Neil Osterweil

Preemptive monitoring and treatment of cytomegalovirus infections in CMV-seronegative liver transplant recipients who receive organs from CMV-positive donors appears to be better at preventing infections than a viral prophylaxis strategy, according to infectious disease and organ transplant specialists.

In a study published in JAMA that may have gotten scant notice because of its publication during the early days of the COVID-19 pandemic, investigators at the University of Pittsburgh and other transplant centers reported results of a randomized clinical trial comparing the two CMV management strategies, and found that the incidence of CMV disease was significantly lower for patients who were started on valganciclovir when asymptomatic CMV viremia was detected, compared with patients on antiviral prophylaxis with valganciclovir.

The study “is a significant game changer for the field of transplantation,” commented Michael G. Ison, MD, professor of infectious diseases and organ transplantation at Northwestern University, Chicago.

Dr. Ison discussed the study and its implications during a session on potentially practice-changing clinical trials presented virtually during IDWeek 2020, an annual scientific meeting on infectious diseases.

In the trial, Nina Singh, MD, and colleagues randomly assigned 100 CMV-seronegative liver transplant recipients to receive preemptive therapy, in which patients underwent weekly testing for 100 days with a highly sensitive real-time plasma polymerase chain reaction assay for CMV. If viremia at any level was detected, the patients received oral valganciclovir 900 mg twice daily until two consecutive tests performed 1 week apart came back negative.

The remaining 105 patients were randomly assigned to 100 days of oral prophylaxis with 900 mg valganciclovir twice daily, started within 10 days of transplant.
 

CMV disease incidence lower

The incidence of CMV disease within 12 months of transplants, the primary outcome, was 9% in the preemptive therapy group, compared with 19% in the prophylaxis group (P = .04)

The difference between the groups was largely accounted for by a reduction in disease onset beyond 100 days in the preemptive therapy group (6% vs. 17%, respectively, P = .01)

There were no significant differences in secondary endpoints of rejection, opportunistic infections, graft loss because of retransplantation, neutropenia, or receipt of one or more doses of granulocyte colony–stimulating factor for the management of neutropenia.

At 1-year follow-up, the incidence of all-cause mortality was 15% in the preemptive therapy group, and 19% in the prophylaxis group; the difference was not statistically significant.

“While most transplant centers utilize universal prophylaxis, I think that this study really suggests that preemptive monitoring, if it can be safely accomplished at your center, may be of the greatest benefit to your patients,” Dr. Ison said.

He noted that Singh et al. also looked in an exploratory analysis at CMV-specific immunity and observed that patients assigned to preemptive therapy “clearly had better CMV-specific immunity, whether CD4 or CD8 cells, and had higher lymphocyte numbers than those patients that had received universal prophylaxis.”

In a comment, Sarah Doernberg, MD, from the division of infectious diseases at the University of California, San Francisco, agreed that “exploratory analysis of CMV-specific immune responses suggested increased CMV-specific immunity in those in the preemptive group, a finding that warrants further study. The feasibility of adopting reliable preemptive monitoring must be considered as individual centers ponder adopting this approach.”

Dr. Doernberg moderated the session where Dr. Ison discussed the data, but was not involved in the research.

The study by Singh et al. was supported by the National Institutes of Health. Dr. Singh reported research grants from NIH. Dr. Ison disclosed research support and paid consultation for several companies. Dr. Doernberg disclosed consulting for Basilea and Genentech.

Preemptive monitoring and treatment of cytomegalovirus infections in CMV-seronegative liver transplant recipients who receive organs from CMV-positive donors appears to be better at preventing infections than a viral prophylaxis strategy, according to infectious disease and organ transplant specialists.

In a study published in JAMA that may have gotten scant notice because of its publication during the early days of the COVID-19 pandemic, investigators at the University of Pittsburgh and other transplant centers reported results of a randomized clinical trial comparing the two CMV management strategies, and found that the incidence of CMV disease was significantly lower for patients who were started on valganciclovir when asymptomatic CMV viremia was detected, compared with patients on antiviral prophylaxis with valganciclovir.

The study “is a significant game changer for the field of transplantation,” commented Michael G. Ison, MD, professor of infectious diseases and organ transplantation at Northwestern University, Chicago.

Dr. Ison discussed the study and its implications during a session on potentially practice-changing clinical trials presented virtually during IDWeek 2020, an annual scientific meeting on infectious diseases.

In the trial, Nina Singh, MD, and colleagues randomly assigned 100 CMV-seronegative liver transplant recipients to receive preemptive therapy, in which patients underwent weekly testing for 100 days with a highly sensitive real-time plasma polymerase chain reaction assay for CMV. If viremia at any level was detected, the patients received oral valganciclovir 900 mg twice daily until two consecutive tests performed 1 week apart came back negative.

The remaining 105 patients were randomly assigned to 100 days of oral prophylaxis with 900 mg valganciclovir twice daily, started within 10 days of transplant.
 

CMV disease incidence lower

The incidence of CMV disease within 12 months of transplants, the primary outcome, was 9% in the preemptive therapy group, compared with 19% in the prophylaxis group (P = .04)

The difference between the groups was largely accounted for by a reduction in disease onset beyond 100 days in the preemptive therapy group (6% vs. 17%, respectively, P = .01)

There were no significant differences in secondary endpoints of rejection, opportunistic infections, graft loss because of retransplantation, neutropenia, or receipt of one or more doses of granulocyte colony–stimulating factor for the management of neutropenia.

At 1-year follow-up, the incidence of all-cause mortality was 15% in the preemptive therapy group, and 19% in the prophylaxis group; the difference was not statistically significant.

“While most transplant centers utilize universal prophylaxis, I think that this study really suggests that preemptive monitoring, if it can be safely accomplished at your center, may be of the greatest benefit to your patients,” Dr. Ison said.

He noted that Singh et al. also looked in an exploratory analysis at CMV-specific immunity and observed that patients assigned to preemptive therapy “clearly had better CMV-specific immunity, whether CD4 or CD8 cells, and had higher lymphocyte numbers than those patients that had received universal prophylaxis.”

In a comment, Sarah Doernberg, MD, from the division of infectious diseases at the University of California, San Francisco, agreed that “exploratory analysis of CMV-specific immune responses suggested increased CMV-specific immunity in those in the preemptive group, a finding that warrants further study. The feasibility of adopting reliable preemptive monitoring must be considered as individual centers ponder adopting this approach.”

Dr. Doernberg moderated the session where Dr. Ison discussed the data, but was not involved in the research.

The study by Singh et al. was supported by the National Institutes of Health. Dr. Singh reported research grants from NIH. Dr. Ison disclosed research support and paid consultation for several companies. Dr. Doernberg disclosed consulting for Basilea and Genentech.

Preemptive monitoring and treatment of cytomegalovirus infections in CMV-seronegative liver transplant recipients who receive organs from CMV-positive donors appears to be better at preventing infections than a viral prophylaxis strategy, according to infectious disease and organ transplant specialists.

In a study published in JAMA that may have gotten scant notice because of its publication during the early days of the COVID-19 pandemic, investigators at the University of Pittsburgh and other transplant centers reported results of a randomized clinical trial comparing the two CMV management strategies, and found that the incidence of CMV disease was significantly lower for patients who were started on valganciclovir when asymptomatic CMV viremia was detected, compared with patients on antiviral prophylaxis with valganciclovir.

The study “is a significant game changer for the field of transplantation,” commented Michael G. Ison, MD, professor of infectious diseases and organ transplantation at Northwestern University, Chicago.

Dr. Ison discussed the study and its implications during a session on potentially practice-changing clinical trials presented virtually during IDWeek 2020, an annual scientific meeting on infectious diseases.

In the trial, Nina Singh, MD, and colleagues randomly assigned 100 CMV-seronegative liver transplant recipients to receive preemptive therapy, in which patients underwent weekly testing for 100 days with a highly sensitive real-time plasma polymerase chain reaction assay for CMV. If viremia at any level was detected, the patients received oral valganciclovir 900 mg twice daily until two consecutive tests performed 1 week apart came back negative.

The remaining 105 patients were randomly assigned to 100 days of oral prophylaxis with 900 mg valganciclovir twice daily, started within 10 days of transplant.
 

CMV disease incidence lower

The incidence of CMV disease within 12 months of transplants, the primary outcome, was 9% in the preemptive therapy group, compared with 19% in the prophylaxis group (P = .04)

The difference between the groups was largely accounted for by a reduction in disease onset beyond 100 days in the preemptive therapy group (6% vs. 17%, respectively, P = .01)

There were no significant differences in secondary endpoints of rejection, opportunistic infections, graft loss because of retransplantation, neutropenia, or receipt of one or more doses of granulocyte colony–stimulating factor for the management of neutropenia.

At 1-year follow-up, the incidence of all-cause mortality was 15% in the preemptive therapy group, and 19% in the prophylaxis group; the difference was not statistically significant.

“While most transplant centers utilize universal prophylaxis, I think that this study really suggests that preemptive monitoring, if it can be safely accomplished at your center, may be of the greatest benefit to your patients,” Dr. Ison said.

He noted that Singh et al. also looked in an exploratory analysis at CMV-specific immunity and observed that patients assigned to preemptive therapy “clearly had better CMV-specific immunity, whether CD4 or CD8 cells, and had higher lymphocyte numbers than those patients that had received universal prophylaxis.”

In a comment, Sarah Doernberg, MD, from the division of infectious diseases at the University of California, San Francisco, agreed that “exploratory analysis of CMV-specific immune responses suggested increased CMV-specific immunity in those in the preemptive group, a finding that warrants further study. The feasibility of adopting reliable preemptive monitoring must be considered as individual centers ponder adopting this approach.”

Dr. Doernberg moderated the session where Dr. Ison discussed the data, but was not involved in the research.

The study by Singh et al. was supported by the National Institutes of Health. Dr. Singh reported research grants from NIH. Dr. Ison disclosed research support and paid consultation for several companies. Dr. Doernberg disclosed consulting for Basilea and Genentech.

A new formulation of an existing antibacterial agent and a potential therapeutic approach to a challenging clinical problem were the focus of a session on potentially practice-changing clinical trials in antimicrobial therapy presented during IDWeek 2020, an annual scientific meeting on infectious diseases.

“I know it has been a big year for viral disease of course, with COVID, but there has been some really good work that has gone on in the bacterial space, and of course as those of you who are on service know, you may have your fair share of COVID patients, but these are infections that we still deal with on a daily basis,” said Michael Satlin, MD, an infectious disease specialist at Weill Cornell Medicine in New York.

He combed through studies published during the previous 12 months in leading medical journals, including the New England Journal of Medicine, JAMA network publications, Lancet Infectious Diseases, Lancet Respiratory Medicine, Clinical Infectious Diseases, and Clinical Microbiology and Infection, looking for randomized trials of interventions to treat bacterial infections, and selecting those most likely to change practice of U.S. infectious diseases practitioners.

He excluded meta-analyses, post hoc analyses, evaluations of diagnostic tests, stewardship, or any studies presented previously at IDWeek.

Two of the trials he highlighted are described here.
 

Fosfomycin for injection

In the United States, fosfomycin, the only antibiotic in its class, is currently available only in an oral sachet formulation (Monurol), “and typically we’ve only given this for patients with cystitis because we know that we don’t achieve significant levels [of drug] in the kidney or in the bloodstream for other types of infections,” Dr. Satlin said.

In Europe, however fosfomycin for injection (ZTI-01) has been available for several years.

“There’s been a lot of interest in fosfomycin because it has a different mechanism of action from other agents. It’s an epoxide antibiotic that inhibits early peptidoglycan synthesis by binding to MurA,” he explained.

The phase 2/3 randomized ZEUS trial compared ZTI-01 with piperacillin/tazobactam (pip/taz) for treatment of complicated urinary tract infection (UTI) including acute pyelonephritis.

A total of 465 hospitalized adults with suspected or microbiologically confirmed complicated UTI or acute pyelonephritis were randomized to 6 g of ZTI-01 every 8 hours or 4.5 g of intravenous pip/taz every 8 hours for a fixed 7-day course with no oral switch; patients with concomitant bacteremia (about 9% of the study population) could receive the assigned therapy for up to 14 days.

The primary endpoint of noninferiority of ZTI-01 was met and clinical cure rates were high and similar between the treatments, at approximately 91% each. Treatment-emergent adverse events, including hypokalemia and elevated serum aminotransferases, were mostly mild and transient.

The hypokalemia seen in the trial may be attributable to the high salt load of fosfomycin relative to pip/taz, Dr. Satlin said.

“How might this change your practice? Well, if IV fosfomycin is ever FDA [Food and Drug Administration] approved – and my understanding is that the delays have been more related to manufacturing than scientific quality of data – it could potentially be an alternative to beta-lactams and fluoroquinolones” and has activity against most extend spectrum beta-lactamase (ESBL)–producing Enterobacteriaceae, he said.

Fosfomycin susceptibility testing is challenging, however, with no Clinical & Laboratory Standards Institute (CLSI) or FDA breakpoints for Enterobacterales other than Escherichia coli, and there are questions about the step-down therapy.

“Do you just give a 3-gram sachet chaser when they walk out the door? Do you switch to another agent? I think that needs to be worked out,” he said.
 

Inhaled amikacin

“We know that some IV antibiotics, particularly for resistant organisms, may not achieve sufficient concentrations in the lung to treat pneumonia. We know that inhaled antibiotics can give a lot of concentration of that drug right at the at the site of infection, but we don’t really have [randomized controlled trial] data to see whether it really helps,” Dr. Satlin said.

The INHALE trial was a double-blind, placebo-controlled superiority trial to see whether adding inhaled amikacin to IV standard-of-care antibiotics could improve outcomes for mechanically ventilated patients with gram-negative pneumonia.

The investigators enrolled 725 adults who were receiving mechanical ventilation for pneumonia, 45% of who had ventilator-associated pneumonia (VAP). Of the total cohort, 508 patients analyzed for efficacy had gram-negative pathogens, including 32% with Pseudomonas aeurginosa, 29% with Acinetobacter baumannii, 30% with E. coli, and the remainder with Klebsiella pneumoniae.

Patients were randomized to standard-of-care intravenous antibiotics plus either inhaled amikacin 400 mg twice daily for 10 days or inhaled saline placebo.

“Of note, the median standard-of-care antibiotics in this study was 18 days, which is certainly longer than what our guidelines recommend.”

There was no significant difference between study arms in the primary endpoint of survival at days 28-32 for all patients who had received at least one dose of study drug, were infected with a gram-negative pathogen, and an Acute Physiology and Chronic Health Evaluation (APACHE) II score of at 10 or higher at diagnosis. The respective survival rates for the inhaled amikacin and placebo groups were 75% and 77%. The incidence of treatment-emergent adverse events or serious treatment-emergent adverse events were similar between the two treatment arms.

“No matter how you sliced and diced it – days of mechanical ventilation, duration of ICU stay – essentially they looked the same. Even for [extensively drug resistant] pathogens where you might expect that you’d see the benefit of inhaled amikacin, they didn’t really see a mortality benefit in this study,” Dr. Satlin said.

The study is practice changing, he said “because I think inhaled aminoglycosides should not be routinely added to the standard of care IV antibiotics for pneumonia in ventilated patients,” he said.

It’s still unclear whether inhaled aminoglycosides might play a role in the treatment of select patients infected with organisms resistant to all beta-lactams and fluoroquinolones, he added.
 

Tempting strategy

“Adding inhaled antibiotics is a tempting strategy for treatment of ventilated pneumonia, which often has poor outcomes,” commented Thomas Holland, MD, a hospitalist and infectious disease specialist at Duke University Hospital in Durham, N.C. “This is valuable and practical information as clinicians choose antibiotics regimens for this difficult-to-treat syndrome,” he said in an interview.

Dr. Holland comoderated the session in which Dr. Satlin presented the study findings and opinions.

No funding source for the presentation was reported. Dr. Satlin reported consulting for Shionogi and Achaogen and research grants from Allergan, Merck, and BioFire Diagnostics. Dr. Holland disclosed consulting fees and other material support from Basilea Pharmaceutica, Genetech, Karius and Theravance.

A new formulation of an existing antibacterial agent and a potential therapeutic approach to a challenging clinical problem were the focus of a session on potentially practice-changing clinical trials in antimicrobial therapy presented during IDWeek 2020, an annual scientific meeting on infectious diseases.

“I know it has been a big year for viral disease of course, with COVID, but there has been some really good work that has gone on in the bacterial space, and of course as those of you who are on service know, you may have your fair share of COVID patients, but these are infections that we still deal with on a daily basis,” said Michael Satlin, MD, an infectious disease specialist at Weill Cornell Medicine in New York.

He combed through studies published during the previous 12 months in leading medical journals, including the New England Journal of Medicine, JAMA network publications, Lancet Infectious Diseases, Lancet Respiratory Medicine, Clinical Infectious Diseases, and Clinical Microbiology and Infection, looking for randomized trials of interventions to treat bacterial infections, and selecting those most likely to change practice of U.S. infectious diseases practitioners.

He excluded meta-analyses, post hoc analyses, evaluations of diagnostic tests, stewardship, or any studies presented previously at IDWeek.

Two of the trials he highlighted are described here.
 

Fosfomycin for injection

In the United States, fosfomycin, the only antibiotic in its class, is currently available only in an oral sachet formulation (Monurol), “and typically we’ve only given this for patients with cystitis because we know that we don’t achieve significant levels [of drug] in the kidney or in the bloodstream for other types of infections,” Dr. Satlin said.

In Europe, however fosfomycin for injection (ZTI-01) has been available for several years.

“There’s been a lot of interest in fosfomycin because it has a different mechanism of action from other agents. It’s an epoxide antibiotic that inhibits early peptidoglycan synthesis by binding to MurA,” he explained.

The phase 2/3 randomized ZEUS trial compared ZTI-01 with piperacillin/tazobactam (pip/taz) for treatment of complicated urinary tract infection (UTI) including acute pyelonephritis.

A total of 465 hospitalized adults with suspected or microbiologically confirmed complicated UTI or acute pyelonephritis were randomized to 6 g of ZTI-01 every 8 hours or 4.5 g of intravenous pip/taz every 8 hours for a fixed 7-day course with no oral switch; patients with concomitant bacteremia (about 9% of the study population) could receive the assigned therapy for up to 14 days.

The primary endpoint of noninferiority of ZTI-01 was met and clinical cure rates were high and similar between the treatments, at approximately 91% each. Treatment-emergent adverse events, including hypokalemia and elevated serum aminotransferases, were mostly mild and transient.

The hypokalemia seen in the trial may be attributable to the high salt load of fosfomycin relative to pip/taz, Dr. Satlin said.

“How might this change your practice? Well, if IV fosfomycin is ever FDA [Food and Drug Administration] approved – and my understanding is that the delays have been more related to manufacturing than scientific quality of data – it could potentially be an alternative to beta-lactams and fluoroquinolones” and has activity against most extend spectrum beta-lactamase (ESBL)–producing Enterobacteriaceae, he said.

Fosfomycin susceptibility testing is challenging, however, with no Clinical & Laboratory Standards Institute (CLSI) or FDA breakpoints for Enterobacterales other than Escherichia coli, and there are questions about the step-down therapy.

“Do you just give a 3-gram sachet chaser when they walk out the door? Do you switch to another agent? I think that needs to be worked out,” he said.
 

Inhaled amikacin

“We know that some IV antibiotics, particularly for resistant organisms, may not achieve sufficient concentrations in the lung to treat pneumonia. We know that inhaled antibiotics can give a lot of concentration of that drug right at the at the site of infection, but we don’t really have [randomized controlled trial] data to see whether it really helps,” Dr. Satlin said.

The INHALE trial was a double-blind, placebo-controlled superiority trial to see whether adding inhaled amikacin to IV standard-of-care antibiotics could improve outcomes for mechanically ventilated patients with gram-negative pneumonia.

