While stressing the urgent need to vaccinate the whole U.S. population, infectious disease experts and medical ethicists are raising questions about the clinical trials needed to answer important questions about the new COVID-19 vaccines.

In a statement released on Nov. 20, Barbara Alexander, MD, president of the Infectious Diseases Society of America (IDSA) and a professor at Duke University, Durham, N.C., commented on Pfizer and BioNTech’s application to the Food and Drug Administration for an emergency use authorization (EUA) for its COVID-19 vaccine. Besides emphasizing the need for a transparent review of the companies’ trial data prior to the FDA’s granting an EUA, she said, “If emergency use authorization is granted, clinical trials and data collection must continue.”

In an interview, Dr. Alexander said she is convinced that both Pfizer and Moderna, which is also expected to seek an EUA soon, will continue their clinical trials to monitor the long-term safety and efficacy of their vaccines.

“The EUA guidance for COVID vaccine authorization is very clear that clinical trials will move forward,” she said. “Any EUA request would have to include a strategy to ensure that the long-term safety and efficacy of a vaccine could be monitored. I see no evidence that either Pfizer or Moderna is not prepared to follow those regulations.”

Eventually, she added, the drug makers will have to seek full FDA approval to replace an EUA, which as its name signifies, is designed for public health emergencies. “The EUA is a tool to help us get the vaccine into circulation and have it start working as quickly as possible in the current health crisis,” she said. “But once the crisis is over, if the sponsors want to continue to market their vaccines, they have to go forward and get full approval.”

Medical ethicists, however, point out there may be ethical and practical dilemmas involved in continuing or initiating clinical trials once a vaccine has been approved for use even on an emergency basis.

In a commentary in Annals of Internal Medicine, Rafael Dal-Re, MD, PhD, Arthur L. Caplan, PhD, and two other ethicists stipulated that the pandemic requires early licensing and deployment of COVID-19 vaccines. Nevertheless, they noted, additional months of data are required to establish the long-term efficacy and safety of the vaccines. “Moreover, early deployment could interfere with the acquisition of long-term data,” both on these vaccines and on others coming through the pipeline, they wrote.

In countries where an approved vaccine is deployed, the ethicists noted, investigators must inform participants in an ongoing trial about the approved vaccine’s status and ask if they want to continue in the study. If enough participants decline, the trial might have to be terminated early. At that point, researchers may not have sufficient long-term data to identify late-term safety issues, determine how long efficacy lasts, determine whether waning immunity is associated with reduced levels of antibodies, or identify the level of neutralizing antibodies that correlates with immunity.

Moreover, they observed, long-term trials are especially important for vaccines that use mRNA technology, because less is known about them than about traditional kinds of vaccines.

The authors also pointed out that early licensing of any vaccine might make it harder to evaluate vaccines that haven’t yet been approved. “Once a vaccine is licensed, new placebo-controlled RCTs [randomized controlled trials] of other vaccines will not be acceptable ethically, and noninferiority RCTs will be the most likely alternative.

“The goal of noninferiority trials will be to demonstrate that the immune response (that is, neutralizing antibody titers or levels) of the candidate vaccine is not inferior to that of the approved vaccine within a prespecified margin, which the FDA has established as less than 10% for COVID-19 vaccines,” the authors noted. 
 

More data with more study designs

Dial Hewlett Jr., MD, medical director for disease control services, Westchester County Department of Health, White Plains, N.Y., said in an interview that the ethicists raise important issues that have been discussed in other forums, including a recent webinar of the National Academy of Medicine.

“As the authors point out, once you have a vaccine that has been shown to be effective and safe, it’s no longer ethical to enroll people in placebo trials,” he said.

Therefore, he said, Pfizer and Moderna will undoubtedly offer their vaccines to the people in their studies’ placebo groups after the vaccines receive an EUA. Then they will follow everyone who has been vaccinated for 2 years to determine long-term safety. Efficacy will also continue to be measured as an adjunct of safety, he said.

With regard to the difficulty of reconsenting individuals to enter a new clinical trial after a vaccine has been approved, he said, “I’d agree that trying to get all the same participants to come into another study would be a challenge. You can, however, design studies that will allow you to obtain the same information. You will have a large number of people out there who haven’t been vaccinated, and you can do single-arm longitudinal studies and measure a number of things in the individuals who are enrolled in those studies,” he said.

“You can look at the immunologic markers, both antibody and T-cell. You can follow these individuals longitudinally to see if they do develop disease over a period of time. If they do, you can determine what their levels of response were,” he added. “So there are opportunities to design studies that would give you some of the same information, although it would not be in the same population that was in the randomized trials.”

For newer vaccines that have yet to be tested, he said, developers can compare “historical controls” from the trials of approved vaccines, i.e., data from the unvaccinated participants in those studies, with the data from inoculating people with the novel agents. The historical data can be sex- and age-matched, among other things, to individuals in the new trials. Moreover, because the study protocols have been harmonized for all trials under Operation Warp Speed, it doesn’t matter what kind of vaccine they’re testing, he said.

It may be necessary to do additional studies to find out how long immunity lasts after people have been vaccinated, Dr. Hewlett pointed out.

“You may have a different trial design. You don’t need a control arm to determine how long immunity lasts. You’re just comparing the patients who were vaccinated to nothing,” he said. “So you could have a single-arm trial on a group of people who consent to be immunized and followed. You can see what their antibody levels are and other surrogate markers, and you can see when they might develop disease, if they do. You’d need a large sample, but you can do that.”

Dr. Hewlett noted that additional studies will be required to determine whether the new vaccines stop transmission of the coronavirus or just prevent symptoms of COVID-19. Until it’s established that a vaccine halts transmission or the country achieves herd immunity, he said, “we’ll still have to wear masks and take other precautions, because a significant portion of people will still be at risk.”
 

‘A lot of redundancy’

Dr. Alexander emphasized that any safety or efficacy issues with the first COVID-19 vaccines must be identified before the vaccine is offered to a large portion of the U.S. population.

“While the data from the Pfizer and Moderna trials are said to be favorable, we at IDSA want to make sure that whatever vaccine comes to market is safe,” she said. “Having an unsafe vaccine on the market would be worse than no vaccine, because you’re compromising the public confidence. We have to make sure the public trusts the process and that sufficient data have been evaluated to ensure the vaccine is safe and efficacious.

“I believe the FDA is being very careful and thoughtful in [its] response,” Dr. Alexander said. “They realize how important it is to get a vaccine and save lives. While they’re doing things differently and moving much faster than before, they’re still trying to be thoughtful and reasonable. They don’t seem to be putting people at risk or circumventing the regulatory standards.”

Moreover, she pointed out, the FDA’s Vaccines and Related Biological Products Advisory Committee, which is expected to meet on Dec. 10, will review the trial data before the agency grants an EUA to Pfizer or Moderna. Then the FDA will post the data publicly.

The next step is for the Advisory Committee on Immunization Practices of the Centers for Disease Control and Prevention to look at the data and decide who in the United States should receive the vaccine first, she pointed out. And both Pfizer and Moderna have shown their data to advisory panels of outside experts.

“There’s a lot of redundancy, and a lot of people are looking at the data,” Dr. Alexander said. “So I don’t think we’re cutting corners to get it out there more quickly.”

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

While stressing the urgent need to vaccinate the whole U.S. population, infectious disease experts and medical ethicists are raising questions about the clinical trials needed to answer important questions about the new COVID-19 vaccines.

In a statement released on Nov. 20, Barbara Alexander, MD, president of the Infectious Diseases Society of America (IDSA) and a professor at Duke University, Durham, N.C., commented on Pfizer and BioNTech’s application to the Food and Drug Administration for an emergency use authorization (EUA) for its COVID-19 vaccine. Besides emphasizing the need for a transparent review of the companies’ trial data prior to the FDA’s granting an EUA, she said, “If emergency use authorization is granted, clinical trials and data collection must continue.”

In an interview, Dr. Alexander said she is convinced that both Pfizer and Moderna, which is also expected to seek an EUA soon, will continue their clinical trials to monitor the long-term safety and efficacy of their vaccines.

“The EUA guidance for COVID vaccine authorization is very clear that clinical trials will move forward,” she said. “Any EUA request would have to include a strategy to ensure that the long-term safety and efficacy of a vaccine could be monitored. I see no evidence that either Pfizer or Moderna is not prepared to follow those regulations.”

Eventually, she added, the drug makers will have to seek full FDA approval to replace an EUA, which as its name signifies, is designed for public health emergencies. “The EUA is a tool to help us get the vaccine into circulation and have it start working as quickly as possible in the current health crisis,” she said. “But once the crisis is over, if the sponsors want to continue to market their vaccines, they have to go forward and get full approval.”

Medical ethicists, however, point out there may be ethical and practical dilemmas involved in continuing or initiating clinical trials once a vaccine has been approved for use even on an emergency basis.

In a commentary in Annals of Internal Medicine, Rafael Dal-Re, MD, PhD, Arthur L. Caplan, PhD, and two other ethicists stipulated that the pandemic requires early licensing and deployment of COVID-19 vaccines. Nevertheless, they noted, additional months of data are required to establish the long-term efficacy and safety of the vaccines. “Moreover, early deployment could interfere with the acquisition of long-term data,” both on these vaccines and on others coming through the pipeline, they wrote.

In countries where an approved vaccine is deployed, the ethicists noted, investigators must inform participants in an ongoing trial about the approved vaccine’s status and ask if they want to continue in the study. If enough participants decline, the trial might have to be terminated early. At that point, researchers may not have sufficient long-term data to identify late-term safety issues, determine how long efficacy lasts, determine whether waning immunity is associated with reduced levels of antibodies, or identify the level of neutralizing antibodies that correlates with immunity.

Moreover, they observed, long-term trials are especially important for vaccines that use mRNA technology, because less is known about them than about traditional kinds of vaccines.

The authors also pointed out that early licensing of any vaccine might make it harder to evaluate vaccines that haven’t yet been approved. “Once a vaccine is licensed, new placebo-controlled RCTs [randomized controlled trials] of other vaccines will not be acceptable ethically, and noninferiority RCTs will be the most likely alternative.

“The goal of noninferiority trials will be to demonstrate that the immune response (that is, neutralizing antibody titers or levels) of the candidate vaccine is not inferior to that of the approved vaccine within a prespecified margin, which the FDA has established as less than 10% for COVID-19 vaccines,” the authors noted. 
 

More data with more study designs

Dial Hewlett Jr., MD, medical director for disease control services, Westchester County Department of Health, White Plains, N.Y., said in an interview that the ethicists raise important issues that have been discussed in other forums, including a recent webinar of the National Academy of Medicine.

“As the authors point out, once you have a vaccine that has been shown to be effective and safe, it’s no longer ethical to enroll people in placebo trials,” he said.

Therefore, he said, Pfizer and Moderna will undoubtedly offer their vaccines to the people in their studies’ placebo groups after the vaccines receive an EUA. Then they will follow everyone who has been vaccinated for 2 years to determine long-term safety. Efficacy will also continue to be measured as an adjunct of safety, he said.

With regard to the difficulty of reconsenting individuals to enter a new clinical trial after a vaccine has been approved, he said, “I’d agree that trying to get all the same participants to come into another study would be a challenge. You can, however, design studies that will allow you to obtain the same information. You will have a large number of people out there who haven’t been vaccinated, and you can do single-arm longitudinal studies and measure a number of things in the individuals who are enrolled in those studies,” he said.

