patients over their lifetimes.”
The Oncologic Drugs Advisory Committee (ODAC) of the Food and Drug Administration voted to support approval of the small molecule kinase inhibitor pexidartinib for the treatment of adults with symptomatic tenosynovial giant cell tumor (TGCT) associated with severe morbidity or functional limitations and is not amenable to improvement with surgery.
The drug was favored by a 12-3 margin (no abstentions), with the majority of panel members agreeing that it offers clinical benefits that outweigh significant risk for elevated liver enzymes and small but real potential for serious or even fatal liver injury.
The FDA usually follows the recommendation of advisory committees in deciding final approval. Daiichi Sankyo plans to market the drug under the trade name Turalio.
Final approval and marketing of the drug will hinge on a mandatory Risk Evaluation and Mitigation Strategy that will require certification of prescribers, patient participation in education about the need for frequent liver function testing and the signs and symptoms of liver injury, and distribution of the drug only to certified pharmacies.
Both the ODAC panel members and pexidartinib’s manufacturer, Daiichi Sankyo, agreed that the drug is effective, but opinions about the degree of clinical benefit and the risk-benefit ratio differed.
TGCT is a rare, nonmalignant, and nonlethal tumor of the synovium, bursae, or tendon sheath that can be locally aggressive, and for some patients completely disabling. Surgery is the primary mode of treatment, but less than 10% of patients have disease that is not amenable to resection; for these patients treatment options are limited, because there are no approved systemic therapies for the disease.
ENLIVEN
Evidence submitted to support the application comes from the phase 3 ENLIVEN trial, in which patients with TGCT not amenable to surgery were randomly assigned to receive pexidartinib or placebo. The trial was designed to enroll 126 patients to provide 90% power to detect a difference in objective response rate at a two-sided alpha level of 0.05, assuming an overall response rate of 10% with placebo, and 35% with pexidartinib.
The actual trial enrollment, however, fell a little short, with a total of 120 patients randomized.
The ORR at week 25 as assessed by blinded independent central reviewers, the primary endpoint, was 39% for the 61 patients in the pexidartinib group, compared with 0% for the 59 patients in the placebo group (P less than .0001).
There were also statistically significant improvements in the pexidartinib arm at week 25 in the secondary endpoints of mean change in range of motion (ROM), ORR by tumor-volume score at week 25, mean change from baseline in the Patient-Reported Outcomes Measurement Information physical function scale, and mean change in the Worst Stiffness numeric rating scale item. There were no significant differences between the groups for worst pain, however.
The FDA briefing document notes that “interpretation of the results of the secondary endpoints should be viewed with caution as there was a high proportion of missing data at week 25 for ROM, physical function, and worst stiffness (27%, 43% 43%, respectively); the proportion of patients with missing data was similar across study arms.”
Risk and benefits
The major issues before the ODAC included the validity of clinical outcome assessment given the large chunks of missing data and the major adverse event of liver injury, with a majority of patients on pexidartinib experiencing transaminase elevations. The potential for liver injury may be exacerbated by chronic use of the drug or by drugs used to treat comorbidities such as diabetes or cardiovascular disease, several panel members noted.
During the clinical development program for the drug, 2 of 768 patients who received the drug developed irreversible liver injury leading to liver transplant in 1 patient and death in the other.
Many of the panelists who voted to support approval did so with some reluctance about the adverse events. For example, Karin Anton Calis, PharmD, of the National Institutes of Health voted yes because of the efficacy of the drug in a disabling condition.
“Hopefully it will be used in a restricted system so that there can be adequate monitoring, but I’m still concerned about those patients that may have this unpredictable liver toxicity, “ he said.
Victor M. Villalobos MD, PhD, from the University of Colorado at Denver, Aurora, also voted yes.
“This is an ultra-rare disease with no good therapies available to patients and it can be highly morbid, and I feel that getting real-world data on how we can use this drug in a safe and effective manner will be really important to the academic community going forward,” he said.
Other panel members who also voted to support approval expressed concerns about the hepatotoxicity, but noted that the drug has the potential to change lives, as attested by TCGT patients who spoke during the public comment portion of the meeting.
However, panelist Doris Strader, MD, from the University of Vermont, Burlington, said that she voted no because, while she was sensitive to the potential benefits of the drug for some patients, “I was concerned about the missing data and was not convinced that there was clinically meaningful benefit. Likewise, while I understand that the hepatic injury is not liver failure, I am concerned that this may be persistent for a long time, and I worry that there is not enough to suggest that there is going to be rigorous monitoring of patients over their lifetimes.”
Immunotherapy Induces Improvements in PML
Key clinical point: Adoptive transfer of donor-derived T cells represents a potentially life-saving strategy for patients with progressive multifocal leukoencephalopathy.
Major finding: Seven of 12 patients stabilized and, in some cases, experienced significant neurological improvement.
Study details: A pilot study including 12 patients with refractory PML.
Disclosures: The study was funded by NINDS. The investigators disclosed no conflicts related to the study.
Citation: Cortese I et al. AAN 2019, Abstract Plen01.002.
Key clinical point: Adoptive transfer of donor-derived T cells represents a potentially life-saving strategy for patients with progressive multifocal leukoencephalopathy.
Major finding: Seven of 12 patients stabilized and, in some cases, experienced significant neurological improvement.
Study details: A pilot study including 12 patients with refractory PML.
Disclosures: The study was funded by NINDS. The investigators disclosed no conflicts related to the study.
Citation: Cortese I et al. AAN 2019, Abstract Plen01.002.
Key clinical point: Adoptive transfer of donor-derived T cells represents a potentially life-saving strategy for patients with progressive multifocal leukoencephalopathy.
Major finding: Seven of 12 patients stabilized and, in some cases, experienced significant neurological improvement.
Study details: A pilot study including 12 patients with refractory PML.
Disclosures: The study was funded by NINDS. The investigators disclosed no conflicts related to the study.
Citation: Cortese I et al. AAN 2019, Abstract Plen01.002.