The investigators enrolled 725 adults who were receiving mechanical ventilation for pneumonia, 45% of who had ventilator-associated pneumonia (VAP). Of the total cohort, 508 patients analyzed for efficacy had gram-negative pathogens, including 32% with Pseudomonas aeurginosa, 29% with Acinetobacter baumannii, 30% with E. coli, and the remainder with Klebsiella pneumoniae.

Patients were randomized to standard-of-care intravenous antibiotics plus either inhaled amikacin 400 mg twice daily for 10 days or inhaled saline placebo.

“Of note, the median standard-of-care antibiotics in this study was 18 days, which is certainly longer than what our guidelines recommend.”

There was no significant difference between study arms in the primary endpoint of survival at days 28-32 for all patients who had received at least one dose of study drug, were infected with a gram-negative pathogen, and an Acute Physiology and Chronic Health Evaluation (APACHE) II score of at 10 or higher at diagnosis. The respective survival rates for the inhaled amikacin and placebo groups were 75% and 77%. The incidence of treatment-emergent adverse events or serious treatment-emergent adverse events were similar between the two treatment arms.

“No matter how you sliced and diced it – days of mechanical ventilation, duration of ICU stay – essentially they looked the same. Even for [extensively drug resistant] pathogens where you might expect that you’d see the benefit of inhaled amikacin, they didn’t really see a mortality benefit in this study,” Dr. Satlin said.

The study is practice changing, he said “because I think inhaled aminoglycosides should not be routinely added to the standard of care IV antibiotics for pneumonia in ventilated patients,” he said.

It’s still unclear whether inhaled aminoglycosides might play a role in the treatment of select patients infected with organisms resistant to all beta-lactams and fluoroquinolones, he added.
 

Tempting strategy

“Adding inhaled antibiotics is a tempting strategy for treatment of ventilated pneumonia, which often has poor outcomes,” commented Thomas Holland, MD, a hospitalist and infectious disease specialist at Duke University Hospital in Durham, N.C. “This is valuable and practical information as clinicians choose antibiotics regimens for this difficult-to-treat syndrome,” he said in an interview.

Dr. Holland comoderated the session in which Dr. Satlin presented the study findings and opinions.

No funding source for the presentation was reported. Dr. Satlin reported consulting for Shionogi and Achaogen and research grants from Allergan, Merck, and BioFire Diagnostics. Dr. Holland disclosed consulting fees and other material support from Basilea Pharmaceutica, Genetech, Karius and Theravance.

A new formulation of an existing antibacterial agent and a potential therapeutic approach to a challenging clinical problem were the focus of a session on potentially practice-changing clinical trials in antimicrobial therapy presented during IDWeek 2020, an annual scientific meeting on infectious diseases.

“I know it has been a big year for viral disease of course, with COVID, but there has been some really good work that has gone on in the bacterial space, and of course as those of you who are on service know, you may have your fair share of COVID patients, but these are infections that we still deal with on a daily basis,” said Michael Satlin, MD, an infectious disease specialist at Weill Cornell Medicine in New York.

He combed through studies published during the previous 12 months in leading medical journals, including the New England Journal of Medicine, JAMA network publications, Lancet Infectious Diseases, Lancet Respiratory Medicine, Clinical Infectious Diseases, and Clinical Microbiology and Infection, looking for randomized trials of interventions to treat bacterial infections, and selecting those most likely to change practice of U.S. infectious diseases practitioners.

He excluded meta-analyses, post hoc analyses, evaluations of diagnostic tests, stewardship, or any studies presented previously at IDWeek.

Two of the trials he highlighted are described here.
 

Fosfomycin for injection

In the United States, fosfomycin, the only antibiotic in its class, is currently available only in an oral sachet formulation (Monurol), “and typically we’ve only given this for patients with cystitis because we know that we don’t achieve significant levels [of drug] in the kidney or in the bloodstream for other types of infections,” Dr. Satlin said.

In Europe, however fosfomycin for injection (ZTI-01) has been available for several years.

“There’s been a lot of interest in fosfomycin because it has a different mechanism of action from other agents. It’s an epoxide antibiotic that inhibits early peptidoglycan synthesis by binding to MurA,” he explained.

The phase 2/3 randomized ZEUS trial compared ZTI-01 with piperacillin/tazobactam (pip/taz) for treatment of complicated urinary tract infection (UTI) including acute pyelonephritis.

A total of 465 hospitalized adults with suspected or microbiologically confirmed complicated UTI or acute pyelonephritis were randomized to 6 g of ZTI-01 every 8 hours or 4.5 g of intravenous pip/taz every 8 hours for a fixed 7-day course with no oral switch; patients with concomitant bacteremia (about 9% of the study population) could receive the assigned therapy for up to 14 days.

The primary endpoint of noninferiority of ZTI-01 was met and clinical cure rates were high and similar between the treatments, at approximately 91% each. Treatment-emergent adverse events, including hypokalemia and elevated serum aminotransferases, were mostly mild and transient.

The hypokalemia seen in the trial may be attributable to the high salt load of fosfomycin relative to pip/taz, Dr. Satlin said.

“How might this change your practice? Well, if IV fosfomycin is ever FDA [Food and Drug Administration] approved – and my understanding is that the delays have been more related to manufacturing than scientific quality of data – it could potentially be an alternative to beta-lactams and fluoroquinolones” and has activity against most extend spectrum beta-lactamase (ESBL)–producing Enterobacteriaceae, he said.

Fosfomycin susceptibility testing is challenging, however, with no Clinical & Laboratory Standards Institute (CLSI) or FDA breakpoints for Enterobacterales other than Escherichia coli, and there are questions about the step-down therapy.

“Do you just give a 3-gram sachet chaser when they walk out the door? Do you switch to another agent? I think that needs to be worked out,” he said.
 

Inhaled amikacin

“We know that some IV antibiotics, particularly for resistant organisms, may not achieve sufficient concentrations in the lung to treat pneumonia. We know that inhaled antibiotics can give a lot of concentration of that drug right at the at the site of infection, but we don’t really have [randomized controlled trial] data to see whether it really helps,” Dr. Satlin said.

The INHALE trial was a double-blind, placebo-controlled superiority trial to see whether adding inhaled amikacin to IV standard-of-care antibiotics could improve outcomes for mechanically ventilated patients with gram-negative pneumonia.

The investigators enrolled 725 adults who were receiving mechanical ventilation for pneumonia, 45% of who had ventilator-associated pneumonia (VAP). Of the total cohort, 508 patients analyzed for efficacy had gram-negative pathogens, including 32% with Pseudomonas aeurginosa, 29% with Acinetobacter baumannii, 30% with E. coli, and the remainder with Klebsiella pneumoniae.

Patients were randomized to standard-of-care intravenous antibiotics plus either inhaled amikacin 400 mg twice daily for 10 days or inhaled saline placebo.

“Of note, the median standard-of-care antibiotics in this study was 18 days, which is certainly longer than what our guidelines recommend.”

There was no significant difference between study arms in the primary endpoint of survival at days 28-32 for all patients who had received at least one dose of study drug, were infected with a gram-negative pathogen, and an Acute Physiology and Chronic Health Evaluation (APACHE) II score of at 10 or higher at diagnosis. The respective survival rates for the inhaled amikacin and placebo groups were 75% and 77%. The incidence of treatment-emergent adverse events or serious treatment-emergent adverse events were similar between the two treatment arms.

“No matter how you sliced and diced it – days of mechanical ventilation, duration of ICU stay – essentially they looked the same. Even for [extensively drug resistant] pathogens where you might expect that you’d see the benefit of inhaled amikacin, they didn’t really see a mortality benefit in this study,” Dr. Satlin said.

The study is practice changing, he said “because I think inhaled aminoglycosides should not be routinely added to the standard of care IV antibiotics for pneumonia in ventilated patients,” he said.

It’s still unclear whether inhaled aminoglycosides might play a role in the treatment of select patients infected with organisms resistant to all beta-lactams and fluoroquinolones, he added.
 

Tempting strategy

“Adding inhaled antibiotics is a tempting strategy for treatment of ventilated pneumonia, which often has poor outcomes,” commented Thomas Holland, MD, a hospitalist and infectious disease specialist at Duke University Hospital in Durham, N.C. “This is valuable and practical information as clinicians choose antibiotics regimens for this difficult-to-treat syndrome,” he said in an interview.

Dr. Holland comoderated the session in which Dr. Satlin presented the study findings and opinions.

No funding source for the presentation was reported. Dr. Satlin reported consulting for Shionogi and Achaogen and research grants from Allergan, Merck, and BioFire Diagnostics. Dr. Holland disclosed consulting fees and other material support from Basilea Pharmaceutica, Genetech, Karius and Theravance.

It’s not ready for the clinic, but new research suggests that angiotensin receptor II blockers (ARBs) widely used to treat hypertension may improve responses to cancer immunotherapy agents targeted against the programmed death-1/ligand-1 (PD-1/PD-L1) pathway.

That conclusion comes from an observational study of 597 patients with more than 3 dozen different cancer types treated in clinical trials at the US National Institutes of Health. Investigators found that both objective response rates and 3-year overall survival (OS) rates were significantly higher for patients treated with a PD-1/PD-L1 inhibitor who were on ARBs, compared with patients who weren’t taking the antihypertensive agents.

An association was also seen between higher ORR and OS rates for patients taking ACE inhibitors, but it was not statistically significant, reported Julius Strauss, MD, from the Center for Cancer Research at the National Cancer Institute in Bethesda, Md.

All study patients received PD-1/PD-L1 inhibitors, and the ORR for patients treated with ARBs was 33.8%, compared with 19.5% for those treated with ACE inhibitors, and 17% for those who took neither drug. The respective complete response (CR) rates were 11.3%, 3.7%, and 3.1%.

Strauss discussed the data during an online briefing prior to his presentation of the findings during the 32nd EORTC-NCI-AACR Symposium on Molecular Targets and Cancer Therapeutics, which is taking place virtually.

Several early studies have suggested that angiotensin II, in addition to its effect on blood pressure, can also affect cancer growth by leading to downstream production of two proteins: vascular endothelial growth factor (VEGF) and transforming growth factor–beta (TGF-beta), he explained.

“Both of these [proteins] have been linked to cancer growth and cancer resistance to immune system attack,” Strauss observed.

He also discussed the mechanics of possible effects. Angiotensin II increases VEGF and TGF-beta through binding to the AT1 receptor, but has the opposite effect when it binds to the AT2 receptor, resulting in a decrease in both of the growth factors, he added.

ACE inhibitors prevent the conversion of angiotensin I to angiotensin II, with the result being that the drugs indirectly block both the AT1 and AT2 receptors.

In contrast, ARBs block only the AT1 receptor and leave the AT2 counter-regulatory receptor alone, said Strauss.
 

More data, including on overall survival

Strauss and colleagues examined whether ACE inhibitors and/or ARBs could have an effect on the response to PD-1/PD-L1 immune checkpoint inhibitors delivered with or without other immunotherapies, such as anti-cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) checkpoint inhibitors, or targeted agents such as tyrosine kinase inhibitors (TKIs).

They pooled data on 597 patients receiving PD-1/PD-L1 inhibitors in clinical trials for various cancers, including 71 receiving concomitant ARBs, 82 receiving an ACE inhibitor, and 444 who were not receiving either class of antihypertensives.

The above-mentioned improvement in ORR with ARBs compared with patients not receiving the drug was statistically significant (P = .001), as was the improvement in CR rates (P = .002). In contrast, neither ORR nor CR were significantly better with patients on ACE inhibitors compared with patients not taking these drugs.

In multiple regression analysis controlling for age, gender, body mass index (BMI), tumor type, and additional therapies given, the superior ORR and CR rates with ARBs remained (P = .039 and .002, respectively), while there continued to be no significant additional benefit with ACE inhibitors.

The median overall survival was 35.2 months for patients on ARBs, 26.2 months for those on ACE inhibitors, and 18.8 months for patients on neither drug. The respective 3-year OS rates were 48.1%, 37.2%, and 31.5%, with the difference between the ARB and no-drug groups being significant (P = .0078).

In regression analysis controlling for the factors mentioned before, the OS advantage with ARBs but not ACE inhibitors remained significant (P = .006 for ARBs, and .078 for ACE inhibitors).

Strauss emphasized that further study is needed to determine if AT1 blockade can improve outcomes when combined anti-PD-1/PD-L1-based therapy.

It might be reasonable for patients who are taking ACE inhibitors to control blood pressure and are also receiving immunotherapy with a PD-1/PD-L1 inhibitor to be switched to an ARB if it is deemed safe and if further research bears it out, said Strauss in response to a question from Medscape Medical News.
 

Hypothesis-generating study

Meeting cochair Emiliano Calvo, MD, PhD, from Hospital de Madrid Norte Sanchinarro in Madrid, who attended the media briefing but was not involved in the study, commented that hypothesis-generating research using drugs already on the market for other indications adds important value to cancer therapy.

James Gulley, MD, PhD, from the Center for Cancer Research at the NCI, also a meeting cochair, agreed with Calvo.

“Thinking about utilizing the data that already exists to really get hypothesis-generating questions, it also opens up the possibility for real-world data, real-world evidence from these big datasets from [electronic medical records] that we could really interrogate and understand what we might see and get these hypothesis-generating findings that we could then prospectively evaluate,” Gulley said.

The research was funded by the National Cancer Institute. Strauss and Gulley are National Cancer Institute employees. Calvo disclosed no relevant financial relationships.

This article first appeared on Medscape.com.

It’s not ready for the clinic, but new research suggests that angiotensin receptor II blockers (ARBs) widely used to treat hypertension may improve responses to cancer immunotherapy agents targeted against the programmed death-1/ligand-1 (PD-1/PD-L1) pathway.

That conclusion comes from an observational study of 597 patients with more than 3 dozen different cancer types treated in clinical trials at the US National Institutes of Health. Investigators found that both objective response rates and 3-year overall survival (OS) rates were significantly higher for patients treated with a PD-1/PD-L1 inhibitor who were on ARBs, compared with patients who weren’t taking the antihypertensive agents.

An association was also seen between higher ORR and OS rates for patients taking ACE inhibitors, but it was not statistically significant, reported Julius Strauss, MD, from the Center for Cancer Research at the National Cancer Institute in Bethesda, Md.

All study patients received PD-1/PD-L1 inhibitors, and the ORR for patients treated with ARBs was 33.8%, compared with 19.5% for those treated with ACE inhibitors, and 17% for those who took neither drug. The respective complete response (CR) rates were 11.3%, 3.7%, and 3.1%.

Strauss discussed the data during an online briefing prior to his presentation of the findings during the 32nd EORTC-NCI-AACR Symposium on Molecular Targets and Cancer Therapeutics, which is taking place virtually.

Several early studies have suggested that angiotensin II, in addition to its effect on blood pressure, can also affect cancer growth by leading to downstream production of two proteins: vascular endothelial growth factor (VEGF) and transforming growth factor–beta (TGF-beta), he explained.

“Both of these [proteins] have been linked to cancer growth and cancer resistance to immune system attack,” Strauss observed.

He also discussed the mechanics of possible effects. Angiotensin II increases VEGF and TGF-beta through binding to the AT1 receptor, but has the opposite effect when it binds to the AT2 receptor, resulting in a decrease in both of the growth factors, he added.

ACE inhibitors prevent the conversion of angiotensin I to angiotensin II, with the result being that the drugs indirectly block both the AT1 and AT2 receptors.

In contrast, ARBs block only the AT1 receptor and leave the AT2 counter-regulatory receptor alone, said Strauss.
 

More data, including on overall survival

Strauss and colleagues examined whether ACE inhibitors and/or ARBs could have an effect on the response to PD-1/PD-L1 immune checkpoint inhibitors delivered with or without other immunotherapies, such as anti-cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) checkpoint inhibitors, or targeted agents such as tyrosine kinase inhibitors (TKIs).

They pooled data on 597 patients receiving PD-1/PD-L1 inhibitors in clinical trials for various cancers, including 71 receiving concomitant ARBs, 82 receiving an ACE inhibitor, and 444 who were not receiving either class of antihypertensives.

The above-mentioned improvement in ORR with ARBs compared with patients not receiving the drug was statistically significant (P = .001), as was the improvement in CR rates (P = .002). In contrast, neither ORR nor CR were significantly better with patients on ACE inhibitors compared with patients not taking these drugs.

In multiple regression analysis controlling for age, gender, body mass index (BMI), tumor type, and additional therapies given, the superior ORR and CR rates with ARBs remained (P = .039 and .002, respectively), while there continued to be no significant additional benefit with ACE inhibitors.

The median overall survival was 35.2 months for patients on ARBs, 26.2 months for those on ACE inhibitors, and 18.8 months for patients on neither drug. The respective 3-year OS rates were 48.1%, 37.2%, and 31.5%, with the difference between the ARB and no-drug groups being significant (P = .0078).

In regression analysis controlling for the factors mentioned before, the OS advantage with ARBs but not ACE inhibitors remained significant (P = .006 for ARBs, and .078 for ACE inhibitors).

Strauss emphasized that further study is needed to determine if AT1 blockade can improve outcomes when combined anti-PD-1/PD-L1-based therapy.

It might be reasonable for patients who are taking ACE inhibitors to control blood pressure and are also receiving immunotherapy with a PD-1/PD-L1 inhibitor to be switched to an ARB if it is deemed safe and if further research bears it out, said Strauss in response to a question from Medscape Medical News.
 

Hypothesis-generating study

Meeting cochair Emiliano Calvo, MD, PhD, from Hospital de Madrid Norte Sanchinarro in Madrid, who attended the media briefing but was not involved in the study, commented that hypothesis-generating research using drugs already on the market for other indications adds important value to cancer therapy.

James Gulley, MD, PhD, from the Center for Cancer Research at the NCI, also a meeting cochair, agreed with Calvo.

“Thinking about utilizing the data that already exists to really get hypothesis-generating questions, it also opens up the possibility for real-world data, real-world evidence from these big datasets from [electronic medical records] that we could really interrogate and understand what we might see and get these hypothesis-generating findings that we could then prospectively evaluate,” Gulley said.

The research was funded by the National Cancer Institute. Strauss and Gulley are National Cancer Institute employees. Calvo disclosed no relevant financial relationships.

This article first appeared on Medscape.com.

It’s not ready for the clinic, but new research suggests that angiotensin receptor II blockers (ARBs) widely used to treat hypertension may improve responses to cancer immunotherapy agents targeted against the programmed death-1/ligand-1 (PD-1/PD-L1) pathway.

That conclusion comes from an observational study of 597 patients with more than 3 dozen different cancer types treated in clinical trials at the US National Institutes of Health. Investigators found that both objective response rates and 3-year overall survival (OS) rates were significantly higher for patients treated with a PD-1/PD-L1 inhibitor who were on ARBs, compared with patients who weren’t taking the antihypertensive agents.

An association was also seen between higher ORR and OS rates for patients taking ACE inhibitors, but it was not statistically significant, reported Julius Strauss, MD, from the Center for Cancer Research at the National Cancer Institute in Bethesda, Md.

All study patients received PD-1/PD-L1 inhibitors, and the ORR for patients treated with ARBs was 33.8%, compared with 19.5% for those treated with ACE inhibitors, and 17% for those who took neither drug. The respective complete response (CR) rates were 11.3%, 3.7%, and 3.1%.

Strauss discussed the data during an online briefing prior to his presentation of the findings during the 32nd EORTC-NCI-AACR Symposium on Molecular Targets and Cancer Therapeutics, which is taking place virtually.

Several early studies have suggested that angiotensin II, in addition to its effect on blood pressure, can also affect cancer growth by leading to downstream production of two proteins: vascular endothelial growth factor (VEGF) and transforming growth factor–beta (TGF-beta), he explained.

“Both of these [proteins] have been linked to cancer growth and cancer resistance to immune system attack,” Strauss observed.

He also discussed the mechanics of possible effects. Angiotensin II increases VEGF and TGF-beta through binding to the AT1 receptor, but has the opposite effect when it binds to the AT2 receptor, resulting in a decrease in both of the growth factors, he added.