“You can look at the immunologic markers, both antibody and T-cell. You can follow these individuals longitudinally to see if they do develop disease over a period of time. If they do, you can determine what their levels of response were,” he added. “So there are opportunities to design studies that would give you some of the same information, although it would not be in the same population that was in the randomized trials.”

For newer vaccines that have yet to be tested, he said, developers can compare “historical controls” from the trials of approved vaccines, i.e., data from the unvaccinated participants in those studies, with the data from inoculating people with the novel agents. The historical data can be sex- and age-matched, among other things, to individuals in the new trials. Moreover, because the study protocols have been harmonized for all trials under Operation Warp Speed, it doesn’t matter what kind of vaccine they’re testing, he said.

It may be necessary to do additional studies to find out how long immunity lasts after people have been vaccinated, Dr. Hewlett pointed out.

“You may have a different trial design. You don’t need a control arm to determine how long immunity lasts. You’re just comparing the patients who were vaccinated to nothing,” he said. “So you could have a single-arm trial on a group of people who consent to be immunized and followed. You can see what their antibody levels are and other surrogate markers, and you can see when they might develop disease, if they do. You’d need a large sample, but you can do that.”

Dr. Hewlett noted that additional studies will be required to determine whether the new vaccines stop transmission of the coronavirus or just prevent symptoms of COVID-19. Until it’s established that a vaccine halts transmission or the country achieves herd immunity, he said, “we’ll still have to wear masks and take other precautions, because a significant portion of people will still be at risk.”
 

‘A lot of redundancy’

Dr. Alexander emphasized that any safety or efficacy issues with the first COVID-19 vaccines must be identified before the vaccine is offered to a large portion of the U.S. population.

“While the data from the Pfizer and Moderna trials are said to be favorable, we at IDSA want to make sure that whatever vaccine comes to market is safe,” she said. “Having an unsafe vaccine on the market would be worse than no vaccine, because you’re compromising the public confidence. We have to make sure the public trusts the process and that sufficient data have been evaluated to ensure the vaccine is safe and efficacious.

“I believe the FDA is being very careful and thoughtful in [its] response,” Dr. Alexander said. “They realize how important it is to get a vaccine and save lives. While they’re doing things differently and moving much faster than before, they’re still trying to be thoughtful and reasonable. They don’t seem to be putting people at risk or circumventing the regulatory standards.”

Moreover, she pointed out, the FDA’s Vaccines and Related Biological Products Advisory Committee, which is expected to meet on Dec. 10, will review the trial data before the agency grants an EUA to Pfizer or Moderna. Then the FDA will post the data publicly.

The next step is for the Advisory Committee on Immunization Practices of the Centers for Disease Control and Prevention to look at the data and decide who in the United States should receive the vaccine first, she pointed out. And both Pfizer and Moderna have shown their data to advisory panels of outside experts.

“There’s a lot of redundancy, and a lot of people are looking at the data,” Dr. Alexander said. “So I don’t think we’re cutting corners to get it out there more quickly.”

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

While stressing the urgent need to vaccinate the whole U.S. population, infectious disease experts and medical ethicists are raising questions about the clinical trials needed to answer important questions about the new COVID-19 vaccines.

In a statement released on Nov. 20, Barbara Alexander, MD, president of the Infectious Diseases Society of America (IDSA) and a professor at Duke University, Durham, N.C., commented on Pfizer and BioNTech’s application to the Food and Drug Administration for an emergency use authorization (EUA) for its COVID-19 vaccine. Besides emphasizing the need for a transparent review of the companies’ trial data prior to the FDA’s granting an EUA, she said, “If emergency use authorization is granted, clinical trials and data collection must continue.”

In an interview, Dr. Alexander said she is convinced that both Pfizer and Moderna, which is also expected to seek an EUA soon, will continue their clinical trials to monitor the long-term safety and efficacy of their vaccines.

“The EUA guidance for COVID vaccine authorization is very clear that clinical trials will move forward,” she said. “Any EUA request would have to include a strategy to ensure that the long-term safety and efficacy of a vaccine could be monitored. I see no evidence that either Pfizer or Moderna is not prepared to follow those regulations.”

Eventually, she added, the drug makers will have to seek full FDA approval to replace an EUA, which as its name signifies, is designed for public health emergencies. “The EUA is a tool to help us get the vaccine into circulation and have it start working as quickly as possible in the current health crisis,” she said. “But once the crisis is over, if the sponsors want to continue to market their vaccines, they have to go forward and get full approval.”

Medical ethicists, however, point out there may be ethical and practical dilemmas involved in continuing or initiating clinical trials once a vaccine has been approved for use even on an emergency basis.

In a commentary in Annals of Internal Medicine, Rafael Dal-Re, MD, PhD, Arthur L. Caplan, PhD, and two other ethicists stipulated that the pandemic requires early licensing and deployment of COVID-19 vaccines. Nevertheless, they noted, additional months of data are required to establish the long-term efficacy and safety of the vaccines. “Moreover, early deployment could interfere with the acquisition of long-term data,” both on these vaccines and on others coming through the pipeline, they wrote.

In countries where an approved vaccine is deployed, the ethicists noted, investigators must inform participants in an ongoing trial about the approved vaccine’s status and ask if they want to continue in the study. If enough participants decline, the trial might have to be terminated early. At that point, researchers may not have sufficient long-term data to identify late-term safety issues, determine how long efficacy lasts, determine whether waning immunity is associated with reduced levels of antibodies, or identify the level of neutralizing antibodies that correlates with immunity.

Moreover, they observed, long-term trials are especially important for vaccines that use mRNA technology, because less is known about them than about traditional kinds of vaccines.

The authors also pointed out that early licensing of any vaccine might make it harder to evaluate vaccines that haven’t yet been approved. “Once a vaccine is licensed, new placebo-controlled RCTs [randomized controlled trials] of other vaccines will not be acceptable ethically, and noninferiority RCTs will be the most likely alternative.

“The goal of noninferiority trials will be to demonstrate that the immune response (that is, neutralizing antibody titers or levels) of the candidate vaccine is not inferior to that of the approved vaccine within a prespecified margin, which the FDA has established as less than 10% for COVID-19 vaccines,” the authors noted. 
 

More data with more study designs

Dial Hewlett Jr., MD, medical director for disease control services, Westchester County Department of Health, White Plains, N.Y., said in an interview that the ethicists raise important issues that have been discussed in other forums, including a recent webinar of the National Academy of Medicine.

“As the authors point out, once you have a vaccine that has been shown to be effective and safe, it’s no longer ethical to enroll people in placebo trials,” he said.

Therefore, he said, Pfizer and Moderna will undoubtedly offer their vaccines to the people in their studies’ placebo groups after the vaccines receive an EUA. Then they will follow everyone who has been vaccinated for 2 years to determine long-term safety. Efficacy will also continue to be measured as an adjunct of safety, he said.

With regard to the difficulty of reconsenting individuals to enter a new clinical trial after a vaccine has been approved, he said, “I’d agree that trying to get all the same participants to come into another study would be a challenge. You can, however, design studies that will allow you to obtain the same information. You will have a large number of people out there who haven’t been vaccinated, and you can do single-arm longitudinal studies and measure a number of things in the individuals who are enrolled in those studies,” he said.

“You can look at the immunologic markers, both antibody and T-cell. You can follow these individuals longitudinally to see if they do develop disease over a period of time. If they do, you can determine what their levels of response were,” he added. “So there are opportunities to design studies that would give you some of the same information, although it would not be in the same population that was in the randomized trials.”

For newer vaccines that have yet to be tested, he said, developers can compare “historical controls” from the trials of approved vaccines, i.e., data from the unvaccinated participants in those studies, with the data from inoculating people with the novel agents. The historical data can be sex- and age-matched, among other things, to individuals in the new trials. Moreover, because the study protocols have been harmonized for all trials under Operation Warp Speed, it doesn’t matter what kind of vaccine they’re testing, he said.

It may be necessary to do additional studies to find out how long immunity lasts after people have been vaccinated, Dr. Hewlett pointed out.

“You may have a different trial design. You don’t need a control arm to determine how long immunity lasts. You’re just comparing the patients who were vaccinated to nothing,” he said. “So you could have a single-arm trial on a group of people who consent to be immunized and followed. You can see what their antibody levels are and other surrogate markers, and you can see when they might develop disease, if they do. You’d need a large sample, but you can do that.”

Dr. Hewlett noted that additional studies will be required to determine whether the new vaccines stop transmission of the coronavirus or just prevent symptoms of COVID-19. Until it’s established that a vaccine halts transmission or the country achieves herd immunity, he said, “we’ll still have to wear masks and take other precautions, because a significant portion of people will still be at risk.”
 

‘A lot of redundancy’

Dr. Alexander emphasized that any safety or efficacy issues with the first COVID-19 vaccines must be identified before the vaccine is offered to a large portion of the U.S. population.

“While the data from the Pfizer and Moderna trials are said to be favorable, we at IDSA want to make sure that whatever vaccine comes to market is safe,” she said. “Having an unsafe vaccine on the market would be worse than no vaccine, because you’re compromising the public confidence. We have to make sure the public trusts the process and that sufficient data have been evaluated to ensure the vaccine is safe and efficacious.

“I believe the FDA is being very careful and thoughtful in [its] response,” Dr. Alexander said. “They realize how important it is to get a vaccine and save lives. While they’re doing things differently and moving much faster than before, they’re still trying to be thoughtful and reasonable. They don’t seem to be putting people at risk or circumventing the regulatory standards.”

Moreover, she pointed out, the FDA’s Vaccines and Related Biological Products Advisory Committee, which is expected to meet on Dec. 10, will review the trial data before the agency grants an EUA to Pfizer or Moderna. Then the FDA will post the data publicly.

The next step is for the Advisory Committee on Immunization Practices of the Centers for Disease Control and Prevention to look at the data and decide who in the United States should receive the vaccine first, she pointed out. And both Pfizer and Moderna have shown their data to advisory panels of outside experts.

“There’s a lot of redundancy, and a lot of people are looking at the data,” Dr. Alexander said. “So I don’t think we’re cutting corners to get it out there more quickly.”

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

Big changes are coming in the use of oral apremilast, currently approved for moderate to severe psoriasis and plaque psoriasis in adults, Bruce E. Strober, MD, PhD, predicted at MedscapeLive’s annual Las Vegas Dermatology Seminar, held virtually this year.

“We’ll have a pediatric indication for apremilast in psoriasis down the line, and probably a mild to moderate indication for psoriasis, meaning we can use this drug in patients in whom we typically think about using only topical therapies. Keep on the lookout: I think the mild to moderate indication may be coming next year, and that’s going to really shake up the whole landscape of psoriasis therapy,” said Dr. Strober, a dermatologist at Yale University in New Haven, Conn., and Central Connecticut Dermatology in Cromwell, Conn.
 

Mild or moderate psoriasis

Apremilast manufacturer Amgen has announced positive topline results from the phase 3 ADVANCE trial, a multicenter, placebo-controlled, double-blind, study of 595 patients with mild or moderate psoriasis as defined by an involved body surface area of 2%-15% and a Psoriasis Area and Severity Index score of 2-15. Participants were randomized to the approved dose of apremilast (Otezla) – 30 mg twice daily – or placebo for 16 weeks, followed by 16 weeks of open-label apremilast for all. The full study findings haven’t yet been published or presented at a medical conference, but Amgen announced that the results were positive for all primary and secondary endpoints, and the company plans to file a request with the Food and Drug Administration for an expanded indication for the oral agent.