ACE inhibitors prevent the conversion of angiotensin I to angiotensin II, with the result being that the drugs indirectly block both the AT1 and AT2 receptors.

In contrast, ARBs block only the AT1 receptor and leave the AT2 counter-regulatory receptor alone, said Strauss.
 

More data, including on overall survival

Strauss and colleagues examined whether ACE inhibitors and/or ARBs could have an effect on the response to PD-1/PD-L1 immune checkpoint inhibitors delivered with or without other immunotherapies, such as anti-cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) checkpoint inhibitors, or targeted agents such as tyrosine kinase inhibitors (TKIs).

They pooled data on 597 patients receiving PD-1/PD-L1 inhibitors in clinical trials for various cancers, including 71 receiving concomitant ARBs, 82 receiving an ACE inhibitor, and 444 who were not receiving either class of antihypertensives.

The above-mentioned improvement in ORR with ARBs compared with patients not receiving the drug was statistically significant (P = .001), as was the improvement in CR rates (P = .002). In contrast, neither ORR nor CR were significantly better with patients on ACE inhibitors compared with patients not taking these drugs.

In multiple regression analysis controlling for age, gender, body mass index (BMI), tumor type, and additional therapies given, the superior ORR and CR rates with ARBs remained (P = .039 and .002, respectively), while there continued to be no significant additional benefit with ACE inhibitors.

The median overall survival was 35.2 months for patients on ARBs, 26.2 months for those on ACE inhibitors, and 18.8 months for patients on neither drug. The respective 3-year OS rates were 48.1%, 37.2%, and 31.5%, with the difference between the ARB and no-drug groups being significant (P = .0078).

In regression analysis controlling for the factors mentioned before, the OS advantage with ARBs but not ACE inhibitors remained significant (P = .006 for ARBs, and .078 for ACE inhibitors).

Strauss emphasized that further study is needed to determine if AT1 blockade can improve outcomes when combined anti-PD-1/PD-L1-based therapy.

It might be reasonable for patients who are taking ACE inhibitors to control blood pressure and are also receiving immunotherapy with a PD-1/PD-L1 inhibitor to be switched to an ARB if it is deemed safe and if further research bears it out, said Strauss in response to a question from Medscape Medical News.
 

Hypothesis-generating study

Meeting cochair Emiliano Calvo, MD, PhD, from Hospital de Madrid Norte Sanchinarro in Madrid, who attended the media briefing but was not involved in the study, commented that hypothesis-generating research using drugs already on the market for other indications adds important value to cancer therapy.

James Gulley, MD, PhD, from the Center for Cancer Research at the NCI, also a meeting cochair, agreed with Calvo.

“Thinking about utilizing the data that already exists to really get hypothesis-generating questions, it also opens up the possibility for real-world data, real-world evidence from these big datasets from [electronic medical records] that we could really interrogate and understand what we might see and get these hypothesis-generating findings that we could then prospectively evaluate,” Gulley said.

The research was funded by the National Cancer Institute. Strauss and Gulley are National Cancer Institute employees. Calvo disclosed no relevant financial relationships.

This article first appeared on Medscape.com.

Although the efficacy of two pre-exposure prophylaxis (PrEP) regimens containing differing prodrug formulations of tenofovir are virtually identical, the balance between benefit and risk tips in favor of the combination using the older formulation, tenofovir disoproxil fumarate (TDF), a pharmacology researcher said.

An analysis of the pharmacologic profiles of TDF plus emtricitabine (FTC; Truvada and generic) with tenofovir alafenamide (TAF) plus FTC (Descovy) shows that the risk of decreased bone mineral density and renal toxicity with TDF are significantly lower than those of weight gain and related metabolic and cardiovascular problems associated with the newer tenofovir formulation TAF, according to pharmacology research fellow Andrew Hill, MD, PhD, from the University of Liverpool (England).

“I think when we’re comparing these two drugs overall, we have a clear benefit/risk, and we need to take both of these potential toxicities seriously, “ he said in an online presentation during IDWeek 2020, an annual scientific meeting on infectious diseases held virtually this year.

“But in my view, treating women – Black women – with TAF/FTC is a bad thing,” he continued. “I think it’s going lead to more harm, more myocardial infarctions, more cases of diabetes, and potentially more adverse birth outcomes, and I think that is a risk that is not worth taking, given that the apparent benefit in terms of bone mineral density and renal markers is a hypothesis at best, and is not translated into hard clinical endpoints.”
 

Adverse event profiles

Dr. Hill compared the side effect profiles of the two agents when used both in antiretroviral therapy (ART) in combination the integrase inhibitor dolutegravir (DTG; Tivicay), and in PrEP.

World Health Organization guidelines for first-line ART recommend the use of TDF/FTC/DTG, reserving TAF plus lamivudine (3TC) and DTG for use in special circumstances only, Dr. Hill noted.

He pointed to a pooled analysis of data from eight randomized, controlled trials of treatment-naive people living with HIV who started on ART from 2003 to 2015. The authors found that demographic factors associated with weight gain included lower CD4 cell counter, higher levels of HIV type 1 RNA, no injection drug use, female sex, and Black race.

They also found that, among nucleoside/nucleotide reverse transcriptase inhibitors, TAF was associated with more weight gain than TDF, abacavir, or zidovudine.

“This pattern is seen consistently across studies both of pre-exposure prophylaxis or treatment comparing tenofovir with either TAF or other nucleoside analogs,” he said.

The greater weight gain with TAF versus TDF was seen in both treatment trials and in the DISCOVER PrEP trial.

In addition, in a crossover trial conducted in Germany, patients who switched from TDF to TAF had an approximately 2 kg increase in body weight.

TAF has also been associated with higher grade 3 or 4 glucose and LDL cholesterol than TDF in clinical trials for the treatment of hepatitis B infections, and with higher LDL cholesterol and total cholesterol levels as well as diabetes in patients treated with the drugs in combination in the EMERALD HIV trial.

Clinical trials also tend to underestimate the real-world population of persons at highest risk for adverse events from TAF, Dr. Hill said, noting that the percentage of Black women in phase 3 trials for dolutegravir was 9%, compared with 42% among persons infected with HIV worldwide. The respective percentages for Black men are 16% versus 30%. These differences are similar across clinical trial programs for other ART agents.

“Generally, it’s women and Black people who seem to be at greatest risk for safety issues,” he said.

In the ADVANCE trial comparing TAF/FTC/DTG with TDF/FTC/DTG and a control arm of TDF, FTC and efavirenz, the mean change in weight among men after 3 years on the TAF-based regimen was a gain of 7.2 kg (15.9 lbs), compared with 5.5 kg (12 lbs) with TDF, and 2.6 kg (5.7 lbs) with the efavirenz-containing regimen.

In women enrolled in the same trial, the respective mean weight gains were 12.3 kg (27 lbs), 7.4 kg (16.3 lbs), and 5.5 kg (12 lbs).

“All of our analyses so far have shown that the weight continues to go up. We’re actually seeing people doubling in their body weight. We’ve seen some women come into clinic and their doctors don’t even recognize them because they’ve put on so much weight,” he said.

In women, most of the gain in weight occurs as limb or trunk fat, with a predominance of visceral fat.

People taking TAF in the trial were also at significantly greater risk for developing the metabolic syndrome, and at week 96, 27% of women on TAF/FTC/DTG had treatment-emergent obesity, compared with 17% for those on TDF/FTC/DTG and 11% for those on TDF/FTC/EFV. In men, the respective 96-week rates of treatment-emergent obesity were 7%, 3%, and 2%.

Clinical obesity itself is a risk factor for obstetric complications and birth outcomes, Alzheimer’s disease, type 2 diabetes, cardiovascular disease, hypertension and cancer, and an average 4-year reduction in life expectancy, Dr. Hill said. “I think it’s actually very unlikely that the [World Health Organization] guidelines will now change and allow the widespread use of TAF/FTC in combination with integrase inhibitors worldwide given these potential implications.”
 

Modern times

The bad rap that TDF gets for its alleged effects on bone mineral density and kidneys comes from studies where the drug was given in a boosted regimen that can amplify tenofovir toxicities, Dr. Hill said.

He noted that data from Gilead Sciences shows through 7 years of therapy in previously ART-naive patients, the combination of TDF/3TC/EFV showed sustained durable efficacy, no discontinuations to renal adverse effects, and no evidence of clinically relevant bone effects.

“I think we need to be very careful when we look at tenofovir and TAF. We need to look at the more modern way that these drugs are used, which is not with pharmacokinetic boosters anymore, and in that situation the toxicity profile of tenofovir/3TC – the original TDF – is very favorable,” he said.

Robert Goldstein, MD, PhD, an infectious disease specialist and medical director of the transgender health program at Massachusetts General Hospital in Boston, who comoderated the session where Dr. Hill presented his data, said that his clinical experience mirrors the pharmacokinetic findings.

“I certainly have strong feelings about the use of TDF in pre-exposure prophylaxis,” he said in an interview. “TDF is an effective and safe formulation of tenofovir to be used in pre-exposure prophylaxis, and one that we have more experience with. It’s the formulation of tenofovir that I use for all of my patients who are on pre-exposure prophylaxis, and I think it is the most cost-effective.’

No funding source was reported. Andrew Hill consults for Tibotec on clinical trial programs for darunavir, etravirine, and rilpivirine. Dr. Goldstein reported having no relevant disclosures.

Although the efficacy of two pre-exposure prophylaxis (PrEP) regimens containing differing prodrug formulations of tenofovir are virtually identical, the balance between benefit and risk tips in favor of the combination using the older formulation, tenofovir disoproxil fumarate (TDF), a pharmacology researcher said.

An analysis of the pharmacologic profiles of TDF plus emtricitabine (FTC; Truvada and generic) with tenofovir alafenamide (TAF) plus FTC (Descovy) shows that the risk of decreased bone mineral density and renal toxicity with TDF are significantly lower than those of weight gain and related metabolic and cardiovascular problems associated with the newer tenofovir formulation TAF, according to pharmacology research fellow Andrew Hill, MD, PhD, from the University of Liverpool (England).

“I think when we’re comparing these two drugs overall, we have a clear benefit/risk, and we need to take both of these potential toxicities seriously, “ he said in an online presentation during IDWeek 2020, an annual scientific meeting on infectious diseases held virtually this year.

“But in my view, treating women – Black women – with TAF/FTC is a bad thing,” he continued. “I think it’s going lead to more harm, more myocardial infarctions, more cases of diabetes, and potentially more adverse birth outcomes, and I think that is a risk that is not worth taking, given that the apparent benefit in terms of bone mineral density and renal markers is a hypothesis at best, and is not translated into hard clinical endpoints.”
 

Adverse event profiles

Dr. Hill compared the side effect profiles of the two agents when used both in antiretroviral therapy (ART) in combination the integrase inhibitor dolutegravir (DTG; Tivicay), and in PrEP.

World Health Organization guidelines for first-line ART recommend the use of TDF/FTC/DTG, reserving TAF plus lamivudine (3TC) and DTG for use in special circumstances only, Dr. Hill noted.

He pointed to a pooled analysis of data from eight randomized, controlled trials of treatment-naive people living with HIV who started on ART from 2003 to 2015. The authors found that demographic factors associated with weight gain included lower CD4 cell counter, higher levels of HIV type 1 RNA, no injection drug use, female sex, and Black race.

They also found that, among nucleoside/nucleotide reverse transcriptase inhibitors, TAF was associated with more weight gain than TDF, abacavir, or zidovudine.

“This pattern is seen consistently across studies both of pre-exposure prophylaxis or treatment comparing tenofovir with either TAF or other nucleoside analogs,” he said.

The greater weight gain with TAF versus TDF was seen in both treatment trials and in the DISCOVER PrEP trial.

In addition, in a crossover trial conducted in Germany, patients who switched from TDF to TAF had an approximately 2 kg increase in body weight.

TAF has also been associated with higher grade 3 or 4 glucose and LDL cholesterol than TDF in clinical trials for the treatment of hepatitis B infections, and with higher LDL cholesterol and total cholesterol levels as well as diabetes in patients treated with the drugs in combination in the EMERALD HIV trial.

Clinical trials also tend to underestimate the real-world population of persons at highest risk for adverse events from TAF, Dr. Hill said, noting that the percentage of Black women in phase 3 trials for dolutegravir was 9%, compared with 42% among persons infected with HIV worldwide. The respective percentages for Black men are 16% versus 30%. These differences are similar across clinical trial programs for other ART agents.

“Generally, it’s women and Black people who seem to be at greatest risk for safety issues,” he said.

In the ADVANCE trial comparing TAF/FTC/DTG with TDF/FTC/DTG and a control arm of TDF, FTC and efavirenz, the mean change in weight among men after 3 years on the TAF-based regimen was a gain of 7.2 kg (15.9 lbs), compared with 5.5 kg (12 lbs) with TDF, and 2.6 kg (5.7 lbs) with the efavirenz-containing regimen.

In women enrolled in the same trial, the respective mean weight gains were 12.3 kg (27 lbs), 7.4 kg (16.3 lbs), and 5.5 kg (12 lbs).

“All of our analyses so far have shown that the weight continues to go up. We’re actually seeing people doubling in their body weight. We’ve seen some women come into clinic and their doctors don’t even recognize them because they’ve put on so much weight,” he said.

In women, most of the gain in weight occurs as limb or trunk fat, with a predominance of visceral fat.

People taking TAF in the trial were also at significantly greater risk for developing the metabolic syndrome, and at week 96, 27% of women on TAF/FTC/DTG had treatment-emergent obesity, compared with 17% for those on TDF/FTC/DTG and 11% for those on TDF/FTC/EFV. In men, the respective 96-week rates of treatment-emergent obesity were 7%, 3%, and 2%.

Clinical obesity itself is a risk factor for obstetric complications and birth outcomes, Alzheimer’s disease, type 2 diabetes, cardiovascular disease, hypertension and cancer, and an average 4-year reduction in life expectancy, Dr. Hill said. “I think it’s actually very unlikely that the [World Health Organization] guidelines will now change and allow the widespread use of TAF/FTC in combination with integrase inhibitors worldwide given these potential implications.”
 

Modern times

The bad rap that TDF gets for its alleged effects on bone mineral density and kidneys comes from studies where the drug was given in a boosted regimen that can amplify tenofovir toxicities, Dr. Hill said.

He noted that data from Gilead Sciences shows through 7 years of therapy in previously ART-naive patients, the combination of TDF/3TC/EFV showed sustained durable efficacy, no discontinuations to renal adverse effects, and no evidence of clinically relevant bone effects.

“I think we need to be very careful when we look at tenofovir and TAF. We need to look at the more modern way that these drugs are used, which is not with pharmacokinetic boosters anymore, and in that situation the toxicity profile of tenofovir/3TC – the original TDF – is very favorable,” he said.

Robert Goldstein, MD, PhD, an infectious disease specialist and medical director of the transgender health program at Massachusetts General Hospital in Boston, who comoderated the session where Dr. Hill presented his data, said that his clinical experience mirrors the pharmacokinetic findings.

“I certainly have strong feelings about the use of TDF in pre-exposure prophylaxis,” he said in an interview. “TDF is an effective and safe formulation of tenofovir to be used in pre-exposure prophylaxis, and one that we have more experience with. It’s the formulation of tenofovir that I use for all of my patients who are on pre-exposure prophylaxis, and I think it is the most cost-effective.’

No funding source was reported. Andrew Hill consults for Tibotec on clinical trial programs for darunavir, etravirine, and rilpivirine. Dr. Goldstein reported having no relevant disclosures.

Although the efficacy of two pre-exposure prophylaxis (PrEP) regimens containing differing prodrug formulations of tenofovir are virtually identical, the balance between benefit and risk tips in favor of the combination using the older formulation, tenofovir disoproxil fumarate (TDF), a pharmacology researcher said.

An analysis of the pharmacologic profiles of TDF plus emtricitabine (FTC; Truvada and generic) with tenofovir alafenamide (TAF) plus FTC (Descovy) shows that the risk of decreased bone mineral density and renal toxicity with TDF are significantly lower than those of weight gain and related metabolic and cardiovascular problems associated with the newer tenofovir formulation TAF, according to pharmacology research fellow Andrew Hill, MD, PhD, from the University of Liverpool (England).

“I think when we’re comparing these two drugs overall, we have a clear benefit/risk, and we need to take both of these potential toxicities seriously, “ he said in an online presentation during IDWeek 2020, an annual scientific meeting on infectious diseases held virtually this year.

“But in my view, treating women – Black women – with TAF/FTC is a bad thing,” he continued. “I think it’s going lead to more harm, more myocardial infarctions, more cases of diabetes, and potentially more adverse birth outcomes, and I think that is a risk that is not worth taking, given that the apparent benefit in terms of bone mineral density and renal markers is a hypothesis at best, and is not translated into hard clinical endpoints.”
 

Adverse event profiles

Dr. Hill compared the side effect profiles of the two agents when used both in antiretroviral therapy (ART) in combination the integrase inhibitor dolutegravir (DTG; Tivicay), and in PrEP.

World Health Organization guidelines for first-line ART recommend the use of TDF/FTC/DTG, reserving TAF plus lamivudine (3TC) and DTG for use in special circumstances only, Dr. Hill noted.

He pointed to a pooled analysis of data from eight randomized, controlled trials of treatment-naive people living with HIV who started on ART from 2003 to 2015. The authors found that demographic factors associated with weight gain included lower CD4 cell counter, higher levels of HIV type 1 RNA, no injection drug use, female sex, and Black race.

They also found that, among nucleoside/nucleotide reverse transcriptase inhibitors, TAF was associated with more weight gain than TDF, abacavir, or zidovudine.

“This pattern is seen consistently across studies both of pre-exposure prophylaxis or treatment comparing tenofovir with either TAF or other nucleoside analogs,” he said.

The greater weight gain with TAF versus TDF was seen in both treatment trials and in the DISCOVER PrEP trial.

In addition, in a crossover trial conducted in Germany, patients who switched from TDF to TAF had an approximately 2 kg increase in body weight.

TAF has also been associated with higher grade 3 or 4 glucose and LDL cholesterol than TDF in clinical trials for the treatment of hepatitis B infections, and with higher LDL cholesterol and total cholesterol levels as well as diabetes in patients treated with the drugs in combination in the EMERALD HIV trial.

Clinical trials also tend to underestimate the real-world population of persons at highest risk for adverse events from TAF, Dr. Hill said, noting that the percentage of Black women in phase 3 trials for dolutegravir was 9%, compared with 42% among persons infected with HIV worldwide. The respective percentages for Black men are 16% versus 30%. These differences are similar across clinical trial programs for other ART agents.

“Generally, it’s women and Black people who seem to be at greatest risk for safety issues,” he said.

In the ADVANCE trial comparing TAF/FTC/DTG with TDF/FTC/DTG and a control arm of TDF, FTC and efavirenz, the mean change in weight among men after 3 years on the TAF-based regimen was a gain of 7.2 kg (15.9 lbs), compared with 5.5 kg (12 lbs) with TDF, and 2.6 kg (5.7 lbs) with the efavirenz-containing regimen.

In women enrolled in the same trial, the respective mean weight gains were 12.3 kg (27 lbs), 7.4 kg (16.3 lbs), and 5.5 kg (12 lbs).

“All of our analyses so far have shown that the weight continues to go up. We’re actually seeing people doubling in their body weight. We’ve seen some women come into clinic and their doctors don’t even recognize them because they’ve put on so much weight,” he said.

In women, most of the gain in weight occurs as limb or trunk fat, with a predominance of visceral fat.

People taking TAF in the trial were also at significantly greater risk for developing the metabolic syndrome, and at week 96, 27% of women on TAF/FTC/DTG had treatment-emergent obesity, compared with 17% for those on TDF/FTC/DTG and 11% for those on TDF/FTC/EFV. In men, the respective 96-week rates of treatment-emergent obesity were 7%, 3%, and 2%.