Pediatric studies

A recently published phase 2, open-label, 1-year study of apremilast in 42 children and adolescents with moderate to severe plaque psoriasis demonstrated that weight-based dosing is the best approach in the pediatric population. The study, which serves as the template for coming phase 3 trials, showed that dosing apremilast at 20 mg twice daily in youths weighing not more than 35 kg and 30 mg twice daily in those who weighed more provided pharmacokinetic exposure similar to that achieved with apremilast at the standard adult dose of 30 mg twice daily. Most participants liked the taste of the tablet.

“My prediction is apremilast will have efficacy in children and teenagers comparable to what it has in adults, with a similar safety and adverse event profile,” Dr. Strober said.

Apremilast works by blocking phosphodiesterase type 4, thereby reducing cyclic AMP metabolism, with a resultant increase in cyclic AMP levels. Cyclic AMP is a regulator of inflammation. Boosting its level has the effect of decreasing tumor necrosis factor and other proinflammatory cytokines while increasing anti-inflammatory mediators, such as interleukin-10.

Dr. Strober characterized apremilast’s efficacy as “modest” by contemporary standards in adults with moderate to severe psoriasis, with week 16 PASI 75 rates of about 30% in randomized trials, compared with 5% in placebo-treated controls. He considers it a good option in patients with moderate disease who are needle phobic and in those averse to the inconvenience of laboratory monitoring. The drug is useful in treating psoriasis in especially challenging locations. Apremilast is specifically approved for scalp psoriasis, and Dr. Strober has anecdotally found it helpful in patients with palmoplantar psoriasis or genital psoriasis.

“Apremilast has tolerability issues: first and foremost diarrhea, nausea, and headache. Probably 15%-20% of patients have nausea or diarrhea ranging from mild to severe, and 1 in 20 have headache. You have to warn patients,” he said.

Roughly 1% of patients experience depressed mood. “I’ve seen it in a few patients. I definitely believe it’s real, so query patients about mood changes while taking apremilast,” the dermatologist advised.

One in 5 patients loses 5% of body weight during the first 6 months on apremilast, but there’s no additional weight loss thereafter. It’s wrong to characterize the oral agent as a weight-loss drug, though, since 80% of patients don’t lose weight, Dr. Strober noted.
 

Topical PDE-4 inhibitor shows promise

Separately at the Las Vegas meeting, Linda Stein Gold, MD, provided highlights of a phase 2b randomized trial of a topical cream formulation of an extremely potent PDE-4 inhibitor, roflumilast, in patients with chronic plaque psoriasis. This molecule is a couple hundred times more effective at inhibiting the PDE-4 receptor than either oral apremilast or topical crisaborole (Eucrisa). And as a once-daily topical agent with very little systemic absorption, roflumilast cream sidesteps the tolerability issues that accompany apremilast.

“Roflumilast is currently available as an oral formulation for treatment of [chronic obstructive pulmonary disease], so it has a fairly well-established safety profile,” noted Dr. Stein Gold, director of dermatology clinical research at the Henry Ford Health System in Detroit.

The 12-week, multicenter, phase 2b study sponsored by Arcutis Biotherapeutics included 331 patients with chronic plaque psoriasis who were randomized to once-daily 0.3% roflumilast cream, 0.15% roflumilast cream, or vehicle. Three-quarters of participants had baseline moderate disease.

A week-8 Investigator’s Global Assessment (IGA) score of 0 or 1, meaning clear skin or almost clear, plus at least a 2-grade improvement from baseline occurred in 32% of the high-dose roflumilast group, 25% of those on the 0.15% formulation, and 10% of controls. On the secondary endpoint of improvement in tough-to-treat intertriginous psoriasis, at week 12 an intertriginous IGA score of 0 or 1 plus at least a 2-point improvement from baseline was seen in 86% of the 0.3% roflumilast cream group, 50% on low-dose therapy, and 29% of controls. Moreover, the clinical improvements in IGA and itch kicked in quickly, with significant separation from placebo by week 2, Dr. Stein Gold noted.

The phase 3 program is now recruiting participants.

Dr. Strober and Dr. Stein Gold reported receiving research funding from and serving as consultants to Amgen and numerous other pharmaceutical companies.

MedscapeLive and this news organization are owned by the same parent company.

[email protected]

Big changes are coming in the use of oral apremilast, currently approved for moderate to severe psoriasis and plaque psoriasis in adults, Bruce E. Strober, MD, PhD, predicted at MedscapeLive’s annual Las Vegas Dermatology Seminar, held virtually this year.

“We’ll have a pediatric indication for apremilast in psoriasis down the line, and probably a mild to moderate indication for psoriasis, meaning we can use this drug in patients in whom we typically think about using only topical therapies. Keep on the lookout: I think the mild to moderate indication may be coming next year, and that’s going to really shake up the whole landscape of psoriasis therapy,” said Dr. Strober, a dermatologist at Yale University in New Haven, Conn., and Central Connecticut Dermatology in Cromwell, Conn.
 

Mild or moderate psoriasis

Apremilast manufacturer Amgen has announced positive topline results from the phase 3 ADVANCE trial, a multicenter, placebo-controlled, double-blind, study of 595 patients with mild or moderate psoriasis as defined by an involved body surface area of 2%-15% and a Psoriasis Area and Severity Index score of 2-15. Participants were randomized to the approved dose of apremilast (Otezla) – 30 mg twice daily – or placebo for 16 weeks, followed by 16 weeks of open-label apremilast for all. The full study findings haven’t yet been published or presented at a medical conference, but Amgen announced that the results were positive for all primary and secondary endpoints, and the company plans to file a request with the Food and Drug Administration for an expanded indication for the oral agent.

Pediatric studies

A recently published phase 2, open-label, 1-year study of apremilast in 42 children and adolescents with moderate to severe plaque psoriasis demonstrated that weight-based dosing is the best approach in the pediatric population. The study, which serves as the template for coming phase 3 trials, showed that dosing apremilast at 20 mg twice daily in youths weighing not more than 35 kg and 30 mg twice daily in those who weighed more provided pharmacokinetic exposure similar to that achieved with apremilast at the standard adult dose of 30 mg twice daily. Most participants liked the taste of the tablet.

“My prediction is apremilast will have efficacy in children and teenagers comparable to what it has in adults, with a similar safety and adverse event profile,” Dr. Strober said.

Apremilast works by blocking phosphodiesterase type 4, thereby reducing cyclic AMP metabolism, with a resultant increase in cyclic AMP levels. Cyclic AMP is a regulator of inflammation. Boosting its level has the effect of decreasing tumor necrosis factor and other proinflammatory cytokines while increasing anti-inflammatory mediators, such as interleukin-10.

Dr. Strober characterized apremilast’s efficacy as “modest” by contemporary standards in adults with moderate to severe psoriasis, with week 16 PASI 75 rates of about 30% in randomized trials, compared with 5% in placebo-treated controls. He considers it a good option in patients with moderate disease who are needle phobic and in those averse to the inconvenience of laboratory monitoring. The drug is useful in treating psoriasis in especially challenging locations. Apremilast is specifically approved for scalp psoriasis, and Dr. Strober has anecdotally found it helpful in patients with palmoplantar psoriasis or genital psoriasis.

“Apremilast has tolerability issues: first and foremost diarrhea, nausea, and headache. Probably 15%-20% of patients have nausea or diarrhea ranging from mild to severe, and 1 in 20 have headache. You have to warn patients,” he said.

Roughly 1% of patients experience depressed mood. “I’ve seen it in a few patients. I definitely believe it’s real, so query patients about mood changes while taking apremilast,” the dermatologist advised.

One in 5 patients loses 5% of body weight during the first 6 months on apremilast, but there’s no additional weight loss thereafter. It’s wrong to characterize the oral agent as a weight-loss drug, though, since 80% of patients don’t lose weight, Dr. Strober noted.
 

Topical PDE-4 inhibitor shows promise

Separately at the Las Vegas meeting, Linda Stein Gold, MD, provided highlights of a phase 2b randomized trial of a topical cream formulation of an extremely potent PDE-4 inhibitor, roflumilast, in patients with chronic plaque psoriasis. This molecule is a couple hundred times more effective at inhibiting the PDE-4 receptor than either oral apremilast or topical crisaborole (Eucrisa). And as a once-daily topical agent with very little systemic absorption, roflumilast cream sidesteps the tolerability issues that accompany apremilast.

“Roflumilast is currently available as an oral formulation for treatment of [chronic obstructive pulmonary disease], so it has a fairly well-established safety profile,” noted Dr. Stein Gold, director of dermatology clinical research at the Henry Ford Health System in Detroit.

The 12-week, multicenter, phase 2b study sponsored by Arcutis Biotherapeutics included 331 patients with chronic plaque psoriasis who were randomized to once-daily 0.3% roflumilast cream, 0.15% roflumilast cream, or vehicle. Three-quarters of participants had baseline moderate disease.

A week-8 Investigator’s Global Assessment (IGA) score of 0 or 1, meaning clear skin or almost clear, plus at least a 2-grade improvement from baseline occurred in 32% of the high-dose roflumilast group, 25% of those on the 0.15% formulation, and 10% of controls. On the secondary endpoint of improvement in tough-to-treat intertriginous psoriasis, at week 12 an intertriginous IGA score of 0 or 1 plus at least a 2-point improvement from baseline was seen in 86% of the 0.3% roflumilast cream group, 50% on low-dose therapy, and 29% of controls. Moreover, the clinical improvements in IGA and itch kicked in quickly, with significant separation from placebo by week 2, Dr. Stein Gold noted.

The phase 3 program is now recruiting participants.

Dr. Strober and Dr. Stein Gold reported receiving research funding from and serving as consultants to Amgen and numerous other pharmaceutical companies.

MedscapeLive and this news organization are owned by the same parent company.

[email protected]

Big changes are coming in the use of oral apremilast, currently approved for moderate to severe psoriasis and plaque psoriasis in adults, Bruce E. Strober, MD, PhD, predicted at MedscapeLive’s annual Las Vegas Dermatology Seminar, held virtually this year.

“We’ll have a pediatric indication for apremilast in psoriasis down the line, and probably a mild to moderate indication for psoriasis, meaning we can use this drug in patients in whom we typically think about using only topical therapies. Keep on the lookout: I think the mild to moderate indication may be coming next year, and that’s going to really shake up the whole landscape of psoriasis therapy,” said Dr. Strober, a dermatologist at Yale University in New Haven, Conn., and Central Connecticut Dermatology in Cromwell, Conn.
 

Mild or moderate psoriasis

Apremilast manufacturer Amgen has announced positive topline results from the phase 3 ADVANCE trial, a multicenter, placebo-controlled, double-blind, study of 595 patients with mild or moderate psoriasis as defined by an involved body surface area of 2%-15% and a Psoriasis Area and Severity Index score of 2-15. Participants were randomized to the approved dose of apremilast (Otezla) – 30 mg twice daily – or placebo for 16 weeks, followed by 16 weeks of open-label apremilast for all. The full study findings haven’t yet been published or presented at a medical conference, but Amgen announced that the results were positive for all primary and secondary endpoints, and the company plans to file a request with the Food and Drug Administration for an expanded indication for the oral agent.

Pediatric studies

A recently published phase 2, open-label, 1-year study of apremilast in 42 children and adolescents with moderate to severe plaque psoriasis demonstrated that weight-based dosing is the best approach in the pediatric population. The study, which serves as the template for coming phase 3 trials, showed that dosing apremilast at 20 mg twice daily in youths weighing not more than 35 kg and 30 mg twice daily in those who weighed more provided pharmacokinetic exposure similar to that achieved with apremilast at the standard adult dose of 30 mg twice daily. Most participants liked the taste of the tablet.

“My prediction is apremilast will have efficacy in children and teenagers comparable to what it has in adults, with a similar safety and adverse event profile,” Dr. Strober said.

Apremilast works by blocking phosphodiesterase type 4, thereby reducing cyclic AMP metabolism, with a resultant increase in cyclic AMP levels. Cyclic AMP is a regulator of inflammation. Boosting its level has the effect of decreasing tumor necrosis factor and other proinflammatory cytokines while increasing anti-inflammatory mediators, such as interleukin-10.

Dr. Strober characterized apremilast’s efficacy as “modest” by contemporary standards in adults with moderate to severe psoriasis, with week 16 PASI 75 rates of about 30% in randomized trials, compared with 5% in placebo-treated controls. He considers it a good option in patients with moderate disease who are needle phobic and in those averse to the inconvenience of laboratory monitoring. The drug is useful in treating psoriasis in especially challenging locations. Apremilast is specifically approved for scalp psoriasis, and Dr. Strober has anecdotally found it helpful in patients with palmoplantar psoriasis or genital psoriasis.

“Apremilast has tolerability issues: first and foremost diarrhea, nausea, and headache. Probably 15%-20% of patients have nausea or diarrhea ranging from mild to severe, and 1 in 20 have headache. You have to warn patients,” he said.

Roughly 1% of patients experience depressed mood. “I’ve seen it in a few patients. I definitely believe it’s real, so query patients about mood changes while taking apremilast,” the dermatologist advised.

One in 5 patients loses 5% of body weight during the first 6 months on apremilast, but there’s no additional weight loss thereafter. It’s wrong to characterize the oral agent as a weight-loss drug, though, since 80% of patients don’t lose weight, Dr. Strober noted.
 

Topical PDE-4 inhibitor shows promise

Separately at the Las Vegas meeting, Linda Stein Gold, MD, provided highlights of a phase 2b randomized trial of a topical cream formulation of an extremely potent PDE-4 inhibitor, roflumilast, in patients with chronic plaque psoriasis. This molecule is a couple hundred times more effective at inhibiting the PDE-4 receptor than either oral apremilast or topical crisaborole (Eucrisa). And as a once-daily topical agent with very little systemic absorption, roflumilast cream sidesteps the tolerability issues that accompany apremilast.

“Roflumilast is currently available as an oral formulation for treatment of [chronic obstructive pulmonary disease], so it has a fairly well-established safety profile,” noted Dr. Stein Gold, director of dermatology clinical research at the Henry Ford Health System in Detroit.

The 12-week, multicenter, phase 2b study sponsored by Arcutis Biotherapeutics included 331 patients with chronic plaque psoriasis who were randomized to once-daily 0.3% roflumilast cream, 0.15% roflumilast cream, or vehicle. Three-quarters of participants had baseline moderate disease.

A week-8 Investigator’s Global Assessment (IGA) score of 0 or 1, meaning clear skin or almost clear, plus at least a 2-grade improvement from baseline occurred in 32% of the high-dose roflumilast group, 25% of those on the 0.15% formulation, and 10% of controls. On the secondary endpoint of improvement in tough-to-treat intertriginous psoriasis, at week 12 an intertriginous IGA score of 0 or 1 plus at least a 2-point improvement from baseline was seen in 86% of the 0.3% roflumilast cream group, 50% on low-dose therapy, and 29% of controls. Moreover, the clinical improvements in IGA and itch kicked in quickly, with significant separation from placebo by week 2, Dr. Stein Gold noted.

The phase 3 program is now recruiting participants.

Dr. Strober and Dr. Stein Gold reported receiving research funding from and serving as consultants to Amgen and numerous other pharmaceutical companies.

MedscapeLive and this news organization are owned by the same parent company.

[email protected]

Historically the standard treatment approach for advanced ovarian cancer has been to perform up-front primary cytoreduction surgery or primary “debulking” surgery (PDS) followed by adjuvant chemotherapy. The goal of surgery was to establish cytoreduction of the tumor to optimal (<1 cm³ disease) or, ideally, complete (no gross residual disease). While PDS has long been considered the default treatment approach, neoadjuvant chemotherapy (NACT) followed by interval cytoreductive surgery, typically after three or four cycles of chemotherapy, was the alternative strategy if it was anticipated or known that an “optimal” cytoreduction was not possible, feasible, or associated with acceptable morbidity. However, NACT was, and to some degree still is, widely considered the inferior strategy, reserved for patients with the worst prognosis. While mounting data challenges the inherent superiority of PDS, it still largely remains the default.

Why was PDS considered superior?

Why was PDS for advanced ovarian cancer considered a superior sequencing when it is so rarely considered appropriate for other disseminated cancers? This was born from the observation among retrospective data showing that survival was best when surgery was performed first, and when surgery was able to remove most or all visible disease (“complete” or “optimal” cytoreduction), NACT was performed.¹ Several theories were proposed to explain the observations. These included the theory that bulky tumors contained avascular regions that would be less well accessed by chemotherapy, as well as the notion that chemotherapy exerts a constant fraction of kill on tumor cells, and if there is a lower burden of tumor cells to begin with, fewer cycles of chemotherapy will be necessary to eliminate all cells. Coupled with this was the notion that, if fewer cycles of chemotherapy are necessary, there would be less opportunity for development of drug resistance. Other theories such as the inflammatory effects of surgery impacting immune-mediated kill of malignant cells also are reported. These theories were largely found in the pages of textbooks, only supported by heavily biased observational series and not in the results of elegant translational studies. Of course, the observed superiority of PDS in these cohort studies was not surprising given that the patients who were historically selected for NACT had their treatment course chosen specifically for their poor prognostic factors (large volume, unresectable disease, poor performance status, and comorbidities). These “studies” were self-fulfilling prophecies.

Anecdotally I can attest that most patients are enthusiastic about a primary surgical approach to their advanced cancer. There is something concretely satisfying for patient and surgeon alike in the physical act of removing disease. As surgeons, if we believe that our added surgical effort will be rewarded with better outcomes for the patients, we will “try harder” in the operating room in order for them to do better. However, mounting data challenges whether it is our aggressive surgical effort as much as it is primary tumor biology that is the driver of prognosis in this disease. And aggressive primary surgery may add little other than perioperative morbidity.
 

Why that perspective may be changing

A culmination of many years of sophisticated translational research led by Anil Sood, MD, from the University of Texas MD Anderson Cancer Center, Houston, established there are fundamental biologic differences in the tumors of patients with ovarian cancer whose disease is amenable or not to a complete cytoreduction with PDS.² In their work, the researchers sampled tumors from patients with advanced ovarian cancer who had been triaged either to PDS or NACT based on a standardized, validated laparoscopic algorithm that predicted a high probability of complete surgical resection. They performed pretreatment biopsies in both groups of patients and conducted a range of “omics” analyses to stratify these two subsets of patients – those who had a disease burden amenable to complete surgical resection versus those whose presenting disease burden exceeded an acceptable surgical effort). They identified several key molecular differences in the pretreatment biopsies of these two groups of patients, including alterations which might explain better or worse responses to therapy. These results suggest that the tumors of patients who go on to have successful PDS to no gross residual disease have different tumor biology to begin with. Otherwise said, perhaps it is favorable tumor biology that is associated with both a disease burden that is more amenable to both primary complete cytoreduction and better oncologic outcomes, rather than the surgical effort in and of itself.

This finding is supported by a study in which ovarian cancer survival outcomes were stratified by disease burden, surgical complexity scores, and postoperative residual disease among patients who were enrolled in GOG-182.³ Investigators led by Neil Horowitz, MD, created scores for surgical complexity, disease burden, and residual disease. They observed that the radicality of surgery (complexity score) was not an independent determinant of survival, but rather, patients who presented with a lower disease burden that required a less radical surgery had the best oncologic outcomes.

If the complexity of surgery does not influence outcomes as much as the predetermined, unmodifiable tumor biology, how should surgeons make decisions about the sequencing of treatment? Over the past 10 years, four randomized trials have been completed including more than 1,600 patients randomized to either PDS or NACT.^4-7 All four have found no difference in the oncologic outcomes (progression-free or overall survival) between patients when randomized to PDS or NACT. While the statistical designs vary slightly, some being designed to look for noninferiority and others for superiority, they all showed that the sequence in which surgery and chemotherapy was performed mattered less than whether optimal cytoreduction was achieved when surgery was performed. As stated above, this phenomenon seems to be best determined by unmodifiable tumor biology. Unsurprisingly, these studies also have consistently found that perioperative outcomes (e.g., surgical complications, length of stay, death) were worse with PDS because of the higher surgical complexity that it demands. In the most recent SCORPION trial, rates of major postoperative complications in the PDS group were 25.9%, compared with only 7.6% in the NACT group (P < .0001) and all of the deaths from postoperative complications occurred in the PDS group at a rate of 8.3% (7 of 84 patients).⁷

Therefore, the wealth of data supports that oncologic outcomes are equivalent, and perioperative outcomes are improved for patients who undergo NACT for advanced, bulky ovarian cancer.
 

Why physicians still are questioning

Unfortunately, because ofthe nature of the disease, these prospective trials include heterogeneous populations of disease presentation, surgeon skill, and hospital settings. They have been criticized for achieving “low” rates of complete or optimal cytoreduction in the PDS arm. They also identified subgroups of patients who may do better with PDS (such as those with lower-volume stage IIIC disease) and those who have better outcomes with NACT (patients with stage IV disease). Therefore, not satisfied that we have definitively answered the question, a fifth randomized study, the TRUST trial, is underway.⁸ This study includes surgeons at high-volume institutions, purported to have the highest degree of skill and quality in executing radical debulking procedures. Perhaps this fifth trial will show that, if performed in the most skilled hands and quality settings, PDS is preferable to NACT. Perhaps. However, the generalizability of these results will be poor for all patients with advanced ovarian cancer, most of whom will have limited access to these highest-volume surgeons.

What can be agreed upon is that an individualized and nuanced approach is best for advanced ovarian cancer. There will be some patients who benefit from PDS (e.g., healthy, young patients with low-volume disease). However, for most patients, the bulk of prospective and translational research supports NACT as the default treatment course, associated with noninferior survival and superior perioperative outcomes (including postoperative death). While it may not be a one-size-fits-all approach, one could argue that NACT should be the default strategy, and surgeons should look for reasons to “opt in” to PDS in special circumstances guided by biomarkers such as imaging, tumor markers, clinical factors, and surgical findings.

Dr. Rossi is assistant professor in the division of gynecologic oncology at the University of North Carolina at Chapel Hill. She has no relevant financial disclosures. Email her at [email protected].

References

1. Gynecol Oncol. 2006 Dec. doi: 10.1016/j.ygyno.2006.06.025.

2. Cell Rep. 2020 Apr 14. doi: 10.1016/j.celrep.2020.03.066.

3. J Clin Oncol. 2015 Mar 10. doi: 10.1200/JCO.2014.56.3106.

4. N Engl J Med. 2010 Sep 2. doi: 10.1056/NEJMoa0908806.

5. Lancet. 2015 Jul 18. doi: 10.1016/S0140-6736(14)62223-6.

6. Eur J Cancer. 2020. doi: 10.1016/j.ejca.2020.02.020.

7. Int J Gynecol Cancer. 2020. doi: 10.1136/ijgc-2020-001640.

8. Int J Gynecol Cancer. 2019. doi: 10.1136/ijgc-2019-000682.

Historically the standard treatment approach for advanced ovarian cancer has been to perform up-front primary cytoreduction surgery or primary “debulking” surgery (PDS) followed by adjuvant chemotherapy. The goal of surgery was to establish cytoreduction of the tumor to optimal (<1 cm³ disease) or, ideally, complete (no gross residual disease). While PDS has long been considered the default treatment approach, neoadjuvant chemotherapy (NACT) followed by interval cytoreductive surgery, typically after three or four cycles of chemotherapy, was the alternative strategy if it was anticipated or known that an “optimal” cytoreduction was not possible, feasible, or associated with acceptable morbidity. However, NACT was, and to some degree still is, widely considered the inferior strategy, reserved for patients with the worst prognosis. While mounting data challenges the inherent superiority of PDS, it still largely remains the default.