Clinical obesity itself is a risk factor for obstetric complications and birth outcomes, Alzheimer’s disease, type 2 diabetes, cardiovascular disease, hypertension and cancer, and an average 4-year reduction in life expectancy, Dr. Hill said. “I think it’s actually very unlikely that the [World Health Organization] guidelines will now change and allow the widespread use of TAF/FTC in combination with integrase inhibitors worldwide given these potential implications.”
 

Modern times

The bad rap that TDF gets for its alleged effects on bone mineral density and kidneys comes from studies where the drug was given in a boosted regimen that can amplify tenofovir toxicities, Dr. Hill said.

He noted that data from Gilead Sciences shows through 7 years of therapy in previously ART-naive patients, the combination of TDF/3TC/EFV showed sustained durable efficacy, no discontinuations to renal adverse effects, and no evidence of clinically relevant bone effects.

“I think we need to be very careful when we look at tenofovir and TAF. We need to look at the more modern way that these drugs are used, which is not with pharmacokinetic boosters anymore, and in that situation the toxicity profile of tenofovir/3TC – the original TDF – is very favorable,” he said.

Robert Goldstein, MD, PhD, an infectious disease specialist and medical director of the transgender health program at Massachusetts General Hospital in Boston, who comoderated the session where Dr. Hill presented his data, said that his clinical experience mirrors the pharmacokinetic findings.

“I certainly have strong feelings about the use of TDF in pre-exposure prophylaxis,” he said in an interview. “TDF is an effective and safe formulation of tenofovir to be used in pre-exposure prophylaxis, and one that we have more experience with. It’s the formulation of tenofovir that I use for all of my patients who are on pre-exposure prophylaxis, and I think it is the most cost-effective.’

No funding source was reported. Andrew Hill consults for Tibotec on clinical trial programs for darunavir, etravirine, and rilpivirine. Dr. Goldstein reported having no relevant disclosures.

A patient-centered approach can help guide persons at risk for HIV exposure to decide on the best choice of pre-exposure prophylaxis (PrEP) regimens for them, stifling the noise generated by direct-to-consumer advertising, an infectious disease specialist recommends.

The decision for patients whether to start or remain on the PrEP combination of tenofovir disoproxil fumarate (TDF) plus emtricitabine (FTC; Truvada and generic) or on tenofovir alafenamide (TAF) plus FTC (Descovy) is made more fraught by confusion regarding the use of the newer and allegedly safer TAF prodrug of tenofovir in HIV treatment regimens, said Oni Blackstock, MD, founder and executive director of Health Justice and an attending physician in the division of infectious diseases at Harlem Hospital, New York.

“There have been commercials on TV as well as on social media around class-action lawsuits against [Truvada maker] Gilead,” she said in an online presentation during IDWeek 2020, an annual scientific meeting on infectious diseases, held virtually this year.

“These lawsuits focus on TDF for HIV treatment, but they have sown a great deal of confusion about TDF versus TAF for PrEP among potential and actual PrEP users,” she added.

Dr. Blackstock described her approach to shared decision-making regarding TDF/FTC versus TAF/FTC, and to helping patients understand the relative benefits and risks of each formulation.

In January of 2020, Dr. Blackstock, who was then assistant commissioner of the HIV bureau of the New York City Department of Health and Mental Hygiene, issued with other Bureau members a “Dear colleague” letter stating why they believed that TDF/FTC should remain the first-line regimen for PrEP.

That opinion, she said, was bolstered by an editorial published in February 2020 by Douglas E. Krakower, MD, from Beth Israel Deaconess Medical Center in Boston, and colleagues, which questioned the rush to shift from TDF to TAF in HIV treatment, and cautioned against the same approach to PrEP.

“Despite evidence that TAF/FTC would not be cost-effective, compared with generic TDF/FTC , the newer regimen quickly and irrevocably displaced TDF/FTC for HIV treatment in the U.S. A similar shift for PrEP – especially for populations in which TAF/FTC is untested – would be premature, costly, and counterproductive for population impact,” Krakower et al. wrote.
 

Shared decision-making

Clinicians can help patients who may be a candidate for either PrEP regimen by engaging them in shared decision-making.

“The clinician provides information in this case about a prevention strategy, options, benefits and risks, alternatives, and the patient provides their preferences and values, and together the clinician and patient make a decision,” Dr. Blackstock said.

The process differs from the model of informed decision-making, where the clinician gives the patient the information and the patient comes to a decision, or the old, “paternalistic” model in which the clinician gives information and makes recommendations to the patient.

“Shared decision-making has been studied extensively and has been shown to improve patient satisfaction, patient communication, and also potentially reducing health inequities that we see,” she said.

The model for shared decision-making for clinical practice includes three distinct portions: a choice talk, option talk, and decision talk.
 

Choice

To begin the discussion, the physician informs the patients of the availability of choices and justifies them, saying, for example, “there is good information about how these two PrEP options differ that I’d like to discuss with you,” and “the two PrEP options have different side effects … some will matter more to you than other people.”

At this stage the clinician should defer closure by offering a more detailed discussion of the choices.
 

Option

Here the clinician solicits information about what the patient has heard or read about PrEP, describes each option in practical terms, and points out where the two regimens differ, being specific about the pros and cons of each (for example, potential bone mineral density loss or renal complications with TDF, and potential weight gain with subsequent metabolic and cardiovascular consequences with TAF).

The TDF versus TAF-based PrEP discussion could also focus on what’s known about the comparative effectiveness of each regimen.

For example, TDF/FTC has been shown to be about 99% effective at preventing infection in men who have sex with men and in transgender women, also about 99% effective in heterosexual women and men, and 74%-84% effective in persons who inject drugs.

In contrast, TAF/FTC has been shown to be about 99% effective in men who have sex with men and transgender women, but it’s efficacy in the other two categories is unknown, Dr. Blackstock said.

The option discussion should include a comparison of the evidence base for each regimen, including the real-world experience with TDF/FTC since 2012, and much more limited experience with TAF/FTC.

Discussing relative costs, although the wholesale costs of the regimens are similar, there is now a generic version of TDF/FTC made by Teva Pharmaceuticals that sells for about $400 less per month than the brand name, which might make the option more acceptable to health insurers.
 

Decision

The decision talk is about considering the patients preferences and deciding with them what is best.

The clinician could say, for example: “What, from your point of view, matters most to you?”

The clinician should also be willing to allow the patient to defer a decision or to guide them depending on their stated wish, asking something like: “Are you ready to decide, or do you want more time? Do you have more questions? Are there more things we should discuss?

Offering the patient a chance to review the decision can also be a good way to arrive at closure, Dr. Blackstock said.

Robert Goldstein, MD, PhD, an infectious disease specialist and medical director of the transgender health program at Massachusetts General Hospital in Boston, who comoderated the session where Dr. Blackstock presented her talk, said that he also uses a similar approach to the PrEP discussion.

“I use a very patient-centered approach of providing information and talking through the data that are available,” he said.

“I will say that, as patients come to me talking about the transition from TDF to TAF for pre-exposure prophylaxis, I am very clear with them about the limited benefit or no benefit that I see with TAF for pre-exposure prophylaxis, and all of my patients have remained on TDF for pre-exposure prophylaxis,” he added.

No funding source for the presentation was reported. Dr. Blackstock and Dr. Goldstein reported having no conflicts of interest to disclose.

A patient-centered approach can help guide persons at risk for HIV exposure to decide on the best choice of pre-exposure prophylaxis (PrEP) regimens for them, stifling the noise generated by direct-to-consumer advertising, an infectious disease specialist recommends.

The decision for patients whether to start or remain on the PrEP combination of tenofovir disoproxil fumarate (TDF) plus emtricitabine (FTC; Truvada and generic) or on tenofovir alafenamide (TAF) plus FTC (Descovy) is made more fraught by confusion regarding the use of the newer and allegedly safer TAF prodrug of tenofovir in HIV treatment regimens, said Oni Blackstock, MD, founder and executive director of Health Justice and an attending physician in the division of infectious diseases at Harlem Hospital, New York.

“There have been commercials on TV as well as on social media around class-action lawsuits against [Truvada maker] Gilead,” she said in an online presentation during IDWeek 2020, an annual scientific meeting on infectious diseases, held virtually this year.

“These lawsuits focus on TDF for HIV treatment, but they have sown a great deal of confusion about TDF versus TAF for PrEP among potential and actual PrEP users,” she added.

Dr. Blackstock described her approach to shared decision-making regarding TDF/FTC versus TAF/FTC, and to helping patients understand the relative benefits and risks of each formulation.

In January of 2020, Dr. Blackstock, who was then assistant commissioner of the HIV bureau of the New York City Department of Health and Mental Hygiene, issued with other Bureau members a “Dear colleague” letter stating why they believed that TDF/FTC should remain the first-line regimen for PrEP.

That opinion, she said, was bolstered by an editorial published in February 2020 by Douglas E. Krakower, MD, from Beth Israel Deaconess Medical Center in Boston, and colleagues, which questioned the rush to shift from TDF to TAF in HIV treatment, and cautioned against the same approach to PrEP.

“Despite evidence that TAF/FTC would not be cost-effective, compared with generic TDF/FTC , the newer regimen quickly and irrevocably displaced TDF/FTC for HIV treatment in the U.S. A similar shift for PrEP – especially for populations in which TAF/FTC is untested – would be premature, costly, and counterproductive for population impact,” Krakower et al. wrote.
 

Shared decision-making

Clinicians can help patients who may be a candidate for either PrEP regimen by engaging them in shared decision-making.

“The clinician provides information in this case about a prevention strategy, options, benefits and risks, alternatives, and the patient provides their preferences and values, and together the clinician and patient make a decision,” Dr. Blackstock said.

The process differs from the model of informed decision-making, where the clinician gives the patient the information and the patient comes to a decision, or the old, “paternalistic” model in which the clinician gives information and makes recommendations to the patient.

“Shared decision-making has been studied extensively and has been shown to improve patient satisfaction, patient communication, and also potentially reducing health inequities that we see,” she said.

The model for shared decision-making for clinical practice includes three distinct portions: a choice talk, option talk, and decision talk.
 

Choice

To begin the discussion, the physician informs the patients of the availability of choices and justifies them, saying, for example, “there is good information about how these two PrEP options differ that I’d like to discuss with you,” and “the two PrEP options have different side effects … some will matter more to you than other people.”

At this stage the clinician should defer closure by offering a more detailed discussion of the choices.
 

Option

Here the clinician solicits information about what the patient has heard or read about PrEP, describes each option in practical terms, and points out where the two regimens differ, being specific about the pros and cons of each (for example, potential bone mineral density loss or renal complications with TDF, and potential weight gain with subsequent metabolic and cardiovascular consequences with TAF).

The TDF versus TAF-based PrEP discussion could also focus on what’s known about the comparative effectiveness of each regimen.

For example, TDF/FTC has been shown to be about 99% effective at preventing infection in men who have sex with men and in transgender women, also about 99% effective in heterosexual women and men, and 74%-84% effective in persons who inject drugs.

In contrast, TAF/FTC has been shown to be about 99% effective in men who have sex with men and transgender women, but it’s efficacy in the other two categories is unknown, Dr. Blackstock said.

The option discussion should include a comparison of the evidence base for each regimen, including the real-world experience with TDF/FTC since 2012, and much more limited experience with TAF/FTC.

Discussing relative costs, although the wholesale costs of the regimens are similar, there is now a generic version of TDF/FTC made by Teva Pharmaceuticals that sells for about $400 less per month than the brand name, which might make the option more acceptable to health insurers.
 

Decision

The decision talk is about considering the patients preferences and deciding with them what is best.

The clinician could say, for example: “What, from your point of view, matters most to you?”

The clinician should also be willing to allow the patient to defer a decision or to guide them depending on their stated wish, asking something like: “Are you ready to decide, or do you want more time? Do you have more questions? Are there more things we should discuss?

Offering the patient a chance to review the decision can also be a good way to arrive at closure, Dr. Blackstock said.

Robert Goldstein, MD, PhD, an infectious disease specialist and medical director of the transgender health program at Massachusetts General Hospital in Boston, who comoderated the session where Dr. Blackstock presented her talk, said that he also uses a similar approach to the PrEP discussion.

“I use a very patient-centered approach of providing information and talking through the data that are available,” he said.

“I will say that, as patients come to me talking about the transition from TDF to TAF for pre-exposure prophylaxis, I am very clear with them about the limited benefit or no benefit that I see with TAF for pre-exposure prophylaxis, and all of my patients have remained on TDF for pre-exposure prophylaxis,” he added.

No funding source for the presentation was reported. Dr. Blackstock and Dr. Goldstein reported having no conflicts of interest to disclose.

A patient-centered approach can help guide persons at risk for HIV exposure to decide on the best choice of pre-exposure prophylaxis (PrEP) regimens for them, stifling the noise generated by direct-to-consumer advertising, an infectious disease specialist recommends.

The decision for patients whether to start or remain on the PrEP combination of tenofovir disoproxil fumarate (TDF) plus emtricitabine (FTC; Truvada and generic) or on tenofovir alafenamide (TAF) plus FTC (Descovy) is made more fraught by confusion regarding the use of the newer and allegedly safer TAF prodrug of tenofovir in HIV treatment regimens, said Oni Blackstock, MD, founder and executive director of Health Justice and an attending physician in the division of infectious diseases at Harlem Hospital, New York.

“There have been commercials on TV as well as on social media around class-action lawsuits against [Truvada maker] Gilead,” she said in an online presentation during IDWeek 2020, an annual scientific meeting on infectious diseases, held virtually this year.

“These lawsuits focus on TDF for HIV treatment, but they have sown a great deal of confusion about TDF versus TAF for PrEP among potential and actual PrEP users,” she added.

Dr. Blackstock described her approach to shared decision-making regarding TDF/FTC versus TAF/FTC, and to helping patients understand the relative benefits and risks of each formulation.

In January of 2020, Dr. Blackstock, who was then assistant commissioner of the HIV bureau of the New York City Department of Health and Mental Hygiene, issued with other Bureau members a “Dear colleague” letter stating why they believed that TDF/FTC should remain the first-line regimen for PrEP.

That opinion, she said, was bolstered by an editorial published in February 2020 by Douglas E. Krakower, MD, from Beth Israel Deaconess Medical Center in Boston, and colleagues, which questioned the rush to shift from TDF to TAF in HIV treatment, and cautioned against the same approach to PrEP.

“Despite evidence that TAF/FTC would not be cost-effective, compared with generic TDF/FTC , the newer regimen quickly and irrevocably displaced TDF/FTC for HIV treatment in the U.S. A similar shift for PrEP – especially for populations in which TAF/FTC is untested – would be premature, costly, and counterproductive for population impact,” Krakower et al. wrote.
 

Shared decision-making

Clinicians can help patients who may be a candidate for either PrEP regimen by engaging them in shared decision-making.

“The clinician provides information in this case about a prevention strategy, options, benefits and risks, alternatives, and the patient provides their preferences and values, and together the clinician and patient make a decision,” Dr. Blackstock said.

The process differs from the model of informed decision-making, where the clinician gives the patient the information and the patient comes to a decision, or the old, “paternalistic” model in which the clinician gives information and makes recommendations to the patient.

“Shared decision-making has been studied extensively and has been shown to improve patient satisfaction, patient communication, and also potentially reducing health inequities that we see,” she said.

The model for shared decision-making for clinical practice includes three distinct portions: a choice talk, option talk, and decision talk.
 

Choice

To begin the discussion, the physician informs the patients of the availability of choices and justifies them, saying, for example, “there is good information about how these two PrEP options differ that I’d like to discuss with you,” and “the two PrEP options have different side effects … some will matter more to you than other people.”

At this stage the clinician should defer closure by offering a more detailed discussion of the choices.
 

Option

Here the clinician solicits information about what the patient has heard or read about PrEP, describes each option in practical terms, and points out where the two regimens differ, being specific about the pros and cons of each (for example, potential bone mineral density loss or renal complications with TDF, and potential weight gain with subsequent metabolic and cardiovascular consequences with TAF).

The TDF versus TAF-based PrEP discussion could also focus on what’s known about the comparative effectiveness of each regimen.

For example, TDF/FTC has been shown to be about 99% effective at preventing infection in men who have sex with men and in transgender women, also about 99% effective in heterosexual women and men, and 74%-84% effective in persons who inject drugs.

In contrast, TAF/FTC has been shown to be about 99% effective in men who have sex with men and transgender women, but it’s efficacy in the other two categories is unknown, Dr. Blackstock said.

The option discussion should include a comparison of the evidence base for each regimen, including the real-world experience with TDF/FTC since 2012, and much more limited experience with TAF/FTC.

Discussing relative costs, although the wholesale costs of the regimens are similar, there is now a generic version of TDF/FTC made by Teva Pharmaceuticals that sells for about $400 less per month than the brand name, which might make the option more acceptable to health insurers.
 

Decision

The decision talk is about considering the patients preferences and deciding with them what is best.

The clinician could say, for example: “What, from your point of view, matters most to you?”

The clinician should also be willing to allow the patient to defer a decision or to guide them depending on their stated wish, asking something like: “Are you ready to decide, or do you want more time? Do you have more questions? Are there more things we should discuss?

Offering the patient a chance to review the decision can also be a good way to arrive at closure, Dr. Blackstock said.

Robert Goldstein, MD, PhD, an infectious disease specialist and medical director of the transgender health program at Massachusetts General Hospital in Boston, who comoderated the session where Dr. Blackstock presented her talk, said that he also uses a similar approach to the PrEP discussion.

“I use a very patient-centered approach of providing information and talking through the data that are available,” he said.

“I will say that, as patients come to me talking about the transition from TDF to TAF for pre-exposure prophylaxis, I am very clear with them about the limited benefit or no benefit that I see with TAF for pre-exposure prophylaxis, and all of my patients have remained on TDF for pre-exposure prophylaxis,” he added.

No funding source for the presentation was reported. Dr. Blackstock and Dr. Goldstein reported having no conflicts of interest to disclose.

It’s an electronic cigarette maker’s dream, but a public health nightmare: The confluence of social isolation and anxiety resulting from the COVID-19 pandemic has the potential to make recent progress against e-cigarette use among teens go up in smoke.

“Stress and worsening mental health issues are well-known predisposing factors for smoking, both in quantity and frequency and in relapse,” said Mary Cataletto, MD, FCCP, clinical professor of pediatrics at New York University Winthrop Hospital, Mineola, during a webinar on e-cigarettes and vaping with asthma in the time of COVID-19, hosted by the Allergy & Asthma Network.

Prior to the pandemic, public health experts appeared to be making inroads into curbing e-cigarette use, according to results of the 2020 National Youth Tobacco Survey, a cross-sectional school-based survey of students from grades 6 to 12.

“In 2020, approximately 1 in 5 high school stu­dents and 1 in 20 middle school students currently used e-cigarettes. By comparison, in 2019, 27.5% of high school students (4.11 million) and 10.5% of middle school students (1.24 million) reported current e-cigarette use,” wrote Brian A. King, PhD, MPH, and colleagues, in an article reporting those results.

“We definitely believe that there was a real decline that occurred up until March. Those data from the National Youth Tobacco Survey were collected prior to youth leaving school settings and prior to the implementation of social distancing and other measures,” said Dr. King, deputy director for research translation in the Office on Smoking and Health within the National Center for Chronic Disease Prevention and Health Promotion at the Centers for Disease Control and Prevention.

“That said, the jury’s still out on what’s going to happen with youth use during the coming year, particularly during the COVID-19 pandemic” he said in an interview.
 

Flavor of the moment

Even though the data through March 2020 showed a distinct decline in e-cigarette use, Dr. King and colleagues found that 3.6 million U.S. adolescents still currently used e-cigarettes in 2020; among current users, more than 80% reported using flavored e-cigarettes.

Dr. Cataletto said in an interview that the 2020 National Youth Tobacco Survey continues to report widespread use of flavored e-cigarettes among young smokers despite Food and Drug Administration admonitions to manufacturers and retailers to remove unauthorized e-cigarettes from the market.

On Jan. 2, 2020, the FDA reported a finalized enforcement policy directed against “unauthorized flavored cartridge-based e-cigarettes that appeal to children, including fruit and mint.”

But as Dr. King and other investigators also mentioned in a separate analysis of e-cigarette unit sales, that enforcement policy applies only to prefilled cartridge e-cigarette products, such as those made by JUUL, and that while sales of mint- or fruit-flavored products of this type declined from September 2014 to May 2020, there was an increase in the sale of disposable e-cigarettes with flavors other than menthol or tobacco.

Dr. Cataletto pointed out that this vaping trend has coincided with the COVID-19 pandemic, noting that, on March 13, 2020, just 2 days after the World Health Organization declared that spread of COVID-19 was officially a pandemic, 16 states closed schools, leaving millions of middle school– and high school–age children at loose ends. She said: “This raised a number of concerns. Would students who used e-cigarettes be at increased risk of COVID-19? Would e-cigarette use increase again due to the social isolation and anxiety as predicted for tobacco smokers? How would access and availability impact e-cigarette use?

“It’s possible that use may go down, because youth may have less access to their typical social sources or other manners in which they obtain the product.” Dr. King said. “Alternatively, youth may have more disposable time on their hands and may be open to other sources of access to these products, and so use could increase.”

There is evidence to suggest that the latter scenario may be true, according to investigators who surveyed more than 1,000 Canadian adolescents about alcohol use, binge drinking, cannabis use, and vaping in the 3 weeks directly before and after social distancing measures took effect.

The investigators found that the frequency of both alcohol and cannabis use increased during social isolation, and that, although about half of respondents reported solitary substance use, 32% reported using substances with peers via technology, and 24% reported using substances face to face, despite social distancing mandates, reported Tara M. Dumas, PhD, from Huron University College, London, Ont.

“These authors suggest that teens who feared loss of friendships during quarantine might be more willing to engage in risky behaviors such as face to face substance use to maintain social status, while solitary substance use was related to both COVID19 fears and depressive symptomatology,” Dr. Cataletto said.
 

E-cigarettes and COVID-19

A recent survey of 4,351 adolescents and young adults in the United States showed that a COVID-19 diagnosis was five times more likely among those who had ever used e-cigarettes, seven times more likely among conventional cigarette and e-cigarette uses, and nearly seven times more likely among those who had used both within the past 30 days .

Perhaps not surprisingly, adolescents and young adults with asthma who also vape may be at especially high risk for COVID-19, but the exact effect may be hard to pin down with current levels of evidence.

“Prior to the pandemic we did see both new-onset asthma and asthma exacerbations in teens who reported either vaping or dual use with tobacco products,” Dr. Cataletto said. “However, numbers were small, were confounded by the bias of subspecialty practice, and the onset of the pandemic, which affected not only face-to-face visits but the opportunity to perform pulmonary function testing for a number of months.”

Dr. King noted: “There is an emerging body of science that does indicate that there could be some respiratory risks related to e-cigarette use, particularly among certain populations. ... That said, there’s no conclusive link between e-cigarette use and specific disease outcomes, which typically requires a robust body of different science conducted in multiple settings.”

He said that e-cigarette vapors contain ultrafine particles and heavy metals that can be inhaled deeply into the lungs, both of which have previously been associated with respiratory risk, including complications from asthma.
 

An ounce of prevention

“When it comes to cessation, we do know that about 50% of youth who are using tobacco products including e-cigarettes, want to quit, and about the same proportion make an effort to quit, so there’s certainly a will there, but we don’t clearly have an evidence-based way,” Dr. King said.

Combinations of behavioral interventions including face-to-face consultations and digital or telephone support can be helpful, Dr. Cataletto said, but both she and Dr. King agree that prevention is the most effective method of reducing e-cigarette use among teens and young adults, including peer support and education efforts.

Asked how she gets her patients to report honestly about their habits, Dr. Cataletto acknowledged that “this is a challenge for many kids. Some are unaware that many of the commercially available e-cigarette products contain nicotine and they are not ‘just vaping flavoring.’ Ongoing education is important, and it is happening in schools, in pediatrician’s offices, at home and in the community.”

Dr. Cataletto and Dr. King reported no relevant conflicts of interest. Dr. Cataletto serves on the editorial advisory board for Chest Physician.

It’s an electronic cigarette maker’s dream, but a public health nightmare: The confluence of social isolation and anxiety resulting from the COVID-19 pandemic has the potential to make recent progress against e-cigarette use among teens go up in smoke.

“Stress and worsening mental health issues are well-known predisposing factors for smoking, both in quantity and frequency and in relapse,” said Mary Cataletto, MD, FCCP, clinical professor of pediatrics at New York University Winthrop Hospital, Mineola, during a webinar on e-cigarettes and vaping with asthma in the time of COVID-19, hosted by the Allergy & Asthma Network.

Prior to the pandemic, public health experts appeared to be making inroads into curbing e-cigarette use, according to results of the 2020 National Youth Tobacco Survey, a cross-sectional school-based survey of students from grades 6 to 12.

“In 2020, approximately 1 in 5 high school stu­dents and 1 in 20 middle school students currently used e-cigarettes. By comparison, in 2019, 27.5% of high school students (4.11 million) and 10.5% of middle school students (1.24 million) reported current e-cigarette use,” wrote Brian A. King, PhD, MPH, and colleagues, in an article reporting those results.

“We definitely believe that there was a real decline that occurred up until March. Those data from the National Youth Tobacco Survey were collected prior to youth leaving school settings and prior to the implementation of social distancing and other measures,” said Dr. King, deputy director for research translation in the Office on Smoking and Health within the National Center for Chronic Disease Prevention and Health Promotion at the Centers for Disease Control and Prevention.

“That said, the jury’s still out on what’s going to happen with youth use during the coming year, particularly during the COVID-19 pandemic” he said in an interview.
 

Flavor of the moment

Even though the data through March 2020 showed a distinct decline in e-cigarette use, Dr. King and colleagues found that 3.6 million U.S. adolescents still currently used e-cigarettes in 2020; among current users, more than 80% reported using flavored e-cigarettes.

Dr. Cataletto said in an interview that the 2020 National Youth Tobacco Survey continues to report widespread use of flavored e-cigarettes among young smokers despite Food and Drug Administration admonitions to manufacturers and retailers to remove unauthorized e-cigarettes from the market.

On Jan. 2, 2020, the FDA reported a finalized enforcement policy directed against “unauthorized flavored cartridge-based e-cigarettes that appeal to children, including fruit and mint.”

But as Dr. King and other investigators also mentioned in a separate analysis of e-cigarette unit sales, that enforcement policy applies only to prefilled cartridge e-cigarette products, such as those made by JUUL, and that while sales of mint- or fruit-flavored products of this type declined from September 2014 to May 2020, there was an increase in the sale of disposable e-cigarettes with flavors other than menthol or tobacco.

Dr. Cataletto pointed out that this vaping trend has coincided with the COVID-19 pandemic, noting that, on March 13, 2020, just 2 days after the World Health Organization declared that spread of COVID-19 was officially a pandemic, 16 states closed schools, leaving millions of middle school– and high school–age children at loose ends. She said: “This raised a number of concerns. Would students who used e-cigarettes be at increased risk of COVID-19? Would e-cigarette use increase again due to the social isolation and anxiety as predicted for tobacco smokers? How would access and availability impact e-cigarette use?

“It’s possible that use may go down, because youth may have less access to their typical social sources or other manners in which they obtain the product.” Dr. King said. “Alternatively, youth may have more disposable time on their hands and may be open to other sources of access to these products, and so use could increase.”

There is evidence to suggest that the latter scenario may be true, according to investigators who surveyed more than 1,000 Canadian adolescents about alcohol use, binge drinking, cannabis use, and vaping in the 3 weeks directly before and after social distancing measures took effect.

The investigators found that the frequency of both alcohol and cannabis use increased during social isolation, and that, although about half of respondents reported solitary substance use, 32% reported using substances with peers via technology, and 24% reported using substances face to face, despite social distancing mandates, reported Tara M. Dumas, PhD, from Huron University College, London, Ont.

“These authors suggest that teens who feared loss of friendships during quarantine might be more willing to engage in risky behaviors such as face to face substance use to maintain social status, while solitary substance use was related to both COVID19 fears and depressive symptomatology,” Dr. Cataletto said.
 

E-cigarettes and COVID-19

A recent survey of 4,351 adolescents and young adults in the United States showed that a COVID-19 diagnosis was five times more likely among those who had ever used e-cigarettes, seven times more likely among conventional cigarette and e-cigarette uses, and nearly seven times more likely among those who had used both within the past 30 days .

Perhaps not surprisingly, adolescents and young adults with asthma who also vape may be at especially high risk for COVID-19, but the exact effect may be hard to pin down with current levels of evidence.

“Prior to the pandemic we did see both new-onset asthma and asthma exacerbations in teens who reported either vaping or dual use with tobacco products,” Dr. Cataletto said. “However, numbers were small, were confounded by the bias of subspecialty practice, and the onset of the pandemic, which affected not only face-to-face visits but the opportunity to perform pulmonary function testing for a number of months.”

Dr. King noted: “There is an emerging body of science that does indicate that there could be some respiratory risks related to e-cigarette use, particularly among certain populations. ... That said, there’s no conclusive link between e-cigarette use and specific disease outcomes, which typically requires a robust body of different science conducted in multiple settings.”

He said that e-cigarette vapors contain ultrafine particles and heavy metals that can be inhaled deeply into the lungs, both of which have previously been associated with respiratory risk, including complications from asthma.
 

An ounce of prevention

“When it comes to cessation, we do know that about 50% of youth who are using tobacco products including e-cigarettes, want to quit, and about the same proportion make an effort to quit, so there’s certainly a will there, but we don’t clearly have an evidence-based way,” Dr. King said.

Combinations of behavioral interventions including face-to-face consultations and digital or telephone support can be helpful, Dr. Cataletto said, but both she and Dr. King agree that prevention is the most effective method of reducing e-cigarette use among teens and young adults, including peer support and education efforts.

Asked how she gets her patients to report honestly about their habits, Dr. Cataletto acknowledged that “this is a challenge for many kids. Some are unaware that many of the commercially available e-cigarette products contain nicotine and they are not ‘just vaping flavoring.’ Ongoing education is important, and it is happening in schools, in pediatrician’s offices, at home and in the community.”

Dr. Cataletto and Dr. King reported no relevant conflicts of interest. Dr. Cataletto serves on the editorial advisory board for Chest Physician.

It’s an electronic cigarette maker’s dream, but a public health nightmare: The confluence of social isolation and anxiety resulting from the COVID-19 pandemic has the potential to make recent progress against e-cigarette use among teens go up in smoke.

“Stress and worsening mental health issues are well-known predisposing factors for smoking, both in quantity and frequency and in relapse,” said Mary Cataletto, MD, FCCP, clinical professor of pediatrics at New York University Winthrop Hospital, Mineola, during a webinar on e-cigarettes and vaping with asthma in the time of COVID-19, hosted by the Allergy & Asthma Network.

Prior to the pandemic, public health experts appeared to be making inroads into curbing e-cigarette use, according to results of the 2020 National Youth Tobacco Survey, a cross-sectional school-based survey of students from grades 6 to 12.

“In 2020, approximately 1 in 5 high school stu­dents and 1 in 20 middle school students currently used e-cigarettes. By comparison, in 2019, 27.5% of high school students (4.11 million) and 10.5% of middle school students (1.24 million) reported current e-cigarette use,” wrote Brian A. King, PhD, MPH, and colleagues, in an article reporting those results.

“We definitely believe that there was a real decline that occurred up until March. Those data from the National Youth Tobacco Survey were collected prior to youth leaving school settings and prior to the implementation of social distancing and other measures,” said Dr. King, deputy director for research translation in the Office on Smoking and Health within the National Center for Chronic Disease Prevention and Health Promotion at the Centers for Disease Control and Prevention.

“That said, the jury’s still out on what’s going to happen with youth use during the coming year, particularly during the COVID-19 pandemic” he said in an interview.
 

Flavor of the moment

Even though the data through March 2020 showed a distinct decline in e-cigarette use, Dr. King and colleagues found that 3.6 million U.S. adolescents still currently used e-cigarettes in 2020; among current users, more than 80% reported using flavored e-cigarettes.

Dr. Cataletto said in an interview that the 2020 National Youth Tobacco Survey continues to report widespread use of flavored e-cigarettes among young smokers despite Food and Drug Administration admonitions to manufacturers and retailers to remove unauthorized e-cigarettes from the market.

On Jan. 2, 2020, the FDA reported a finalized enforcement policy directed against “unauthorized flavored cartridge-based e-cigarettes that appeal to children, including fruit and mint.”

But as Dr. King and other investigators also mentioned in a separate analysis of e-cigarette unit sales, that enforcement policy applies only to prefilled cartridge e-cigarette products, such as those made by JUUL, and that while sales of mint- or fruit-flavored products of this type declined from September 2014 to May 2020, there was an increase in the sale of disposable e-cigarettes with flavors other than menthol or tobacco.

Dr. Cataletto pointed out that this vaping trend has coincided with the COVID-19 pandemic, noting that, on March 13, 2020, just 2 days after the World Health Organization declared that spread of COVID-19 was officially a pandemic, 16 states closed schools, leaving millions of middle school– and high school–age children at loose ends. She said: “This raised a number of concerns. Would students who used e-cigarettes be at increased risk of COVID-19? Would e-cigarette use increase again due to the social isolation and anxiety as predicted for tobacco smokers? How would access and availability impact e-cigarette use?

“It’s possible that use may go down, because youth may have less access to their typical social sources or other manners in which they obtain the product.” Dr. King said. “Alternatively, youth may have more disposable time on their hands and may be open to other sources of access to these products, and so use could increase.”

There is evidence to suggest that the latter scenario may be true, according to investigators who surveyed more than 1,000 Canadian adolescents about alcohol use, binge drinking, cannabis use, and vaping in the 3 weeks directly before and after social distancing measures took effect.

The investigators found that the frequency of both alcohol and cannabis use increased during social isolation, and that, although about half of respondents reported solitary substance use, 32% reported using substances with peers via technology, and 24% reported using substances face to face, despite social distancing mandates, reported Tara M. Dumas, PhD, from Huron University College, London, Ont.

“These authors suggest that teens who feared loss of friendships during quarantine might be more willing to engage in risky behaviors such as face to face substance use to maintain social status, while solitary substance use was related to both COVID19 fears and depressive symptomatology,” Dr. Cataletto said.
 

E-cigarettes and COVID-19

A recent survey of 4,351 adolescents and young adults in the United States showed that a COVID-19 diagnosis was five times more likely among those who had ever used e-cigarettes, seven times more likely among conventional cigarette and e-cigarette uses, and nearly seven times more likely among those who had used both within the past 30 days .

Perhaps not surprisingly, adolescents and young adults with asthma who also vape may be at especially high risk for COVID-19, but the exact effect may be hard to pin down with current levels of evidence.

“Prior to the pandemic we did see both new-onset asthma and asthma exacerbations in teens who reported either vaping or dual use with tobacco products,” Dr. Cataletto said. “However, numbers were small, were confounded by the bias of subspecialty practice, and the onset of the pandemic, which affected not only face-to-face visits but the opportunity to perform pulmonary function testing for a number of months.”

Dr. King noted: “There is an emerging body of science that does indicate that there could be some respiratory risks related to e-cigarette use, particularly among certain populations. ... That said, there’s no conclusive link between e-cigarette use and specific disease outcomes, which typically requires a robust body of different science conducted in multiple settings.”

He said that e-cigarette vapors contain ultrafine particles and heavy metals that can be inhaled deeply into the lungs, both of which have previously been associated with respiratory risk, including complications from asthma.
 

An ounce of prevention

“When it comes to cessation, we do know that about 50% of youth who are using tobacco products including e-cigarettes, want to quit, and about the same proportion make an effort to quit, so there’s certainly a will there, but we don’t clearly have an evidence-based way,” Dr. King said.

Combinations of behavioral interventions including face-to-face consultations and digital or telephone support can be helpful, Dr. Cataletto said, but both she and Dr. King agree that prevention is the most effective method of reducing e-cigarette use among teens and young adults, including peer support and education efforts.

Asked how she gets her patients to report honestly about their habits, Dr. Cataletto acknowledged that “this is a challenge for many kids. Some are unaware that many of the commercially available e-cigarette products contain nicotine and they are not ‘just vaping flavoring.’ Ongoing education is important, and it is happening in schools, in pediatrician’s offices, at home and in the community.”

Dr. Cataletto and Dr. King reported no relevant conflicts of interest. Dr. Cataletto serves on the editorial advisory board for Chest Physician.

Switching patients with HIV from a protease inhibitor–based antiretroviral therapy regimen to an integrase inhibitor–based regimen can be performed safely, with maintenance of high levels of virologic suppression and improvements in both bone mineral density and renal function biomarkers, data from a randomized trial indicate.

Among 212 women with successful HIV virologic suppression following 48 weeks of treatment with ritonavir-boosted atazanavir plus tenofovir disoproxil fumarate (ATV/r +TDF), among those who were switched to continued therapy with an integrase inhibitor–based regimen of elvitegravir/cobicistat/emtricitabine and tenofovir alafenamide (E/C/F/TAF), mean increases in lumbar spine bone mineral density (BMD) were greater and renal function was improved compared with patients who were maintained with ATV/r + TDF, reported Monica Thormann, MD, from Salvador B. Gautier Hospital in Santo Domingo, Dominican Republic, and colleagues at the HIV Glasgow drug therapy meeting, which was held online in 2020.

Although the E/C/F/TAF regimen was associated with a significantly greater increase in lipids, there was no significant change in the total cholesterol to high-density lipoprotein (HDL) cholesterol ratio.

The patients in the study had previously participated in a blinded randomized trial comparing the integrase inhibitor combination plus TDF with ATV/r + TDF in treatment-naive women.

In the current study, patients were randomly assigned in a 3:1 ratio to maintenance with either E/C/F/TAF (159 patients) or ATV/r + TDF (53 patients).

Forty-eight weeks after the switch, virologic suppression (to fewer than 50 copies/mL) was maintained among 94.3% of those on the integrase inhibitor–based regimen, compared with 86.8% of those on the protease inhibitor–based regimen. Virologic failure was seen in 1.9% of those on the integrase inhibitor–based regimen and in 3.8% of those on the protease inhibitor–based regimen.

In addition, virologic suppression below 20 c/mL at week 48 was more common among women maintained on E/C/F/TAF, at 84.9% vs 71.7% (P = .041). No treatment-emergent resistance was seen with either regimen.

As noted, there were higher mean percentage increases in BMD in the E/C/F/TAF group for both total hip and lumbar spine, but only the latter measure improved significantly in comparison with patients treated with ATV/r + TDF (2.82% vs 0%, P < .001).

Markers of renal tubule damage, including the beta-2 microglobulin to creatinine ratio and the rentinol-binding protein to creatinine ratio, were significantly improved with the integrase inhibitor regimen.

Increases in total cholesterol, LDL cholesterol, and HDL cholesterol were 27 vs 5 mg/dL, 16 vs 8 mg/dL, and 5 vs 0 mg/dL in each case comparing the integrase inhibitor–based regimen to the protease inhibitor–based regimen. All of those comparisons were statistically significant.

As noted, however, the total cholesterol to HDL cholesterol ratio was not significantly different between the treatment arms. The rate or initiation of lipid-modifying agents was 1.3% in the E/C/F/TAF group vs 0 in the ATV/r + TDF group, but this difference was not statistically significant.

“These data demonstrate that women who switch to an integrase inhibitor + TAF‐based regimen maintain high levels of virologic suppression with improvement in BMD and renal function biomarkers, as compared with those remaining on their ritonavir boosted atazanavir + TDF‐based regimen,” the authors wrote.
 