Why was PDS considered superior?

Why was PDS for advanced ovarian cancer considered a superior sequencing when it is so rarely considered appropriate for other disseminated cancers? This was born from the observation among retrospective data showing that survival was best when surgery was performed first, and when surgery was able to remove most or all visible disease (“complete” or “optimal” cytoreduction), NACT was performed.¹ Several theories were proposed to explain the observations. These included the theory that bulky tumors contained avascular regions that would be less well accessed by chemotherapy, as well as the notion that chemotherapy exerts a constant fraction of kill on tumor cells, and if there is a lower burden of tumor cells to begin with, fewer cycles of chemotherapy will be necessary to eliminate all cells. Coupled with this was the notion that, if fewer cycles of chemotherapy are necessary, there would be less opportunity for development of drug resistance. Other theories such as the inflammatory effects of surgery impacting immune-mediated kill of malignant cells also are reported. These theories were largely found in the pages of textbooks, only supported by heavily biased observational series and not in the results of elegant translational studies. Of course, the observed superiority of PDS in these cohort studies was not surprising given that the patients who were historically selected for NACT had their treatment course chosen specifically for their poor prognostic factors (large volume, unresectable disease, poor performance status, and comorbidities). These “studies” were self-fulfilling prophecies.

Anecdotally I can attest that most patients are enthusiastic about a primary surgical approach to their advanced cancer. There is something concretely satisfying for patient and surgeon alike in the physical act of removing disease. As surgeons, if we believe that our added surgical effort will be rewarded with better outcomes for the patients, we will “try harder” in the operating room in order for them to do better. However, mounting data challenges whether it is our aggressive surgical effort as much as it is primary tumor biology that is the driver of prognosis in this disease. And aggressive primary surgery may add little other than perioperative morbidity.
 

Why that perspective may be changing

A culmination of many years of sophisticated translational research led by Anil Sood, MD, from the University of Texas MD Anderson Cancer Center, Houston, established there are fundamental biologic differences in the tumors of patients with ovarian cancer whose disease is amenable or not to a complete cytoreduction with PDS.² In their work, the researchers sampled tumors from patients with advanced ovarian cancer who had been triaged either to PDS or NACT based on a standardized, validated laparoscopic algorithm that predicted a high probability of complete surgical resection. They performed pretreatment biopsies in both groups of patients and conducted a range of “omics” analyses to stratify these two subsets of patients – those who had a disease burden amenable to complete surgical resection versus those whose presenting disease burden exceeded an acceptable surgical effort). They identified several key molecular differences in the pretreatment biopsies of these two groups of patients, including alterations which might explain better or worse responses to therapy. These results suggest that the tumors of patients who go on to have successful PDS to no gross residual disease have different tumor biology to begin with. Otherwise said, perhaps it is favorable tumor biology that is associated with both a disease burden that is more amenable to both primary complete cytoreduction and better oncologic outcomes, rather than the surgical effort in and of itself.

This finding is supported by a study in which ovarian cancer survival outcomes were stratified by disease burden, surgical complexity scores, and postoperative residual disease among patients who were enrolled in GOG-182.³ Investigators led by Neil Horowitz, MD, created scores for surgical complexity, disease burden, and residual disease. They observed that the radicality of surgery (complexity score) was not an independent determinant of survival, but rather, patients who presented with a lower disease burden that required a less radical surgery had the best oncologic outcomes.

If the complexity of surgery does not influence outcomes as much as the predetermined, unmodifiable tumor biology, how should surgeons make decisions about the sequencing of treatment? Over the past 10 years, four randomized trials have been completed including more than 1,600 patients randomized to either PDS or NACT.^4-7 All four have found no difference in the oncologic outcomes (progression-free or overall survival) between patients when randomized to PDS or NACT. While the statistical designs vary slightly, some being designed to look for noninferiority and others for superiority, they all showed that the sequence in which surgery and chemotherapy was performed mattered less than whether optimal cytoreduction was achieved when surgery was performed. As stated above, this phenomenon seems to be best determined by unmodifiable tumor biology. Unsurprisingly, these studies also have consistently found that perioperative outcomes (e.g., surgical complications, length of stay, death) were worse with PDS because of the higher surgical complexity that it demands. In the most recent SCORPION trial, rates of major postoperative complications in the PDS group were 25.9%, compared with only 7.6% in the NACT group (P < .0001) and all of the deaths from postoperative complications occurred in the PDS group at a rate of 8.3% (7 of 84 patients).⁷

Therefore, the wealth of data supports that oncologic outcomes are equivalent, and perioperative outcomes are improved for patients who undergo NACT for advanced, bulky ovarian cancer.
 

Why physicians still are questioning

Unfortunately, because ofthe nature of the disease, these prospective trials include heterogeneous populations of disease presentation, surgeon skill, and hospital settings. They have been criticized for achieving “low” rates of complete or optimal cytoreduction in the PDS arm. They also identified subgroups of patients who may do better with PDS (such as those with lower-volume stage IIIC disease) and those who have better outcomes with NACT (patients with stage IV disease). Therefore, not satisfied that we have definitively answered the question, a fifth randomized study, the TRUST trial, is underway.⁸ This study includes surgeons at high-volume institutions, purported to have the highest degree of skill and quality in executing radical debulking procedures. Perhaps this fifth trial will show that, if performed in the most skilled hands and quality settings, PDS is preferable to NACT. Perhaps. However, the generalizability of these results will be poor for all patients with advanced ovarian cancer, most of whom will have limited access to these highest-volume surgeons.

What can be agreed upon is that an individualized and nuanced approach is best for advanced ovarian cancer. There will be some patients who benefit from PDS (e.g., healthy, young patients with low-volume disease). However, for most patients, the bulk of prospective and translational research supports NACT as the default treatment course, associated with noninferior survival and superior perioperative outcomes (including postoperative death). While it may not be a one-size-fits-all approach, one could argue that NACT should be the default strategy, and surgeons should look for reasons to “opt in” to PDS in special circumstances guided by biomarkers such as imaging, tumor markers, clinical factors, and surgical findings.

Dr. Rossi is assistant professor in the division of gynecologic oncology at the University of North Carolina at Chapel Hill. She has no relevant financial disclosures. Email her at [email protected].

References

1. Gynecol Oncol. 2006 Dec. doi: 10.1016/j.ygyno.2006.06.025.

2. Cell Rep. 2020 Apr 14. doi: 10.1016/j.celrep.2020.03.066.

3. J Clin Oncol. 2015 Mar 10. doi: 10.1200/JCO.2014.56.3106.

4. N Engl J Med. 2010 Sep 2. doi: 10.1056/NEJMoa0908806.

5. Lancet. 2015 Jul 18. doi: 10.1016/S0140-6736(14)62223-6.

6. Eur J Cancer. 2020. doi: 10.1016/j.ejca.2020.02.020.

7. Int J Gynecol Cancer. 2020. doi: 10.1136/ijgc-2020-001640.

8. Int J Gynecol Cancer. 2019. doi: 10.1136/ijgc-2019-000682.

Historically the standard treatment approach for advanced ovarian cancer has been to perform up-front primary cytoreduction surgery or primary “debulking” surgery (PDS) followed by adjuvant chemotherapy. The goal of surgery was to establish cytoreduction of the tumor to optimal (<1 cm³ disease) or, ideally, complete (no gross residual disease). While PDS has long been considered the default treatment approach, neoadjuvant chemotherapy (NACT) followed by interval cytoreductive surgery, typically after three or four cycles of chemotherapy, was the alternative strategy if it was anticipated or known that an “optimal” cytoreduction was not possible, feasible, or associated with acceptable morbidity. However, NACT was, and to some degree still is, widely considered the inferior strategy, reserved for patients with the worst prognosis. While mounting data challenges the inherent superiority of PDS, it still largely remains the default.

Why was PDS considered superior?

Why was PDS for advanced ovarian cancer considered a superior sequencing when it is so rarely considered appropriate for other disseminated cancers? This was born from the observation among retrospective data showing that survival was best when surgery was performed first, and when surgery was able to remove most or all visible disease (“complete” or “optimal” cytoreduction), NACT was performed.¹ Several theories were proposed to explain the observations. These included the theory that bulky tumors contained avascular regions that would be less well accessed by chemotherapy, as well as the notion that chemotherapy exerts a constant fraction of kill on tumor cells, and if there is a lower burden of tumor cells to begin with, fewer cycles of chemotherapy will be necessary to eliminate all cells. Coupled with this was the notion that, if fewer cycles of chemotherapy are necessary, there would be less opportunity for development of drug resistance. Other theories such as the inflammatory effects of surgery impacting immune-mediated kill of malignant cells also are reported. These theories were largely found in the pages of textbooks, only supported by heavily biased observational series and not in the results of elegant translational studies. Of course, the observed superiority of PDS in these cohort studies was not surprising given that the patients who were historically selected for NACT had their treatment course chosen specifically for their poor prognostic factors (large volume, unresectable disease, poor performance status, and comorbidities). These “studies” were self-fulfilling prophecies.

Anecdotally I can attest that most patients are enthusiastic about a primary surgical approach to their advanced cancer. There is something concretely satisfying for patient and surgeon alike in the physical act of removing disease. As surgeons, if we believe that our added surgical effort will be rewarded with better outcomes for the patients, we will “try harder” in the operating room in order for them to do better. However, mounting data challenges whether it is our aggressive surgical effort as much as it is primary tumor biology that is the driver of prognosis in this disease. And aggressive primary surgery may add little other than perioperative morbidity.
 

Why that perspective may be changing

A culmination of many years of sophisticated translational research led by Anil Sood, MD, from the University of Texas MD Anderson Cancer Center, Houston, established there are fundamental biologic differences in the tumors of patients with ovarian cancer whose disease is amenable or not to a complete cytoreduction with PDS.² In their work, the researchers sampled tumors from patients with advanced ovarian cancer who had been triaged either to PDS or NACT based on a standardized, validated laparoscopic algorithm that predicted a high probability of complete surgical resection. They performed pretreatment biopsies in both groups of patients and conducted a range of “omics” analyses to stratify these two subsets of patients – those who had a disease burden amenable to complete surgical resection versus those whose presenting disease burden exceeded an acceptable surgical effort). They identified several key molecular differences in the pretreatment biopsies of these two groups of patients, including alterations which might explain better or worse responses to therapy. These results suggest that the tumors of patients who go on to have successful PDS to no gross residual disease have different tumor biology to begin with. Otherwise said, perhaps it is favorable tumor biology that is associated with both a disease burden that is more amenable to both primary complete cytoreduction and better oncologic outcomes, rather than the surgical effort in and of itself.