This article first appeared on Medscape.com.

Switching patients with HIV from a protease inhibitor–based antiretroviral therapy regimen to an integrase inhibitor–based regimen can be performed safely, with maintenance of high levels of virologic suppression and improvements in both bone mineral density and renal function biomarkers, data from a randomized trial indicate.

Among 212 women with successful HIV virologic suppression following 48 weeks of treatment with ritonavir-boosted atazanavir plus tenofovir disoproxil fumarate (ATV/r +TDF), among those who were switched to continued therapy with an integrase inhibitor–based regimen of elvitegravir/cobicistat/emtricitabine and tenofovir alafenamide (E/C/F/TAF), mean increases in lumbar spine bone mineral density (BMD) were greater and renal function was improved compared with patients who were maintained with ATV/r + TDF, reported Monica Thormann, MD, from Salvador B. Gautier Hospital in Santo Domingo, Dominican Republic, and colleagues at the HIV Glasgow drug therapy meeting, which was held online in 2020.

Although the E/C/F/TAF regimen was associated with a significantly greater increase in lipids, there was no significant change in the total cholesterol to high-density lipoprotein (HDL) cholesterol ratio.

The patients in the study had previously participated in a blinded randomized trial comparing the integrase inhibitor combination plus TDF with ATV/r + TDF in treatment-naive women.

In the current study, patients were randomly assigned in a 3:1 ratio to maintenance with either E/C/F/TAF (159 patients) or ATV/r + TDF (53 patients).

Forty-eight weeks after the switch, virologic suppression (to fewer than 50 copies/mL) was maintained among 94.3% of those on the integrase inhibitor–based regimen, compared with 86.8% of those on the protease inhibitor–based regimen. Virologic failure was seen in 1.9% of those on the integrase inhibitor–based regimen and in 3.8% of those on the protease inhibitor–based regimen.

In addition, virologic suppression below 20 c/mL at week 48 was more common among women maintained on E/C/F/TAF, at 84.9% vs 71.7% (P = .041). No treatment-emergent resistance was seen with either regimen.

As noted, there were higher mean percentage increases in BMD in the E/C/F/TAF group for both total hip and lumbar spine, but only the latter measure improved significantly in comparison with patients treated with ATV/r + TDF (2.82% vs 0%, P < .001).

Markers of renal tubule damage, including the beta-2 microglobulin to creatinine ratio and the rentinol-binding protein to creatinine ratio, were significantly improved with the integrase inhibitor regimen.

Increases in total cholesterol, LDL cholesterol, and HDL cholesterol were 27 vs 5 mg/dL, 16 vs 8 mg/dL, and 5 vs 0 mg/dL in each case comparing the integrase inhibitor–based regimen to the protease inhibitor–based regimen. All of those comparisons were statistically significant.

As noted, however, the total cholesterol to HDL cholesterol ratio was not significantly different between the treatment arms. The rate or initiation of lipid-modifying agents was 1.3% in the E/C/F/TAF group vs 0 in the ATV/r + TDF group, but this difference was not statistically significant.

“These data demonstrate that women who switch to an integrase inhibitor + TAF‐based regimen maintain high levels of virologic suppression with improvement in BMD and renal function biomarkers, as compared with those remaining on their ritonavir boosted atazanavir + TDF‐based regimen,” the authors wrote.
 

This article first appeared on Medscape.com.

Switching patients with HIV from a protease inhibitor–based antiretroviral therapy regimen to an integrase inhibitor–based regimen can be performed safely, with maintenance of high levels of virologic suppression and improvements in both bone mineral density and renal function biomarkers, data from a randomized trial indicate.

Among 212 women with successful HIV virologic suppression following 48 weeks of treatment with ritonavir-boosted atazanavir plus tenofovir disoproxil fumarate (ATV/r +TDF), among those who were switched to continued therapy with an integrase inhibitor–based regimen of elvitegravir/cobicistat/emtricitabine and tenofovir alafenamide (E/C/F/TAF), mean increases in lumbar spine bone mineral density (BMD) were greater and renal function was improved compared with patients who were maintained with ATV/r + TDF, reported Monica Thormann, MD, from Salvador B. Gautier Hospital in Santo Domingo, Dominican Republic, and colleagues at the HIV Glasgow drug therapy meeting, which was held online in 2020.

Although the E/C/F/TAF regimen was associated with a significantly greater increase in lipids, there was no significant change in the total cholesterol to high-density lipoprotein (HDL) cholesterol ratio.

The patients in the study had previously participated in a blinded randomized trial comparing the integrase inhibitor combination plus TDF with ATV/r + TDF in treatment-naive women.

In the current study, patients were randomly assigned in a 3:1 ratio to maintenance with either E/C/F/TAF (159 patients) or ATV/r + TDF (53 patients).

Forty-eight weeks after the switch, virologic suppression (to fewer than 50 copies/mL) was maintained among 94.3% of those on the integrase inhibitor–based regimen, compared with 86.8% of those on the protease inhibitor–based regimen. Virologic failure was seen in 1.9% of those on the integrase inhibitor–based regimen and in 3.8% of those on the protease inhibitor–based regimen.

In addition, virologic suppression below 20 c/mL at week 48 was more common among women maintained on E/C/F/TAF, at 84.9% vs 71.7% (P = .041). No treatment-emergent resistance was seen with either regimen.

As noted, there were higher mean percentage increases in BMD in the E/C/F/TAF group for both total hip and lumbar spine, but only the latter measure improved significantly in comparison with patients treated with ATV/r + TDF (2.82% vs 0%, P < .001).

Markers of renal tubule damage, including the beta-2 microglobulin to creatinine ratio and the rentinol-binding protein to creatinine ratio, were significantly improved with the integrase inhibitor regimen.

Increases in total cholesterol, LDL cholesterol, and HDL cholesterol were 27 vs 5 mg/dL, 16 vs 8 mg/dL, and 5 vs 0 mg/dL in each case comparing the integrase inhibitor–based regimen to the protease inhibitor–based regimen. All of those comparisons were statistically significant.

As noted, however, the total cholesterol to HDL cholesterol ratio was not significantly different between the treatment arms. The rate or initiation of lipid-modifying agents was 1.3% in the E/C/F/TAF group vs 0 in the ATV/r + TDF group, but this difference was not statistically significant.

“These data demonstrate that women who switch to an integrase inhibitor + TAF‐based regimen maintain high levels of virologic suppression with improvement in BMD and renal function biomarkers, as compared with those remaining on their ritonavir boosted atazanavir + TDF‐based regimen,” the authors wrote.
 

This article first appeared on Medscape.com.

A comparison of U.S. and European treatment patterns for glioblastomas provides further evidence that adding systemic chemotherapy with temozolomide to radiotherapy offers a significant survival benefit over radiotherapy alone, and wider uptake of chemoradiation in Europe would extend the benefit to more patients.

That conclusion comes from a study of registry data from both sides of the Atlantic. The study showed a doubling in 2-year survival rates for patients with glioblastomas treated with radiotherapy plus chemotherapy compared with radiotherapy alone, a practice change that was prompted by a phase 3 trial published in The New England Journal of Medicine in 2005.

“Using population data from cancer registries, we observed a huge increase in radiotherapy plus chemotherapy between 1999 and 2013 in Europe and the U.S.,” said Francesco Giusti, PhD, of the European Commission Joint Research Center in Ispra, Italy.

“Data from 1999 to 2005 was already showing a clear survival advantage for patients treated with chemotherapy plus radiotherapy compared with radiotherapy alone,” he added.

However, when Dr. Giusti and colleagues compared practice patterns from before and after the publication of the practice-changing trial, they found that about 10% more patients in the United States were receiving combined chemotherapy and radiation, a difference reflected in superior survival rates in the U.S., he said.

Dr. Giusti presented these findings at the European Society for Medical Oncology Virtual Congress 2020.

He and his colleagues looked at data from cancer registries contributing to the European Cancer Information System and the U.S. National Cancer Institute’s Surveillance Epidemiology and End Results data.

The data set included patients diagnosed from 1999 through 2013 with glioblastoma as a first tumor.

During that time, results from the aforementioned phase 3 trial were published. They showed that, at a median follow-up of 28 months, the median survival was 14.6 months for the 287 patients assigned to radiotherapy plus temozolomide, compared with 12.1 months for the 286 patients randomized to radiotherapy alone.

The unadjusted hazard ratio for death in the combination therapy group was 0.63 (P < .001). The 2-year survival rate was 26.5% for chemoradiation and 10.4% for radiation alone.

Adding temozolomide to radiotherapy in the trial also appeared to be safe. The incidence of grade 3 or 4 hematologic adverse events was 7%.
 

Registry data study

To see how practice patterns changed in the United States and Europe after publication of the trial, Dr. Giusti and colleagues used registry data to calculate the proportion of cases by treatment type and overall survival during 1999-2005 (pre-study) and 2009-2013 (post-study).

The data included 34,229 cases from 11 countries in Europe and 36,925 cases from the United States.

The percentage of patients receiving both chemotherapy and radiation increased steadily over the study period. For example, among 18- to 49-year-olds, the percentage receiving the combined modalities in Europe increased from 20% in 1999-2001 to 70% in 2010-2013. In the United States, 40% of the same age group received combination therapy in 1999-2001, and this percentage grew to 80% in 2010-2013.

Overall survival rates in the general population were similar to those seen in the clinical trial during 1999-2005, when 2-year overall survival rates for patients treated with radiation alone were 11% in Europe and 12% in the United States. For patients treated with combined therapy, the respective 2-year survival rates in Europe and the United States were 24% and 25%.

“In the period after the trial, we observed a increasing 2-year survival rate to 28% in Europe and 29% in the U.S. for patients with radiotherapy plus chemotherapy,” Dr. Giusti said.
 

Real-world results

Invited discussant Matthias Preusser, MD, of the Medical University of Vienna in Austria, said the study shows that “population-based investigations are very valuable and should be further developed so that we can see how treatment patterns vary between countries and what the regional variations are, and whether new treatment standards actually reach clinical practice, and also to see whether there’s an effect on a population basis that is different from what is seen in controlled clinical trials.”

Dr. Preusser said it’s clear from the study that survival is increased with the addition of chemotherapy to radiotherapy, and more patients in the United States than in Europe received the combination during the study period.

Pointing to a treatment algorithm from the European Association of Neuro-oncology published in 2017, Dr. Preusser noted that radiotherapy alone may still be recommended for patients with unfavorable prognostic factors or patients 70 years and older with methylguanine-DNA methyltransferase promoter non-methylated tumors.

“It seems the differences in the age distribution between the U.S. and European populations that were analyzed could be one explanation why the radiochemotherapy combination was applied more often in the U.S. population,” Dr. Preusser said.

No outside funding was used to support the study. Dr. Giusti and coauthors reported having no conflicts of interest. Dr. Preusser disclosed relationships with multiple companies, including Merck, which markets temozolomide under the name Temodar.

SOURCE: Giusti F et al. ESMO 2020. Abstract 365MO.

A comparison of U.S. and European treatment patterns for glioblastomas provides further evidence that adding systemic chemotherapy with temozolomide to radiotherapy offers a significant survival benefit over radiotherapy alone, and wider uptake of chemoradiation in Europe would extend the benefit to more patients.

That conclusion comes from a study of registry data from both sides of the Atlantic. The study showed a doubling in 2-year survival rates for patients with glioblastomas treated with radiotherapy plus chemotherapy compared with radiotherapy alone, a practice change that was prompted by a phase 3 trial published in The New England Journal of Medicine in 2005.

“Using population data from cancer registries, we observed a huge increase in radiotherapy plus chemotherapy between 1999 and 2013 in Europe and the U.S.,” said Francesco Giusti, PhD, of the European Commission Joint Research Center in Ispra, Italy.

“Data from 1999 to 2005 was already showing a clear survival advantage for patients treated with chemotherapy plus radiotherapy compared with radiotherapy alone,” he added.

However, when Dr. Giusti and colleagues compared practice patterns from before and after the publication of the practice-changing trial, they found that about 10% more patients in the United States were receiving combined chemotherapy and radiation, a difference reflected in superior survival rates in the U.S., he said.

Dr. Giusti presented these findings at the European Society for Medical Oncology Virtual Congress 2020.

He and his colleagues looked at data from cancer registries contributing to the European Cancer Information System and the U.S. National Cancer Institute’s Surveillance Epidemiology and End Results data.

The data set included patients diagnosed from 1999 through 2013 with glioblastoma as a first tumor.

During that time, results from the aforementioned phase 3 trial were published. They showed that, at a median follow-up of 28 months, the median survival was 14.6 months for the 287 patients assigned to radiotherapy plus temozolomide, compared with 12.1 months for the 286 patients randomized to radiotherapy alone.

The unadjusted hazard ratio for death in the combination therapy group was 0.63 (P < .001). The 2-year survival rate was 26.5% for chemoradiation and 10.4% for radiation alone.

Adding temozolomide to radiotherapy in the trial also appeared to be safe. The incidence of grade 3 or 4 hematologic adverse events was 7%.
 

Registry data study

To see how practice patterns changed in the United States and Europe after publication of the trial, Dr. Giusti and colleagues used registry data to calculate the proportion of cases by treatment type and overall survival during 1999-2005 (pre-study) and 2009-2013 (post-study).

The data included 34,229 cases from 11 countries in Europe and 36,925 cases from the United States.

The percentage of patients receiving both chemotherapy and radiation increased steadily over the study period. For example, among 18- to 49-year-olds, the percentage receiving the combined modalities in Europe increased from 20% in 1999-2001 to 70% in 2010-2013. In the United States, 40% of the same age group received combination therapy in 1999-2001, and this percentage grew to 80% in 2010-2013.

Overall survival rates in the general population were similar to those seen in the clinical trial during 1999-2005, when 2-year overall survival rates for patients treated with radiation alone were 11% in Europe and 12% in the United States. For patients treated with combined therapy, the respective 2-year survival rates in Europe and the United States were 24% and 25%.

“In the period after the trial, we observed a increasing 2-year survival rate to 28% in Europe and 29% in the U.S. for patients with radiotherapy plus chemotherapy,” Dr. Giusti said.
 

Real-world results

Invited discussant Matthias Preusser, MD, of the Medical University of Vienna in Austria, said the study shows that “population-based investigations are very valuable and should be further developed so that we can see how treatment patterns vary between countries and what the regional variations are, and whether new treatment standards actually reach clinical practice, and also to see whether there’s an effect on a population basis that is different from what is seen in controlled clinical trials.”

Dr. Preusser said it’s clear from the study that survival is increased with the addition of chemotherapy to radiotherapy, and more patients in the United States than in Europe received the combination during the study period.

Pointing to a treatment algorithm from the European Association of Neuro-oncology published in 2017, Dr. Preusser noted that radiotherapy alone may still be recommended for patients with unfavorable prognostic factors or patients 70 years and older with methylguanine-DNA methyltransferase promoter non-methylated tumors.

“It seems the differences in the age distribution between the U.S. and European populations that were analyzed could be one explanation why the radiochemotherapy combination was applied more often in the U.S. population,” Dr. Preusser said.

No outside funding was used to support the study. Dr. Giusti and coauthors reported having no conflicts of interest. Dr. Preusser disclosed relationships with multiple companies, including Merck, which markets temozolomide under the name Temodar.

SOURCE: Giusti F et al. ESMO 2020. Abstract 365MO.

A comparison of U.S. and European treatment patterns for glioblastomas provides further evidence that adding systemic chemotherapy with temozolomide to radiotherapy offers a significant survival benefit over radiotherapy alone, and wider uptake of chemoradiation in Europe would extend the benefit to more patients.

That conclusion comes from a study of registry data from both sides of the Atlantic. The study showed a doubling in 2-year survival rates for patients with glioblastomas treated with radiotherapy plus chemotherapy compared with radiotherapy alone, a practice change that was prompted by a phase 3 trial published in The New England Journal of Medicine in 2005.

“Using population data from cancer registries, we observed a huge increase in radiotherapy plus chemotherapy between 1999 and 2013 in Europe and the U.S.,” said Francesco Giusti, PhD, of the European Commission Joint Research Center in Ispra, Italy.

“Data from 1999 to 2005 was already showing a clear survival advantage for patients treated with chemotherapy plus radiotherapy compared with radiotherapy alone,” he added.

However, when Dr. Giusti and colleagues compared practice patterns from before and after the publication of the practice-changing trial, they found that about 10% more patients in the United States were receiving combined chemotherapy and radiation, a difference reflected in superior survival rates in the U.S., he said.

Dr. Giusti presented these findings at the European Society for Medical Oncology Virtual Congress 2020.

He and his colleagues looked at data from cancer registries contributing to the European Cancer Information System and the U.S. National Cancer Institute’s Surveillance Epidemiology and End Results data.

The data set included patients diagnosed from 1999 through 2013 with glioblastoma as a first tumor.

During that time, results from the aforementioned phase 3 trial were published. They showed that, at a median follow-up of 28 months, the median survival was 14.6 months for the 287 patients assigned to radiotherapy plus temozolomide, compared with 12.1 months for the 286 patients randomized to radiotherapy alone.

The unadjusted hazard ratio for death in the combination therapy group was 0.63 (P < .001). The 2-year survival rate was 26.5% for chemoradiation and 10.4% for radiation alone.

Adding temozolomide to radiotherapy in the trial also appeared to be safe. The incidence of grade 3 or 4 hematologic adverse events was 7%.
 

Registry data study

To see how practice patterns changed in the United States and Europe after publication of the trial, Dr. Giusti and colleagues used registry data to calculate the proportion of cases by treatment type and overall survival during 1999-2005 (pre-study) and 2009-2013 (post-study).

The data included 34,229 cases from 11 countries in Europe and 36,925 cases from the United States.

The percentage of patients receiving both chemotherapy and radiation increased steadily over the study period. For example, among 18- to 49-year-olds, the percentage receiving the combined modalities in Europe increased from 20% in 1999-2001 to 70% in 2010-2013. In the United States, 40% of the same age group received combination therapy in 1999-2001, and this percentage grew to 80% in 2010-2013.

Overall survival rates in the general population were similar to those seen in the clinical trial during 1999-2005, when 2-year overall survival rates for patients treated with radiation alone were 11% in Europe and 12% in the United States. For patients treated with combined therapy, the respective 2-year survival rates in Europe and the United States were 24% and 25%.

“In the period after the trial, we observed a increasing 2-year survival rate to 28% in Europe and 29% in the U.S. for patients with radiotherapy plus chemotherapy,” Dr. Giusti said.
 

Real-world results

Invited discussant Matthias Preusser, MD, of the Medical University of Vienna in Austria, said the study shows that “population-based investigations are very valuable and should be further developed so that we can see how treatment patterns vary between countries and what the regional variations are, and whether new treatment standards actually reach clinical practice, and also to see whether there’s an effect on a population basis that is different from what is seen in controlled clinical trials.”

Dr. Preusser said it’s clear from the study that survival is increased with the addition of chemotherapy to radiotherapy, and more patients in the United States than in Europe received the combination during the study period.

Pointing to a treatment algorithm from the European Association of Neuro-oncology published in 2017, Dr. Preusser noted that radiotherapy alone may still be recommended for patients with unfavorable prognostic factors or patients 70 years and older with methylguanine-DNA methyltransferase promoter non-methylated tumors.

“It seems the differences in the age distribution between the U.S. and European populations that were analyzed could be one explanation why the radiochemotherapy combination was applied more often in the U.S. population,” Dr. Preusser said.

No outside funding was used to support the study. Dr. Giusti and coauthors reported having no conflicts of interest. Dr. Preusser disclosed relationships with multiple companies, including Merck, which markets temozolomide under the name Temodar.

SOURCE: Giusti F et al. ESMO 2020. Abstract 365MO.

Pembrolizumab (Keytruda) is already approved for use in the treatment of esophageal cancer, but in the second-line setting.

New results show that it also improves outcomes when used in the first-line setting, and the investigators suggest that pembrolizumab in combination with chemotherapy should be the new standard of care.

The results come from an interim analysis of the phase 3 KEYNOTE-590 trial, conducted with 740 patients who had advanced cancers of the esophagus or esophagogastric junction (EGJ). The patients were followed for a median of 10.8 months.

The findings show that the combination offered patients a modest but distinct survival benefit over chemotherapy alone.

Median overall survival (OS), one of two primary endpoints for the trial, was 12.4 months for pembrolizumab plus chemotherapy, compared with 9.8 months for patients who received chemotherapy plus placebo.

This difference translated into a hazard ratio (HR) for death with pembrolizumab of 0.73 (P < .0001), reported Peter Enzinger, MD, from the Dana-Farber Cancer Institute in Boston. Progression-free survival (PFS), the trial’s other primary endpoint, was superior with the combination, at a median of 6.3 months compared with 5.8 months for chemotherapy alone, translating into an HR for progression with pembrolizumab of 0.65 (P < .0001).

“Pembrolizumab plus chemotherapy should be a new standard of care as first-line therapy in patients with locally advanced unresectable or metastastic esophageal cancer, including the EGJ, regardless of the histology and biomarker status,” Enzinger concluded.

He was speaking at a press briefing prior to a presentation of the data in a presidential symposium at the European Society of Medical Oncology (ESMO) Virtual Congress 2020. (The data were presented in oral session by Ken Kato, MD, from the National Cancer Center Hospital in Tokyo, Japan.)
 

Little change in treatment

“Unfortunately, for esophageal cancer, the standard of care has remained relatively unchanged for a long period of time,” Enzinger said.

Standard first-line therapy for patients with advanced esophageal, EGJ, or gastric adenocarcinoma is primarily a chemotherapy doublet consisting of a fluoropyrimidine plus a platinum agent.

Pembrolizumab was previously shown to have some activity as monotherapy against advanced or metastatic esophageal cancer in the third line in the KEYNOTE-180 trial. It yielded an overall response rate (ORR) of 14%. A median duration of response was not reached among patients with esophageal squamous cell carcinoma (ESCC) and tumors with programmed cell death–ligand-1 (PD-L1) that had combined positive scores (CPSs) of 10 or higher.

Another previous trial, KEYNOTE-181, showed that pembrolizumab monotherapy in the second line was associated with an ORR of 22% vs 7% for chemotherapy and respective median OS of 10.3 vs 6.7 months. This trial led to US Food and Drug Administration approval of pembrolizumab for the treatment of patients with recurrent locally advanced or metastatic ESCC with PD-L1 CPS ≥10 who have experienced disease progression after at least one prior line of therapy.

The trial now being reported, KEYNOTE-590, assessed use of the drug in the first-line setting. It was designed to see whether combining standard-of-care chemotherapy with pembrolizumab would improve outcomes.
 

Study details

Patients were randomly assigned to receive chemotherapy with 5-fluorauracil (5-FU) 800 mg/m² intravenously on days 1–5 every 3 weeks for up to 35 cycles and cisplatin 80 mg/m² IV every 3 weeks for up to 6 cycles, plus either pembrolizumab 200 mg IV every 3 weeks for up to 35 cycles or saline placebo IV.

Rates of treatment-related adverse events of grade 3 or higher were similar between study arms, occurring in 71.9% with the combination and in 67.6% with chemotherapy alone. Adverse events leading to drug discontinuation occurred in 19.5% and 11.6%, respectively. Fatal adverse events occurred in 2.4% of patients who received the combination and in 1.4% of patients who received chemotherapy and placebo.

Immune-mediated adverse events of grade 3 or higher and infusion reactions occurred in 7% and 2.2% of patients, respectively.

Patient-reported quality of life was similar between the groups.
 

Mixed histologies muddy results

The improvement in OS was observed across all patient populations, including patients with ESCC, esophageal adenocarcinoma (EAC), and EGJ tumors, the researchers noted.

However, invited discussant Andres Cervantes, MD, PhD, from the University of Valencia, Spain, commented that ESCC and EAC have very different histologies and that including patients with both in a single trial can make the results very confusing.

He pointed out that, in the KEYNOTE-590 population, 73% of patients had ESCCs and 27% had EACs.

The OS improvement was seen regardless of PD-L1 expression, although the best results occurred in patients with high expression.

However, Cervantes noted that PD-L1 expression was not used as a stratification factor prior to randomization, even though it was included in the complex, step-wise statistical plan for the study.

Another expert, Salah-Eddin Al-Batran, MD, from the Krankenhaus Nordwest in Frankfurt, Germany, questioned the researchers’ recommendation that all patients with esophageal cancer receive this regimen, regardless of PD-L1 expression.

“We have to be sure that we do not inflate the results for the all-comers by the very responsive group of high [PD-L1] expressers,” he said at the press briefing.

He said the trial report also leaves open the question of efficacy in tumors with microsatellite instability and/or high tumor mutational burden.

“I think these questions have to be addressed to give us a clear picture of how to treat a patient sitting in front of us as doctors,” he said.

Also adding to the concerns about this trial is the fact that the “selected chemotherapy schedule is not much currently used as the standard of care,” said Cervantes, although he added that it “is acceptable for this protocol.”

Despite these caveats, the trial was clearly positive, Cervantes said. The greatest benefit appeared to accrue for patients with ESCC.

“The addition of pembrolizumab to platinum-based chemotherapy significantly increases response rate, PFS, and OS in patients with advanced esophageal carcinomas over chemotherapy alone,” he said, and therefore he agreed with the investigators that “this is a new standard of care.”

The study was funded by Merck Sharp & Dohme. Enzinger disclosed honoraria and advisory or consulting roles for Merck and others. Cervantes disclosed consulting or advising and research funding from Merck Serono and others. He is president-elect of ESMO. Al-Batran has disclosed no relevant financial relationships.
 

This story first appeared on Medscape.com.

Pembrolizumab (Keytruda) is already approved for use in the treatment of esophageal cancer, but in the second-line setting.

New results show that it also improves outcomes when used in the first-line setting, and the investigators suggest that pembrolizumab in combination with chemotherapy should be the new standard of care.

The results come from an interim analysis of the phase 3 KEYNOTE-590 trial, conducted with 740 patients who had advanced cancers of the esophagus or esophagogastric junction (EGJ). The patients were followed for a median of 10.8 months.

The findings show that the combination offered patients a modest but distinct survival benefit over chemotherapy alone.

Median overall survival (OS), one of two primary endpoints for the trial, was 12.4 months for pembrolizumab plus chemotherapy, compared with 9.8 months for patients who received chemotherapy plus placebo.

This difference translated into a hazard ratio (HR) for death with pembrolizumab of 0.73 (P < .0001), reported Peter Enzinger, MD, from the Dana-Farber Cancer Institute in Boston. Progression-free survival (PFS), the trial’s other primary endpoint, was superior with the combination, at a median of 6.3 months compared with 5.8 months for chemotherapy alone, translating into an HR for progression with pembrolizumab of 0.65 (P < .0001).

“Pembrolizumab plus chemotherapy should be a new standard of care as first-line therapy in patients with locally advanced unresectable or metastastic esophageal cancer, including the EGJ, regardless of the histology and biomarker status,” Enzinger concluded.

He was speaking at a press briefing prior to a presentation of the data in a presidential symposium at the European Society of Medical Oncology (ESMO) Virtual Congress 2020. (The data were presented in oral session by Ken Kato, MD, from the National Cancer Center Hospital in Tokyo, Japan.)
 

Little change in treatment

“Unfortunately, for esophageal cancer, the standard of care has remained relatively unchanged for a long period of time,” Enzinger said.

Standard first-line therapy for patients with advanced esophageal, EGJ, or gastric adenocarcinoma is primarily a chemotherapy doublet consisting of a fluoropyrimidine plus a platinum agent.

Pembrolizumab was previously shown to have some activity as monotherapy against advanced or metastatic esophageal cancer in the third line in the KEYNOTE-180 trial. It yielded an overall response rate (ORR) of 14%. A median duration of response was not reached among patients with esophageal squamous cell carcinoma (ESCC) and tumors with programmed cell death–ligand-1 (PD-L1) that had combined positive scores (CPSs) of 10 or higher.

Another previous trial, KEYNOTE-181, showed that pembrolizumab monotherapy in the second line was associated with an ORR of 22% vs 7% for chemotherapy and respective median OS of 10.3 vs 6.7 months. This trial led to US Food and Drug Administration approval of pembrolizumab for the treatment of patients with recurrent locally advanced or metastatic ESCC with PD-L1 CPS ≥10 who have experienced disease progression after at least one prior line of therapy.

The trial now being reported, KEYNOTE-590, assessed use of the drug in the first-line setting. It was designed to see whether combining standard-of-care chemotherapy with pembrolizumab would improve outcomes.
 

Study details

Patients were randomly assigned to receive chemotherapy with 5-fluorauracil (5-FU) 800 mg/m² intravenously on days 1–5 every 3 weeks for up to 35 cycles and cisplatin 80 mg/m² IV every 3 weeks for up to 6 cycles, plus either pembrolizumab 200 mg IV every 3 weeks for up to 35 cycles or saline placebo IV.

Rates of treatment-related adverse events of grade 3 or higher were similar between study arms, occurring in 71.9% with the combination and in 67.6% with chemotherapy alone. Adverse events leading to drug discontinuation occurred in 19.5% and 11.6%, respectively. Fatal adverse events occurred in 2.4% of patients who received the combination and in 1.4% of patients who received chemotherapy and placebo.

Immune-mediated adverse events of grade 3 or higher and infusion reactions occurred in 7% and 2.2% of patients, respectively.

Patient-reported quality of life was similar between the groups.
 

Mixed histologies muddy results

The improvement in OS was observed across all patient populations, including patients with ESCC, esophageal adenocarcinoma (EAC), and EGJ tumors, the researchers noted.

However, invited discussant Andres Cervantes, MD, PhD, from the University of Valencia, Spain, commented that ESCC and EAC have very different histologies and that including patients with both in a single trial can make the results very confusing.

He pointed out that, in the KEYNOTE-590 population, 73% of patients had ESCCs and 27% had EACs.

The OS improvement was seen regardless of PD-L1 expression, although the best results occurred in patients with high expression.

However, Cervantes noted that PD-L1 expression was not used as a stratification factor prior to randomization, even though it was included in the complex, step-wise statistical plan for the study.

Another expert, Salah-Eddin Al-Batran, MD, from the Krankenhaus Nordwest in Frankfurt, Germany, questioned the researchers’ recommendation that all patients with esophageal cancer receive this regimen, regardless of PD-L1 expression.

“We have to be sure that we do not inflate the results for the all-comers by the very responsive group of high [PD-L1] expressers,” he said at the press briefing.

He said the trial report also leaves open the question of efficacy in tumors with microsatellite instability and/or high tumor mutational burden.

“I think these questions have to be addressed to give us a clear picture of how to treat a patient sitting in front of us as doctors,” he said.

Also adding to the concerns about this trial is the fact that the “selected chemotherapy schedule is not much currently used as the standard of care,” said Cervantes, although he added that it “is acceptable for this protocol.”

Despite these caveats, the trial was clearly positive, Cervantes said. The greatest benefit appeared to accrue for patients with ESCC.

“The addition of pembrolizumab to platinum-based chemotherapy significantly increases response rate, PFS, and OS in patients with advanced esophageal carcinomas over chemotherapy alone,” he said, and therefore he agreed with the investigators that “this is a new standard of care.”

The study was funded by Merck Sharp & Dohme. Enzinger disclosed honoraria and advisory or consulting roles for Merck and others. Cervantes disclosed consulting or advising and research funding from Merck Serono and others. He is president-elect of ESMO. Al-Batran has disclosed no relevant financial relationships.
 

This story first appeared on Medscape.com.

Pembrolizumab (Keytruda) is already approved for use in the treatment of esophageal cancer, but in the second-line setting.

New results show that it also improves outcomes when used in the first-line setting, and the investigators suggest that pembrolizumab in combination with chemotherapy should be the new standard of care.

The results come from an interim analysis of the phase 3 KEYNOTE-590 trial, conducted with 740 patients who had advanced cancers of the esophagus or esophagogastric junction (EGJ). The patients were followed for a median of 10.8 months.

The findings show that the combination offered patients a modest but distinct survival benefit over chemotherapy alone.

Median overall survival (OS), one of two primary endpoints for the trial, was 12.4 months for pembrolizumab plus chemotherapy, compared with 9.8 months for patients who received chemotherapy plus placebo.

This difference translated into a hazard ratio (HR) for death with pembrolizumab of 0.73 (P < .0001), reported Peter Enzinger, MD, from the Dana-Farber Cancer Institute in Boston. Progression-free survival (PFS), the trial’s other primary endpoint, was superior with the combination, at a median of 6.3 months compared with 5.8 months for chemotherapy alone, translating into an HR for progression with pembrolizumab of 0.65 (P < .0001).

“Pembrolizumab plus chemotherapy should be a new standard of care as first-line therapy in patients with locally advanced unresectable or metastastic esophageal cancer, including the EGJ, regardless of the histology and biomarker status,” Enzinger concluded.

He was speaking at a press briefing prior to a presentation of the data in a presidential symposium at the European Society of Medical Oncology (ESMO) Virtual Congress 2020. (The data were presented in oral session by Ken Kato, MD, from the National Cancer Center Hospital in Tokyo, Japan.)
 

Little change in treatment

“Unfortunately, for esophageal cancer, the standard of care has remained relatively unchanged for a long period of time,” Enzinger said.

Standard first-line therapy for patients with advanced esophageal, EGJ, or gastric adenocarcinoma is primarily a chemotherapy doublet consisting of a fluoropyrimidine plus a platinum agent.

Pembrolizumab was previously shown to have some activity as monotherapy against advanced or metastatic esophageal cancer in the third line in the KEYNOTE-180 trial. It yielded an overall response rate (ORR) of 14%. A median duration of response was not reached among patients with esophageal squamous cell carcinoma (ESCC) and tumors with programmed cell death–ligand-1 (PD-L1) that had combined positive scores (CPSs) of 10 or higher.

Another previous trial, KEYNOTE-181, showed that pembrolizumab monotherapy in the second line was associated with an ORR of 22% vs 7% for chemotherapy and respective median OS of 10.3 vs 6.7 months. This trial led to US Food and Drug Administration approval of pembrolizumab for the treatment of patients with recurrent locally advanced or metastatic ESCC with PD-L1 CPS ≥10 who have experienced disease progression after at least one prior line of therapy.

The trial now being reported, KEYNOTE-590, assessed use of the drug in the first-line setting. It was designed to see whether combining standard-of-care chemotherapy with pembrolizumab would improve outcomes.
 

Study details

Patients were randomly assigned to receive chemotherapy with 5-fluorauracil (5-FU) 800 mg/m² intravenously on days 1–5 every 3 weeks for up to 35 cycles and cisplatin 80 mg/m² IV every 3 weeks for up to 6 cycles, plus either pembrolizumab 200 mg IV every 3 weeks for up to 35 cycles or saline placebo IV.

Rates of treatment-related adverse events of grade 3 or higher were similar between study arms, occurring in 71.9% with the combination and in 67.6% with chemotherapy alone. Adverse events leading to drug discontinuation occurred in 19.5% and 11.6%, respectively. Fatal adverse events occurred in 2.4% of patients who received the combination and in 1.4% of patients who received chemotherapy and placebo.

Immune-mediated adverse events of grade 3 or higher and infusion reactions occurred in 7% and 2.2% of patients, respectively.

Patient-reported quality of life was similar between the groups.
 

Mixed histologies muddy results

The improvement in OS was observed across all patient populations, including patients with ESCC, esophageal adenocarcinoma (EAC), and EGJ tumors, the researchers noted.

However, invited discussant Andres Cervantes, MD, PhD, from the University of Valencia, Spain, commented that ESCC and EAC have very different histologies and that including patients with both in a single trial can make the results very confusing.

He pointed out that, in the KEYNOTE-590 population, 73% of patients had ESCCs and 27% had EACs.

The OS improvement was seen regardless of PD-L1 expression, although the best results occurred in patients with high expression.

However, Cervantes noted that PD-L1 expression was not used as a stratification factor prior to randomization, even though it was included in the complex, step-wise statistical plan for the study.

Another expert, Salah-Eddin Al-Batran, MD, from the Krankenhaus Nordwest in Frankfurt, Germany, questioned the researchers’ recommendation that all patients with esophageal cancer receive this regimen, regardless of PD-L1 expression.

“We have to be sure that we do not inflate the results for the all-comers by the very responsive group of high [PD-L1] expressers,” he said at the press briefing.

He said the trial report also leaves open the question of efficacy in tumors with microsatellite instability and/or high tumor mutational burden.

“I think these questions have to be addressed to give us a clear picture of how to treat a patient sitting in front of us as doctors,” he said.

Also adding to the concerns about this trial is the fact that the “selected chemotherapy schedule is not much currently used as the standard of care,” said Cervantes, although he added that it “is acceptable for this protocol.”

Despite these caveats, the trial was clearly positive, Cervantes said. The greatest benefit appeared to accrue for patients with ESCC.

“The addition of pembrolizumab to platinum-based chemotherapy significantly increases response rate, PFS, and OS in patients with advanced esophageal carcinomas over chemotherapy alone,” he said, and therefore he agreed with the investigators that “this is a new standard of care.”

The study was funded by Merck Sharp & Dohme. Enzinger disclosed honoraria and advisory or consulting roles for Merck and others. Cervantes disclosed consulting or advising and research funding from Merck Serono and others. He is president-elect of ESMO. Al-Batran has disclosed no relevant financial relationships.
 

This story first appeared on Medscape.com.

KRAS, one of the most frequently mutated oncogenes in human cancer, has long been thought to be “undruggable,” but early results from a clinical trial of the experimental KRAS inhibitor sotorasib (Amgen) suggest that at least one KRAS mutation common in non–small cell lung cancers (NSCLC) has a soft underbelly.

In the phase 1 CodeBreaK 100 trial, sotorasib, an investigational first-in-class inhibitor of the KRAS p.G12C mutation, showed encouraging activity against advanced NSCLC and other solid tumors.

Among patients with NSCLC, 19 (32.2%) of 59 had a confirmed objective response to sotorasib monotherapy, and 52 (88.1%) had disease control, reported David S. Hong, MD, from the University of Texas MD Anderson Cancer Center, Houston.

“Sotorasib also demonstrated durable disease control in heavily pretreated patients with non–small cell lung cancer,” said Dr. Hong.

He presented secondary efficacy endpoint results from the trial in an online presentation during the European Society of Medical Oncology Virtual Congress 2020. The study was also published simultaneously online in the New England Journal of Medicine.

The trial met its primary endpoint of safety of sotorasib, with no dose-limiting toxicities or treatment-related fatal adverse events, and treatment-emergent grade 3 or higher adverse events occurring in less than 20% of patients.

“The safety profile is more favorable than that of other targeted agents, and I think the reason why you have a quite safe compound here is that sotorasib is very specific in its binding to KRAS G12C, and KRAS G12C is only present in the tumor,” coinvestigator Marwan G. Fakih, MD, a medical oncologist at City of Hope Comprehensive Cancer Center in Duarte, Calif., said in an interview. Fakih was co–lead author of the report in the New England Journal of Medicine.
 

A real “triumph”

Sotorasib is “a triumph of drug discovery,” commented Colin Lindsay, MD, from the University of Manchester (England), the invited discussant.

“We know that KRAS, over many years, over 3 decades, has been very difficult to target,” he said.

“The early development of KRAS G12C–targeted agents is just the beginning, lending hope that the ability to target not only other KRAS mutations but also other targets previously thought to be undruggable may be within reach,” write Patricia M. LoRusso, DO, from the Yale Cancer Center in New Haven, Conn., and Judith S. Sebolt-Leopold, PhD, from the University of Michigan Rogel Cancer Center, Ann Arbor, in an accompanying editorial.