This finding is supported by a study in which ovarian cancer survival outcomes were stratified by disease burden, surgical complexity scores, and postoperative residual disease among patients who were enrolled in GOG-182.³ Investigators led by Neil Horowitz, MD, created scores for surgical complexity, disease burden, and residual disease. They observed that the radicality of surgery (complexity score) was not an independent determinant of survival, but rather, patients who presented with a lower disease burden that required a less radical surgery had the best oncologic outcomes.

If the complexity of surgery does not influence outcomes as much as the predetermined, unmodifiable tumor biology, how should surgeons make decisions about the sequencing of treatment? Over the past 10 years, four randomized trials have been completed including more than 1,600 patients randomized to either PDS or NACT.^4-7 All four have found no difference in the oncologic outcomes (progression-free or overall survival) between patients when randomized to PDS or NACT. While the statistical designs vary slightly, some being designed to look for noninferiority and others for superiority, they all showed that the sequence in which surgery and chemotherapy was performed mattered less than whether optimal cytoreduction was achieved when surgery was performed. As stated above, this phenomenon seems to be best determined by unmodifiable tumor biology. Unsurprisingly, these studies also have consistently found that perioperative outcomes (e.g., surgical complications, length of stay, death) were worse with PDS because of the higher surgical complexity that it demands. In the most recent SCORPION trial, rates of major postoperative complications in the PDS group were 25.9%, compared with only 7.6% in the NACT group (P < .0001) and all of the deaths from postoperative complications occurred in the PDS group at a rate of 8.3% (7 of 84 patients).⁷

Therefore, the wealth of data supports that oncologic outcomes are equivalent, and perioperative outcomes are improved for patients who undergo NACT for advanced, bulky ovarian cancer.
 

Why physicians still are questioning

Unfortunately, because ofthe nature of the disease, these prospective trials include heterogeneous populations of disease presentation, surgeon skill, and hospital settings. They have been criticized for achieving “low” rates of complete or optimal cytoreduction in the PDS arm. They also identified subgroups of patients who may do better with PDS (such as those with lower-volume stage IIIC disease) and those who have better outcomes with NACT (patients with stage IV disease). Therefore, not satisfied that we have definitively answered the question, a fifth randomized study, the TRUST trial, is underway.⁸ This study includes surgeons at high-volume institutions, purported to have the highest degree of skill and quality in executing radical debulking procedures. Perhaps this fifth trial will show that, if performed in the most skilled hands and quality settings, PDS is preferable to NACT. Perhaps. However, the generalizability of these results will be poor for all patients with advanced ovarian cancer, most of whom will have limited access to these highest-volume surgeons.

What can be agreed upon is that an individualized and nuanced approach is best for advanced ovarian cancer. There will be some patients who benefit from PDS (e.g., healthy, young patients with low-volume disease). However, for most patients, the bulk of prospective and translational research supports NACT as the default treatment course, associated with noninferior survival and superior perioperative outcomes (including postoperative death). While it may not be a one-size-fits-all approach, one could argue that NACT should be the default strategy, and surgeons should look for reasons to “opt in” to PDS in special circumstances guided by biomarkers such as imaging, tumor markers, clinical factors, and surgical findings.

Dr. Rossi is assistant professor in the division of gynecologic oncology at the University of North Carolina at Chapel Hill. She has no relevant financial disclosures. Email her at [email protected].

References

1. Gynecol Oncol. 2006 Dec. doi: 10.1016/j.ygyno.2006.06.025.

2. Cell Rep. 2020 Apr 14. doi: 10.1016/j.celrep.2020.03.066.

3. J Clin Oncol. 2015 Mar 10. doi: 10.1200/JCO.2014.56.3106.

4. N Engl J Med. 2010 Sep 2. doi: 10.1056/NEJMoa0908806.

5. Lancet. 2015 Jul 18. doi: 10.1016/S0140-6736(14)62223-6.

6. Eur J Cancer. 2020. doi: 10.1016/j.ejca.2020.02.020.

7. Int J Gynecol Cancer. 2020. doi: 10.1136/ijgc-2020-001640.

8. Int J Gynecol Cancer. 2019. doi: 10.1136/ijgc-2019-000682.

The Food and Drug Administration has granted accelerated approval for naxitamab (Danyelza) to treat certain patients with neuroblastoma, based on response rates in two small trials.

Naxitamab is a humanized monoclonal antibody that targets GD2, a disialoganglioside highly expressed on neuroblastomas.

The FDA approved naxitamab for use in combination with granulocyte-macrophage colony-stimulating factor (GM-CSF) in adults and children aged 1 year and older who have relapsed or refractory, high-risk neuroblastoma in the bone or bone marrow that demonstrated a partial response, minor response, or stable disease to prior therapy.

Naxitamab was originally developed at Memorial Sloan Kettering Cancer Center in New York, and licensed exclusively to Y-mAbs Therapeutics. As a result of the licensing arrangement, MSKCC has institutional financial interests in the product, the company noted.
 

Study results

The accelerated approval of naxitamab was based on the overall response rate (ORR) and duration of response in two single-arm, open-label trials: Study 201 (NCT03363373) in 22 patients and Study 12-230 (NCT01757626) in 38 patients.

In both studies, patients received naxitamab at 3 mg/kg administered as an intravenous infusion on days 1, 3, and 5 of each 4-week cycle in combination with GM-CSF subcutaneously at 250 mcg/m²/day on days -4 to 0 and at 500 mcg/m²/day on days 1-5.

Some patients also received radiotherapy. At the investigator’s discretion, patients were permitted to receive preplanned radiation to the primary disease site in Study 201 and radiation to nontarget bony lesions or soft tissue disease in Study 12-230.

The ORR was 45% in Study 201 and 34% in Study 12-230. Responses were observed in the bone and/or bone marrow, the FDA noted.

Less than a third of patients had a duration of response that lasted 6 months or more – 30% of responders in Study 201 and 23% of responders in Study 12-230.

The FDA noted that continued approval of naxitamab may be contingent upon verification and description of clinical benefit in confirmatory trials.

The agency also noted that naxitamab was granted priority review, breakthrough therapy, and orphan drug designation. In addition, a priority review voucher was issued for the rare pediatric disease product application.
 

Boxed warning and adverse events

Naxitamab has a boxed warning about serious infusion-related reactions and neurotoxicity.

The product information notes that, in clinical studies, naxitamab has been shown to cause serious infusion reactions, including anaphylaxis, cardiac arrest, bronchospasm, stridor, and hypotension. Infusion reactions generally occurred within 24 hours of completing an infusion, most often within 30 minutes of initiation. Infusion reactions were most frequent during the first infusion in each cycle.

To mitigate these risks, Y-mAbs Therapeutics recommends premedication with an antihistamine, acetaminophen, an H2 antagonist, and corticosteroid, as well as close monitoring of patients during and for at least 2 hours after each infusion in a setting where cardiopulmonary resuscitation medication and equipment are available.

Based on its mechanism of action, naxitamab can cause severe pain, according to Y-mAbs Therapeutics. The company recommends premedication with gabapentin and, for example, oral oxycodone, and recommends treating break-through pain with intravenous hydromorphone or an equivalent intervention.

In addition, naxitamab may cause severe hypertension. The onset of hypertension may be delayed, so blood pressure should be monitored both during and after infusion.

The product insert also notes that one case of transverse myelitis (grade 3) and two cases of posterior reversible encephalopathy syndrome have been reported.

The most common adverse reactions (incidence ≥ 25% in either trial) were infusion-related reactions, pain, tachycardia, vomiting, cough, nausea, diarrhea, decreased appetite, hypertension, fatigue, erythema multiforme, peripheral neuropathy, urticaria, pyrexia, headache, injection site reaction, edema, anxiety, localized edema, and irritability.

The most common grade 3 or 4 laboratory abnormalities (≥ 5% in either trial) were decreased lymphocytes, decreased neutrophils, decreased hemoglobin, decreased platelet count, decreased potassium, increased alanine aminotransferase, decreased glucose, decreased calcium, decreased albumin, decreased sodium, and decreased phosphate.
 

A version of this article appeared on Medscape.com.

The Food and Drug Administration has granted accelerated approval for naxitamab (Danyelza) to treat certain patients with neuroblastoma, based on response rates in two small trials.

Naxitamab is a humanized monoclonal antibody that targets GD2, a disialoganglioside highly expressed on neuroblastomas.

The FDA approved naxitamab for use in combination with granulocyte-macrophage colony-stimulating factor (GM-CSF) in adults and children aged 1 year and older who have relapsed or refractory, high-risk neuroblastoma in the bone or bone marrow that demonstrated a partial response, minor response, or stable disease to prior therapy.

Naxitamab was originally developed at Memorial Sloan Kettering Cancer Center in New York, and licensed exclusively to Y-mAbs Therapeutics. As a result of the licensing arrangement, MSKCC has institutional financial interests in the product, the company noted.
 

Study results

The accelerated approval of naxitamab was based on the overall response rate (ORR) and duration of response in two single-arm, open-label trials: Study 201 (NCT03363373) in 22 patients and Study 12-230 (NCT01757626) in 38 patients.

In both studies, patients received naxitamab at 3 mg/kg administered as an intravenous infusion on days 1, 3, and 5 of each 4-week cycle in combination with GM-CSF subcutaneously at 250 mcg/m²/day on days -4 to 0 and at 500 mcg/m²/day on days 1-5.

Some patients also received radiotherapy. At the investigator’s discretion, patients were permitted to receive preplanned radiation to the primary disease site in Study 201 and radiation to nontarget bony lesions or soft tissue disease in Study 12-230.

The ORR was 45% in Study 201 and 34% in Study 12-230. Responses were observed in the bone and/or bone marrow, the FDA noted.

Less than a third of patients had a duration of response that lasted 6 months or more – 30% of responders in Study 201 and 23% of responders in Study 12-230.

The FDA noted that continued approval of naxitamab may be contingent upon verification and description of clinical benefit in confirmatory trials.

The agency also noted that naxitamab was granted priority review, breakthrough therapy, and orphan drug designation. In addition, a priority review voucher was issued for the rare pediatric disease product application.
 

Boxed warning and adverse events

Naxitamab has a boxed warning about serious infusion-related reactions and neurotoxicity.

The product information notes that, in clinical studies, naxitamab has been shown to cause serious infusion reactions, including anaphylaxis, cardiac arrest, bronchospasm, stridor, and hypotension. Infusion reactions generally occurred within 24 hours of completing an infusion, most often within 30 minutes of initiation. Infusion reactions were most frequent during the first infusion in each cycle.

To mitigate these risks, Y-mAbs Therapeutics recommends premedication with an antihistamine, acetaminophen, an H2 antagonist, and corticosteroid, as well as close monitoring of patients during and for at least 2 hours after each infusion in a setting where cardiopulmonary resuscitation medication and equipment are available.

Based on its mechanism of action, naxitamab can cause severe pain, according to Y-mAbs Therapeutics. The company recommends premedication with gabapentin and, for example, oral oxycodone, and recommends treating break-through pain with intravenous hydromorphone or an equivalent intervention.

In addition, naxitamab may cause severe hypertension. The onset of hypertension may be delayed, so blood pressure should be monitored both during and after infusion.

The product insert also notes that one case of transverse myelitis (grade 3) and two cases of posterior reversible encephalopathy syndrome have been reported.

The most common adverse reactions (incidence ≥ 25% in either trial) were infusion-related reactions, pain, tachycardia, vomiting, cough, nausea, diarrhea, decreased appetite, hypertension, fatigue, erythema multiforme, peripheral neuropathy, urticaria, pyrexia, headache, injection site reaction, edema, anxiety, localized edema, and irritability.

The most common grade 3 or 4 laboratory abnormalities (≥ 5% in either trial) were decreased lymphocytes, decreased neutrophils, decreased hemoglobin, decreased platelet count, decreased potassium, increased alanine aminotransferase, decreased glucose, decreased calcium, decreased albumin, decreased sodium, and decreased phosphate.
 

A version of this article appeared on Medscape.com.

The Food and Drug Administration has granted accelerated approval for naxitamab (Danyelza) to treat certain patients with neuroblastoma, based on response rates in two small trials.

Naxitamab is a humanized monoclonal antibody that targets GD2, a disialoganglioside highly expressed on neuroblastomas.

The FDA approved naxitamab for use in combination with granulocyte-macrophage colony-stimulating factor (GM-CSF) in adults and children aged 1 year and older who have relapsed or refractory, high-risk neuroblastoma in the bone or bone marrow that demonstrated a partial response, minor response, or stable disease to prior therapy.

Naxitamab was originally developed at Memorial Sloan Kettering Cancer Center in New York, and licensed exclusively to Y-mAbs Therapeutics. As a result of the licensing arrangement, MSKCC has institutional financial interests in the product, the company noted.
 

Study results

The accelerated approval of naxitamab was based on the overall response rate (ORR) and duration of response in two single-arm, open-label trials: Study 201 (NCT03363373) in 22 patients and Study 12-230 (NCT01757626) in 38 patients.

In both studies, patients received naxitamab at 3 mg/kg administered as an intravenous infusion on days 1, 3, and 5 of each 4-week cycle in combination with GM-CSF subcutaneously at 250 mcg/m²/day on days -4 to 0 and at 500 mcg/m²/day on days 1-5.

Some patients also received radiotherapy. At the investigator’s discretion, patients were permitted to receive preplanned radiation to the primary disease site in Study 201 and radiation to nontarget bony lesions or soft tissue disease in Study 12-230.

The ORR was 45% in Study 201 and 34% in Study 12-230. Responses were observed in the bone and/or bone marrow, the FDA noted.

Less than a third of patients had a duration of response that lasted 6 months or more – 30% of responders in Study 201 and 23% of responders in Study 12-230.

The FDA noted that continued approval of naxitamab may be contingent upon verification and description of clinical benefit in confirmatory trials.

The agency also noted that naxitamab was granted priority review, breakthrough therapy, and orphan drug designation. In addition, a priority review voucher was issued for the rare pediatric disease product application.
 

Boxed warning and adverse events

Naxitamab has a boxed warning about serious infusion-related reactions and neurotoxicity.

The product information notes that, in clinical studies, naxitamab has been shown to cause serious infusion reactions, including anaphylaxis, cardiac arrest, bronchospasm, stridor, and hypotension. Infusion reactions generally occurred within 24 hours of completing an infusion, most often within 30 minutes of initiation. Infusion reactions were most frequent during the first infusion in each cycle.

To mitigate these risks, Y-mAbs Therapeutics recommends premedication with an antihistamine, acetaminophen, an H2 antagonist, and corticosteroid, as well as close monitoring of patients during and for at least 2 hours after each infusion in a setting where cardiopulmonary resuscitation medication and equipment are available.

Based on its mechanism of action, naxitamab can cause severe pain, according to Y-mAbs Therapeutics. The company recommends premedication with gabapentin and, for example, oral oxycodone, and recommends treating break-through pain with intravenous hydromorphone or an equivalent intervention.

In addition, naxitamab may cause severe hypertension. The onset of hypertension may be delayed, so blood pressure should be monitored both during and after infusion.

The product insert also notes that one case of transverse myelitis (grade 3) and two cases of posterior reversible encephalopathy syndrome have been reported.

The most common adverse reactions (incidence ≥ 25% in either trial) were infusion-related reactions, pain, tachycardia, vomiting, cough, nausea, diarrhea, decreased appetite, hypertension, fatigue, erythema multiforme, peripheral neuropathy, urticaria, pyrexia, headache, injection site reaction, edema, anxiety, localized edema, and irritability.

The most common grade 3 or 4 laboratory abnormalities (≥ 5% in either trial) were decreased lymphocytes, decreased neutrophils, decreased hemoglobin, decreased platelet count, decreased potassium, increased alanine aminotransferase, decreased glucose, decreased calcium, decreased albumin, decreased sodium, and decreased phosphate.
 

A version of this article appeared on Medscape.com.

Anti-kickback statutes (AKSs) were originally enacted in 1931 to stop Great Depression–era employers from circumventing wage provisions in federal contracts. Since its enactment, AKSs’ main focus has changed and is currently aimed at the health care industry. In addition to AKSs, Stark laws were enacted over 30 years ago to address physician self-referral of Medicare patients. Both laws comprise the government’s main tools for fighting fraud, waste, and abuse.

Dr. Losurdo is the AGA’s Alternate Advisor to the American Medical Association’s CPT Editorial Panel, a member of the AGA Practice Management and Economics Committee’s Coverage and Reimbursement Subcommittee and is a partner with Elgin Gastro Endoscopy, who owns and ASC, and Managing Partner and Medical Director of Illinois Gastroenterology Group/GI Alliance, Elgin, Ill.

This story was updated on 12/11/2020.

Anti-kickback statutes (AKSs) were originally enacted in 1931 to stop Great Depression–era employers from circumventing wage provisions in federal contracts. Since its enactment, AKSs’ main focus has changed and is currently aimed at the health care industry. In addition to AKSs, Stark laws were enacted over 30 years ago to address physician self-referral of Medicare patients. Both laws comprise the government’s main tools for fighting fraud, waste, and abuse.

Dr. Losurdo is the AGA’s Alternate Advisor to the American Medical Association’s CPT Editorial Panel, a member of the AGA Practice Management and Economics Committee’s Coverage and Reimbursement Subcommittee and is a partner with Elgin Gastro Endoscopy, who owns and ASC, and Managing Partner and Medical Director of Illinois Gastroenterology Group/GI Alliance, Elgin, Ill.

This story was updated on 12/11/2020.

Anti-kickback statutes (AKSs) were originally enacted in 1931 to stop Great Depression–era employers from circumventing wage provisions in federal contracts. Since its enactment, AKSs’ main focus has changed and is currently aimed at the health care industry. In addition to AKSs, Stark laws were enacted over 30 years ago to address physician self-referral of Medicare patients. Both laws comprise the government’s main tools for fighting fraud, waste, and abuse.

Dr. Losurdo is the AGA’s Alternate Advisor to the American Medical Association’s CPT Editorial Panel, a member of the AGA Practice Management and Economics Committee’s Coverage and Reimbursement Subcommittee and is a partner with Elgin Gastro Endoscopy, who owns and ASC, and Managing Partner and Medical Director of Illinois Gastroenterology Group/GI Alliance, Elgin, Ill.

This story was updated on 12/11/2020.

Physicians with difficult patient scenarios regularly bring their questions to the AGA Community (https://community.gastro.org) to seek advice from colleagues about therapy and disease management options, best practices, and diagnoses. The upgraded networking platform now features a newsfeed for difficult patient scenarios and regularly scheduled Roundtable discussions with experts in the field.

In case you missed it, here are some clinical discussions and Roundtables in the newsfeed this month:

Practice update: Small intestinal bacteria overgrowth (SIBO) (https://community.gastro.org/posts/22838)

Case: Polypectomy with low neutrophils (https://community.gastro.org/posts/22844)

Case: Esophagus adenocarcinoma after sleeve gastrectomy (https://community.gastro.org/posts/22868)

Case: Restarting infliximab after shingles – when is it safe? (https://community.gastro.org/posts/22890)

Case: Flatulence in Colorado (https://community.gastro.org/posts/22901)

Case: Serrated epithelial change (SEC) in IBD (https://community.gastro.org/posts/22948)

Case: Multiloculated pancreatic cyst (https://community.gastro.org/posts/22935)

View all upcoming Roundtables in the community at https://community.gastro.org/discussions.

Physicians with difficult patient scenarios regularly bring their questions to the AGA Community (https://community.gastro.org) to seek advice from colleagues about therapy and disease management options, best practices, and diagnoses. The upgraded networking platform now features a newsfeed for difficult patient scenarios and regularly scheduled Roundtable discussions with experts in the field.

In case you missed it, here are some clinical discussions and Roundtables in the newsfeed this month:

Practice update: Small intestinal bacteria overgrowth (SIBO) (https://community.gastro.org/posts/22838)

Case: Polypectomy with low neutrophils (https://community.gastro.org/posts/22844)

Case: Esophagus adenocarcinoma after sleeve gastrectomy (https://community.gastro.org/posts/22868)

Case: Restarting infliximab after shingles – when is it safe? (https://community.gastro.org/posts/22890)

Case: Flatulence in Colorado (https://community.gastro.org/posts/22901)

Case: Serrated epithelial change (SEC) in IBD (https://community.gastro.org/posts/22948)

Case: Multiloculated pancreatic cyst (https://community.gastro.org/posts/22935)

View all upcoming Roundtables in the community at https://community.gastro.org/discussions.

Physicians with difficult patient scenarios regularly bring their questions to the AGA Community (https://community.gastro.org) to seek advice from colleagues about therapy and disease management options, best practices, and diagnoses. The upgraded networking platform now features a newsfeed for difficult patient scenarios and regularly scheduled Roundtable discussions with experts in the field.

In case you missed it, here are some clinical discussions and Roundtables in the newsfeed this month:

Practice update: Small intestinal bacteria overgrowth (SIBO) (https://community.gastro.org/posts/22838)

Case: Polypectomy with low neutrophils (https://community.gastro.org/posts/22844)

Case: Esophagus adenocarcinoma after sleeve gastrectomy (https://community.gastro.org/posts/22868)

Case: Restarting infliximab after shingles – when is it safe? (https://community.gastro.org/posts/22890)

Case: Flatulence in Colorado (https://community.gastro.org/posts/22901)

Case: Serrated epithelial change (SEC) in IBD (https://community.gastro.org/posts/22948)

Case: Multiloculated pancreatic cyst (https://community.gastro.org/posts/22935)

View all upcoming Roundtables in the community at https://community.gastro.org/discussions.

Articles include guidance on cancer progression in Barrett’s esophagus patients, CRC surveillance, and HCC incidence and risk.

Clinical Gastroenterology and Hepatology (CGH) is proud to release its first themed issue on GI cancers. This “issue within an issue” includes a collection of articles, selected by editor-in-chief Dr. Fasiha Kanwal, that will provide you with practical research to help guide cancer prevention, surveillance and treatment decisions for your patients.

View the themed issue on CGH’s website. and access other curated collections on cghjournal.org.

How can we combat health disparities in GI?

Hear from Craig Munroe, MD, on why we all need to donate to AGA Giving Day, now through Dec. 3, in order to fund GI health disparities research.

“Health disparities exist and negatively impact patients every day across our country. Working to solve these inequities for the good of our patients and workforce is fundamental to our calling as physicians,” says Craig A. Munroe, MD, associate chief for clinical innovation, University of California, San Francisco, AGA Diversity Committee member, AGA Equity Project advisory board member. “Although we have made tremendous strides over the decades, there is still much more that needs to be done. Disparate systems of care and legacies of inequality continue to cause great harm.”

That is why AGA is bringing together the GI community to fund health disparity research with the goal of improving care for all patients. With contributions raised through AGA Giving Day campaign, the AGA Research Foundation will fund research projects that help us understand health disparities and create strategies for overcoming them.