The KRAS, which stands for Kristen rat sarcoma viral oncogene homologue, p.G12C mutation is a glycine-to-cysteine substitution that results in the oncogene being switched on in its active form. The mutation has been identified in approximately 13% of NSCLC tumors, in 1% to 7% of colorectal cancers, and in other solid tumors.

But the mutation has been considered too difficult to target because of KRAS’ strong binding affinity for guanosine triphosphate (GTP), an essential building block of RNA synthesis, and by a lack of accessible drug binding sites.

Sotorasib is a small-molecule, specific, and irreversible inhibitor of KRAS that interacts with a “pocket” on the gene’s surface that is present only in an inactive conformation of KRAS. The drug inhibits oncogenic signaling and tumorigenesis by preventing cycling of the oncogene into its active form, Dr. Fakih explained.
 

Study details

The CodeBreaK 100 investigators enrolled patients with 13 different locally advanced or metastatic solid tumor types, all bearing the KRAS p.G12C mutation.

The trial began with a dose-escalation phase, with two to four patients per cohort assigned to receive daily oral sotorasib at doses of 180, 360, 720, or 960 mg. The 960 mg dose was selected for expansion cohorts and for planned phase 2 studies, based on the safety profile and the lack of dose-limiting toxicities.

Hong and colleagues reported results for 129 patients treated in the dose-escalation and expansion cohorts, including 59 with NSCLC, 42 with colorectal cancer and 28 with other tumor types, but focused primarily on patients with NSCLC.

After a median follow-up of 11.7 months, 59 patients with NSCLC had been treated, 3 at the 180 mg dose, 16 at 360 mg, 6 at 720 mg, and 34 at 960 mg. At the time of data cutoff in June of this year, 14 patients were still on treatment and 45 had discontinued, either from disease progression (35 patients), death (5), patient request (4) or adverse events (1).

As noted, there were no dose-limiting toxicities or treatment-related fatalities reported.

Grade 3-4 treatment-related adverse events were reported in 18.6% of patients. The only grade 4 treatment-related event was diarrhea, in one patient. Grade 3 events included elevated liver transaminases in nine patients, increased alkaline phosphatase in two, anemia in one, and increased gamma-glutamyl transferase levels, decreased lymphocyte count, hepatitis, and hyponatremia in one patient each.

Dr. Fakih said that, given sotorasib’s high degree of specificity, it’s unclear what might be causing the observed adverse events.
 

Responses at all dose levels

The confirmed partial response rate was 32.2% for patients with NSCLC treated at all dose levels, and 35.3% for patients who received the 960 mg dose.

Among all NSCLC patients, and all treated at the highest 960-mg dose level, the stable disease rates were 55.9%. The respective disease control rates were 88.1% and 91.2%.

Tumor reductions occurred across all dose levels in patients with NSCLC. The median progression-free survival was 6.3 months.

Hong reported results for one patient, a 59-year-old man with the mutation who had experienced disease progression on five prior therapies including targeted agents, chemotherapy, and a checkpoint inhibitor, and had gamma-knife surgery for brain lesions.

This patient had a complete response in target lesions and a partial response overall, which included shrinkage of central nervous system metastases. He recently had progression in non-target lesions, after 1.5 years in response, Dr. Hong said.

The median duration of response was 10.9 months for patients with partial responses and 4 months for patients with stable disease.

Hong noted that response to sotorasib was seen across a range of co-mutational profiles, including several patients with four mutations in addition to KRAS p.G12C.
 

Other tumors, possible combinations

Among 42 patients with colorectal cancers bearing the KRAS p.G12C mutation, 3 (7.1%) had a partial response. There were also partial responses seen in one patient each with melanoma and with appendiceal, endometrial, and pancreatic tumors.

“Overall, the results of this trial are very encouraging, showing the first step in ‘drugging the undruggable,’ ” Dr. LoRusso and Dr. Sebolt-Leopold wrote in their editorial.

They suggested that therapy with sotorasib may be improved by combining it with other agents that could target resistance to KRAS inhibition.

“A recent study showed that KRAS G12C colorectal cancer cells have higher basal epidermal growth factor receptor (EGFR) activity than NSCLC cells, leading to a rapid rebound in mitogen-activated protein (MAP) kinase signaling and resistance to KRAS G12C inhibition,” the editorialists wrote. “This observation is consistent with the weaker observed clinical activity of sotorasib in patients with colorectal cancer, a problem that may be addressed by combining it with an EGFR inhibitor [e.g., cetuximab], as seen preclinically.”

“I think this drug is being positioned not only in refractory disease, but we’re hoping to see it move upfront in non–small cell lung cancer, and we’re hoping to improve its efficacy in colorectal cancer,” Dr. Fakih said in an interview.

The study was sponsored by Amgen and by grants from the National Institutes of Health. Dr. Hong disclosed research/grant funding and an advisory/consulting role with Amgen and others. Dr. Fakih disclosed a speaking engagement for Amgen and consulting for and grant support from others. Dr. Lindsay disclosed consulting for Amgen and institutional research funding from the company and others. Dr. LoRusso disclosed fees from multiple companies, not including Amgen. Dr. Sebolt-Leopold disclosed no relevant financial relationships.

This article first appeared on Medscape.com.

KRAS, one of the most frequently mutated oncogenes in human cancer, has long been thought to be “undruggable,” but early results from a clinical trial of the experimental KRAS inhibitor sotorasib (Amgen) suggest that at least one KRAS mutation common in non–small cell lung cancers (NSCLC) has a soft underbelly.

In the phase 1 CodeBreaK 100 trial, sotorasib, an investigational first-in-class inhibitor of the KRAS p.G12C mutation, showed encouraging activity against advanced NSCLC and other solid tumors.

Among patients with NSCLC, 19 (32.2%) of 59 had a confirmed objective response to sotorasib monotherapy, and 52 (88.1%) had disease control, reported David S. Hong, MD, from the University of Texas MD Anderson Cancer Center, Houston.

“Sotorasib also demonstrated durable disease control in heavily pretreated patients with non–small cell lung cancer,” said Dr. Hong.

He presented secondary efficacy endpoint results from the trial in an online presentation during the European Society of Medical Oncology Virtual Congress 2020. The study was also published simultaneously online in the New England Journal of Medicine.

The trial met its primary endpoint of safety of sotorasib, with no dose-limiting toxicities or treatment-related fatal adverse events, and treatment-emergent grade 3 or higher adverse events occurring in less than 20% of patients.

“The safety profile is more favorable than that of other targeted agents, and I think the reason why you have a quite safe compound here is that sotorasib is very specific in its binding to KRAS G12C, and KRAS G12C is only present in the tumor,” coinvestigator Marwan G. Fakih, MD, a medical oncologist at City of Hope Comprehensive Cancer Center in Duarte, Calif., said in an interview. Fakih was co–lead author of the report in the New England Journal of Medicine.
 

A real “triumph”

Sotorasib is “a triumph of drug discovery,” commented Colin Lindsay, MD, from the University of Manchester (England), the invited discussant.

“We know that KRAS, over many years, over 3 decades, has been very difficult to target,” he said.

“The early development of KRAS G12C–targeted agents is just the beginning, lending hope that the ability to target not only other KRAS mutations but also other targets previously thought to be undruggable may be within reach,” write Patricia M. LoRusso, DO, from the Yale Cancer Center in New Haven, Conn., and Judith S. Sebolt-Leopold, PhD, from the University of Michigan Rogel Cancer Center, Ann Arbor, in an accompanying editorial.

The KRAS, which stands for Kristen rat sarcoma viral oncogene homologue, p.G12C mutation is a glycine-to-cysteine substitution that results in the oncogene being switched on in its active form. The mutation has been identified in approximately 13% of NSCLC tumors, in 1% to 7% of colorectal cancers, and in other solid tumors.

But the mutation has been considered too difficult to target because of KRAS’ strong binding affinity for guanosine triphosphate (GTP), an essential building block of RNA synthesis, and by a lack of accessible drug binding sites.

Sotorasib is a small-molecule, specific, and irreversible inhibitor of KRAS that interacts with a “pocket” on the gene’s surface that is present only in an inactive conformation of KRAS. The drug inhibits oncogenic signaling and tumorigenesis by preventing cycling of the oncogene into its active form, Dr. Fakih explained.
 

Study details

The CodeBreaK 100 investigators enrolled patients with 13 different locally advanced or metastatic solid tumor types, all bearing the KRAS p.G12C mutation.

The trial began with a dose-escalation phase, with two to four patients per cohort assigned to receive daily oral sotorasib at doses of 180, 360, 720, or 960 mg. The 960 mg dose was selected for expansion cohorts and for planned phase 2 studies, based on the safety profile and the lack of dose-limiting toxicities.

Hong and colleagues reported results for 129 patients treated in the dose-escalation and expansion cohorts, including 59 with NSCLC, 42 with colorectal cancer and 28 with other tumor types, but focused primarily on patients with NSCLC.

After a median follow-up of 11.7 months, 59 patients with NSCLC had been treated, 3 at the 180 mg dose, 16 at 360 mg, 6 at 720 mg, and 34 at 960 mg. At the time of data cutoff in June of this year, 14 patients were still on treatment and 45 had discontinued, either from disease progression (35 patients), death (5), patient request (4) or adverse events (1).

As noted, there were no dose-limiting toxicities or treatment-related fatalities reported.

Grade 3-4 treatment-related adverse events were reported in 18.6% of patients. The only grade 4 treatment-related event was diarrhea, in one patient. Grade 3 events included elevated liver transaminases in nine patients, increased alkaline phosphatase in two, anemia in one, and increased gamma-glutamyl transferase levels, decreased lymphocyte count, hepatitis, and hyponatremia in one patient each.

Dr. Fakih said that, given sotorasib’s high degree of specificity, it’s unclear what might be causing the observed adverse events.
 

Responses at all dose levels

The confirmed partial response rate was 32.2% for patients with NSCLC treated at all dose levels, and 35.3% for patients who received the 960 mg dose.

Among all NSCLC patients, and all treated at the highest 960-mg dose level, the stable disease rates were 55.9%. The respective disease control rates were 88.1% and 91.2%.

Tumor reductions occurred across all dose levels in patients with NSCLC. The median progression-free survival was 6.3 months.

Hong reported results for one patient, a 59-year-old man with the mutation who had experienced disease progression on five prior therapies including targeted agents, chemotherapy, and a checkpoint inhibitor, and had gamma-knife surgery for brain lesions.

This patient had a complete response in target lesions and a partial response overall, which included shrinkage of central nervous system metastases. He recently had progression in non-target lesions, after 1.5 years in response, Dr. Hong said.

The median duration of response was 10.9 months for patients with partial responses and 4 months for patients with stable disease.

Hong noted that response to sotorasib was seen across a range of co-mutational profiles, including several patients with four mutations in addition to KRAS p.G12C.
 

Other tumors, possible combinations

Among 42 patients with colorectal cancers bearing the KRAS p.G12C mutation, 3 (7.1%) had a partial response. There were also partial responses seen in one patient each with melanoma and with appendiceal, endometrial, and pancreatic tumors.

“Overall, the results of this trial are very encouraging, showing the first step in ‘drugging the undruggable,’ ” Dr. LoRusso and Dr. Sebolt-Leopold wrote in their editorial.

They suggested that therapy with sotorasib may be improved by combining it with other agents that could target resistance to KRAS inhibition.

“A recent study showed that KRAS G12C colorectal cancer cells have higher basal epidermal growth factor receptor (EGFR) activity than NSCLC cells, leading to a rapid rebound in mitogen-activated protein (MAP) kinase signaling and resistance to KRAS G12C inhibition,” the editorialists wrote. “This observation is consistent with the weaker observed clinical activity of sotorasib in patients with colorectal cancer, a problem that may be addressed by combining it with an EGFR inhibitor [e.g., cetuximab], as seen preclinically.”

“I think this drug is being positioned not only in refractory disease, but we’re hoping to see it move upfront in non–small cell lung cancer, and we’re hoping to improve its efficacy in colorectal cancer,” Dr. Fakih said in an interview.

The study was sponsored by Amgen and by grants from the National Institutes of Health. Dr. Hong disclosed research/grant funding and an advisory/consulting role with Amgen and others. Dr. Fakih disclosed a speaking engagement for Amgen and consulting for and grant support from others. Dr. Lindsay disclosed consulting for Amgen and institutional research funding from the company and others. Dr. LoRusso disclosed fees from multiple companies, not including Amgen. Dr. Sebolt-Leopold disclosed no relevant financial relationships.

This article first appeared on Medscape.com.

KRAS, one of the most frequently mutated oncogenes in human cancer, has long been thought to be “undruggable,” but early results from a clinical trial of the experimental KRAS inhibitor sotorasib (Amgen) suggest that at least one KRAS mutation common in non–small cell lung cancers (NSCLC) has a soft underbelly.

In the phase 1 CodeBreaK 100 trial, sotorasib, an investigational first-in-class inhibitor of the KRAS p.G12C mutation, showed encouraging activity against advanced NSCLC and other solid tumors.

Among patients with NSCLC, 19 (32.2%) of 59 had a confirmed objective response to sotorasib monotherapy, and 52 (88.1%) had disease control, reported David S. Hong, MD, from the University of Texas MD Anderson Cancer Center, Houston.

“Sotorasib also demonstrated durable disease control in heavily pretreated patients with non–small cell lung cancer,” said Dr. Hong.

He presented secondary efficacy endpoint results from the trial in an online presentation during the European Society of Medical Oncology Virtual Congress 2020. The study was also published simultaneously online in the New England Journal of Medicine.

The trial met its primary endpoint of safety of sotorasib, with no dose-limiting toxicities or treatment-related fatal adverse events, and treatment-emergent grade 3 or higher adverse events occurring in less than 20% of patients.

“The safety profile is more favorable than that of other targeted agents, and I think the reason why you have a quite safe compound here is that sotorasib is very specific in its binding to KRAS G12C, and KRAS G12C is only present in the tumor,” coinvestigator Marwan G. Fakih, MD, a medical oncologist at City of Hope Comprehensive Cancer Center in Duarte, Calif., said in an interview. Fakih was co–lead author of the report in the New England Journal of Medicine.
 

A real “triumph”

Sotorasib is “a triumph of drug discovery,” commented Colin Lindsay, MD, from the University of Manchester (England), the invited discussant.

“We know that KRAS, over many years, over 3 decades, has been very difficult to target,” he said.

“The early development of KRAS G12C–targeted agents is just the beginning, lending hope that the ability to target not only other KRAS mutations but also other targets previously thought to be undruggable may be within reach,” write Patricia M. LoRusso, DO, from the Yale Cancer Center in New Haven, Conn., and Judith S. Sebolt-Leopold, PhD, from the University of Michigan Rogel Cancer Center, Ann Arbor, in an accompanying editorial.

The KRAS, which stands for Kristen rat sarcoma viral oncogene homologue, p.G12C mutation is a glycine-to-cysteine substitution that results in the oncogene being switched on in its active form. The mutation has been identified in approximately 13% of NSCLC tumors, in 1% to 7% of colorectal cancers, and in other solid tumors.

But the mutation has been considered too difficult to target because of KRAS’ strong binding affinity for guanosine triphosphate (GTP), an essential building block of RNA synthesis, and by a lack of accessible drug binding sites.

Sotorasib is a small-molecule, specific, and irreversible inhibitor of KRAS that interacts with a “pocket” on the gene’s surface that is present only in an inactive conformation of KRAS. The drug inhibits oncogenic signaling and tumorigenesis by preventing cycling of the oncogene into its active form, Dr. Fakih explained.
 

Study details

The CodeBreaK 100 investigators enrolled patients with 13 different locally advanced or metastatic solid tumor types, all bearing the KRAS p.G12C mutation.

The trial began with a dose-escalation phase, with two to four patients per cohort assigned to receive daily oral sotorasib at doses of 180, 360, 720, or 960 mg. The 960 mg dose was selected for expansion cohorts and for planned phase 2 studies, based on the safety profile and the lack of dose-limiting toxicities.

Hong and colleagues reported results for 129 patients treated in the dose-escalation and expansion cohorts, including 59 with NSCLC, 42 with colorectal cancer and 28 with other tumor types, but focused primarily on patients with NSCLC.

After a median follow-up of 11.7 months, 59 patients with NSCLC had been treated, 3 at the 180 mg dose, 16 at 360 mg, 6 at 720 mg, and 34 at 960 mg. At the time of data cutoff in June of this year, 14 patients were still on treatment and 45 had discontinued, either from disease progression (35 patients), death (5), patient request (4) or adverse events (1).

As noted, there were no dose-limiting toxicities or treatment-related fatalities reported.

Grade 3-4 treatment-related adverse events were reported in 18.6% of patients. The only grade 4 treatment-related event was diarrhea, in one patient. Grade 3 events included elevated liver transaminases in nine patients, increased alkaline phosphatase in two, anemia in one, and increased gamma-glutamyl transferase levels, decreased lymphocyte count, hepatitis, and hyponatremia in one patient each.

Dr. Fakih said that, given sotorasib’s high degree of specificity, it’s unclear what might be causing the observed adverse events.
 

Responses at all dose levels

The confirmed partial response rate was 32.2% for patients with NSCLC treated at all dose levels, and 35.3% for patients who received the 960 mg dose.

Among all NSCLC patients, and all treated at the highest 960-mg dose level, the stable disease rates were 55.9%. The respective disease control rates were 88.1% and 91.2%.

Tumor reductions occurred across all dose levels in patients with NSCLC. The median progression-free survival was 6.3 months.

Hong reported results for one patient, a 59-year-old man with the mutation who had experienced disease progression on five prior therapies including targeted agents, chemotherapy, and a checkpoint inhibitor, and had gamma-knife surgery for brain lesions.

This patient had a complete response in target lesions and a partial response overall, which included shrinkage of central nervous system metastases. He recently had progression in non-target lesions, after 1.5 years in response, Dr. Hong said.

The median duration of response was 10.9 months for patients with partial responses and 4 months for patients with stable disease.

Hong noted that response to sotorasib was seen across a range of co-mutational profiles, including several patients with four mutations in addition to KRAS p.G12C.
 

Other tumors, possible combinations

Among 42 patients with colorectal cancers bearing the KRAS p.G12C mutation, 3 (7.1%) had a partial response. There were also partial responses seen in one patient each with melanoma and with appendiceal, endometrial, and pancreatic tumors.

“Overall, the results of this trial are very encouraging, showing the first step in ‘drugging the undruggable,’ ” Dr. LoRusso and Dr. Sebolt-Leopold wrote in their editorial.

They suggested that therapy with sotorasib may be improved by combining it with other agents that could target resistance to KRAS inhibition.

“A recent study showed that KRAS G12C colorectal cancer cells have higher basal epidermal growth factor receptor (EGFR) activity than NSCLC cells, leading to a rapid rebound in mitogen-activated protein (MAP) kinase signaling and resistance to KRAS G12C inhibition,” the editorialists wrote. “This observation is consistent with the weaker observed clinical activity of sotorasib in patients with colorectal cancer, a problem that may be addressed by combining it with an EGFR inhibitor [e.g., cetuximab], as seen preclinically.”

“I think this drug is being positioned not only in refractory disease, but we’re hoping to see it move upfront in non–small cell lung cancer, and we’re hoping to improve its efficacy in colorectal cancer,” Dr. Fakih said in an interview.

The study was sponsored by Amgen and by grants from the National Institutes of Health. Dr. Hong disclosed research/grant funding and an advisory/consulting role with Amgen and others. Dr. Fakih disclosed a speaking engagement for Amgen and consulting for and grant support from others. Dr. Lindsay disclosed consulting for Amgen and institutional research funding from the company and others. Dr. LoRusso disclosed fees from multiple companies, not including Amgen. Dr. Sebolt-Leopold disclosed no relevant financial relationships.

This article first appeared on Medscape.com.