“I’m donating to AGA Giving Day because I believe the work being done will have an immediate positive impact, and will continue to benefit future generations of patients, physicians, scientists, health providers, and trainees.”

Please join Dr. Munroe and your AGA colleagues in making a tax-deductible donation to the AGA Research Foundation to support AGA Giving Day today through Dec. 3. Contributors will be recognized as supporters of our fight to achieve equity and eradicate disparities in digestive diseases. www.Gastro.org/GivingDay
 

Articles include guidance on cancer progression in Barrett’s esophagus patients, CRC surveillance, and HCC incidence and risk.

Clinical Gastroenterology and Hepatology (CGH) is proud to release its first themed issue on GI cancers. This “issue within an issue” includes a collection of articles, selected by editor-in-chief Dr. Fasiha Kanwal, that will provide you with practical research to help guide cancer prevention, surveillance and treatment decisions for your patients.

View the themed issue on CGH’s website. and access other curated collections on cghjournal.org.

How can we combat health disparities in GI?

Hear from Craig Munroe, MD, on why we all need to donate to AGA Giving Day, now through Dec. 3, in order to fund GI health disparities research.

“Health disparities exist and negatively impact patients every day across our country. Working to solve these inequities for the good of our patients and workforce is fundamental to our calling as physicians,” says Craig A. Munroe, MD, associate chief for clinical innovation, University of California, San Francisco, AGA Diversity Committee member, AGA Equity Project advisory board member. “Although we have made tremendous strides over the decades, there is still much more that needs to be done. Disparate systems of care and legacies of inequality continue to cause great harm.”

That is why AGA is bringing together the GI community to fund health disparity research with the goal of improving care for all patients. With contributions raised through AGA Giving Day campaign, the AGA Research Foundation will fund research projects that help us understand health disparities and create strategies for overcoming them.

“I’m donating to AGA Giving Day because I believe the work being done will have an immediate positive impact, and will continue to benefit future generations of patients, physicians, scientists, health providers, and trainees.”

Please join Dr. Munroe and your AGA colleagues in making a tax-deductible donation to the AGA Research Foundation to support AGA Giving Day today through Dec. 3. Contributors will be recognized as supporters of our fight to achieve equity and eradicate disparities in digestive diseases. www.Gastro.org/GivingDay
 

Articles include guidance on cancer progression in Barrett’s esophagus patients, CRC surveillance, and HCC incidence and risk.

Clinical Gastroenterology and Hepatology (CGH) is proud to release its first themed issue on GI cancers. This “issue within an issue” includes a collection of articles, selected by editor-in-chief Dr. Fasiha Kanwal, that will provide you with practical research to help guide cancer prevention, surveillance and treatment decisions for your patients.

View the themed issue on CGH’s website. and access other curated collections on cghjournal.org.

How can we combat health disparities in GI?

Hear from Craig Munroe, MD, on why we all need to donate to AGA Giving Day, now through Dec. 3, in order to fund GI health disparities research.

“Health disparities exist and negatively impact patients every day across our country. Working to solve these inequities for the good of our patients and workforce is fundamental to our calling as physicians,” says Craig A. Munroe, MD, associate chief for clinical innovation, University of California, San Francisco, AGA Diversity Committee member, AGA Equity Project advisory board member. “Although we have made tremendous strides over the decades, there is still much more that needs to be done. Disparate systems of care and legacies of inequality continue to cause great harm.”

That is why AGA is bringing together the GI community to fund health disparity research with the goal of improving care for all patients. With contributions raised through AGA Giving Day campaign, the AGA Research Foundation will fund research projects that help us understand health disparities and create strategies for overcoming them.

“I’m donating to AGA Giving Day because I believe the work being done will have an immediate positive impact, and will continue to benefit future generations of patients, physicians, scientists, health providers, and trainees.”

Please join Dr. Munroe and your AGA colleagues in making a tax-deductible donation to the AGA Research Foundation to support AGA Giving Day today through Dec. 3. Contributors will be recognized as supporters of our fight to achieve equity and eradicate disparities in digestive diseases. www.Gastro.org/GivingDay
 

We’re proud to share the news of two AGA members elected to the prestigious National Academy of Medicine and three honored with the 2020 Sherman Prize.

Congratulations to AGA members Judy H. Cho, MD, and B. Mark Evers, MD, who were recently elected to the National Academy of Medicine.

Judy H. Cho, MD, professor of medicine at Icahn School of Medicine at Mount Sinai, New York, for “establishing that uncommon, loss-of-function variants in the microbial-sensing domain of NOD2 confer risk for Crohn’s disease, and identifying a loss-of-function allele in the IL-23 receptor that protects against Crohn’s disease and ulcerative colitis, leading to new, approved therapies.”

B. Mark Evers, MD, physician in chief of oncology service at University of Kentucky Healthcare, for “his expertise on intestinal hormones and hormonal arcades in oncogenesis. His seminal insights defined the role of gut hormones on normal physiology and metabolism, pioneering innovative understanding of neuroendocrine cell biology and the role of neurohormonal pathways in the development and progression of neuroendocrine tumors.”

Being selected to the Academy is one of the highest honors in the fields of health and medicine and recognizes individuals who have demonstrated outstanding professional achievement and commitment to service.

In addition, the 2020 Sherman Prize was awarded to the following three AGA members:

David Rubin, MD, AGAF, chief, section of gastroenterology, hepatology and nutrition at University of Chicago Medicine, for his “renown in the IBD community as a brilliant clinician, creative researcher, tireless advocate, and trailblazing educator.”

Gary Wu, MD, professor of medicine at University of Pennsylvania, Perelman School of Medicine, for “pioneering the study of the gut microbiome in IBD, publishing seminal research on the relationship between diet and the microbiome — enabling multiple areas of research into dietary interventions for IBD.“

Jessica Allegretti, MD, MPH, director of clinical trials at Brigham and Women’s Hospital, as a “highly regarded expert in the field of fecal microbiota transplantation (FMT) and microbiome therapeutics, establishing the therapy as an effective treatment in IBD patients with recurrent C. difficile.”

Presented by the Bruce and Cynthia Sherman Charitable Foundation, the Sherman Prize is awarded to experts in the field of Crohn’s disease and ulcerative colitis who have exhibited their commitment to advancing inflammatory bowel disease care and have dedicated their careers to overcome these diseases.

[email protected]

We’re proud to share the news of two AGA members elected to the prestigious National Academy of Medicine and three honored with the 2020 Sherman Prize.

Congratulations to AGA members Judy H. Cho, MD, and B. Mark Evers, MD, who were recently elected to the National Academy of Medicine.

Judy H. Cho, MD, professor of medicine at Icahn School of Medicine at Mount Sinai, New York, for “establishing that uncommon, loss-of-function variants in the microbial-sensing domain of NOD2 confer risk for Crohn’s disease, and identifying a loss-of-function allele in the IL-23 receptor that protects against Crohn’s disease and ulcerative colitis, leading to new, approved therapies.”

B. Mark Evers, MD, physician in chief of oncology service at University of Kentucky Healthcare, for “his expertise on intestinal hormones and hormonal arcades in oncogenesis. His seminal insights defined the role of gut hormones on normal physiology and metabolism, pioneering innovative understanding of neuroendocrine cell biology and the role of neurohormonal pathways in the development and progression of neuroendocrine tumors.”

Being selected to the Academy is one of the highest honors in the fields of health and medicine and recognizes individuals who have demonstrated outstanding professional achievement and commitment to service.

In addition, the 2020 Sherman Prize was awarded to the following three AGA members:

David Rubin, MD, AGAF, chief, section of gastroenterology, hepatology and nutrition at University of Chicago Medicine, for his “renown in the IBD community as a brilliant clinician, creative researcher, tireless advocate, and trailblazing educator.”

Gary Wu, MD, professor of medicine at University of Pennsylvania, Perelman School of Medicine, for “pioneering the study of the gut microbiome in IBD, publishing seminal research on the relationship between diet and the microbiome — enabling multiple areas of research into dietary interventions for IBD.“

Jessica Allegretti, MD, MPH, director of clinical trials at Brigham and Women’s Hospital, as a “highly regarded expert in the field of fecal microbiota transplantation (FMT) and microbiome therapeutics, establishing the therapy as an effective treatment in IBD patients with recurrent C. difficile.”

Presented by the Bruce and Cynthia Sherman Charitable Foundation, the Sherman Prize is awarded to experts in the field of Crohn’s disease and ulcerative colitis who have exhibited their commitment to advancing inflammatory bowel disease care and have dedicated their careers to overcome these diseases.

[email protected]

We’re proud to share the news of two AGA members elected to the prestigious National Academy of Medicine and three honored with the 2020 Sherman Prize.

Congratulations to AGA members Judy H. Cho, MD, and B. Mark Evers, MD, who were recently elected to the National Academy of Medicine.

Judy H. Cho, MD, professor of medicine at Icahn School of Medicine at Mount Sinai, New York, for “establishing that uncommon, loss-of-function variants in the microbial-sensing domain of NOD2 confer risk for Crohn’s disease, and identifying a loss-of-function allele in the IL-23 receptor that protects against Crohn’s disease and ulcerative colitis, leading to new, approved therapies.”

B. Mark Evers, MD, physician in chief of oncology service at University of Kentucky Healthcare, for “his expertise on intestinal hormones and hormonal arcades in oncogenesis. His seminal insights defined the role of gut hormones on normal physiology and metabolism, pioneering innovative understanding of neuroendocrine cell biology and the role of neurohormonal pathways in the development and progression of neuroendocrine tumors.”

Being selected to the Academy is one of the highest honors in the fields of health and medicine and recognizes individuals who have demonstrated outstanding professional achievement and commitment to service.

In addition, the 2020 Sherman Prize was awarded to the following three AGA members:

David Rubin, MD, AGAF, chief, section of gastroenterology, hepatology and nutrition at University of Chicago Medicine, for his “renown in the IBD community as a brilliant clinician, creative researcher, tireless advocate, and trailblazing educator.”

Gary Wu, MD, professor of medicine at University of Pennsylvania, Perelman School of Medicine, for “pioneering the study of the gut microbiome in IBD, publishing seminal research on the relationship between diet and the microbiome — enabling multiple areas of research into dietary interventions for IBD.“

Jessica Allegretti, MD, MPH, director of clinical trials at Brigham and Women’s Hospital, as a “highly regarded expert in the field of fecal microbiota transplantation (FMT) and microbiome therapeutics, establishing the therapy as an effective treatment in IBD patients with recurrent C. difficile.”

Presented by the Bruce and Cynthia Sherman Charitable Foundation, the Sherman Prize is awarded to experts in the field of Crohn’s disease and ulcerative colitis who have exhibited their commitment to advancing inflammatory bowel disease care and have dedicated their careers to overcome these diseases.

[email protected]

Early identification and removal of cancerous colorectal polyps is critical to preventing the progression of colorectal cancer and improving survival rates. The U.S. Multisociety Task Force (U.S. MSTF) on Colorectal Cancer has released new guidance for endoscopists on how to assess colorectal lesions for features associated with cancer, discuss how these factors guide management and outline when to advise surgery after malignant polyp removal.

Key recommendations from the U.S. Multisociety Task Force on Colorectal Cancer, which is comprised of leading experts representing AGA, ACG and ASGE, include:

1. Management of malignant polyps must begin with a thorough and knowledgeable endoscopic assessment designed to identify features of deep submucosal invasion.

2. In nonpedunculated lesions with features of deep submucosal invasion, endoscopic biopsy and tattooing should be followed by surgical resection.

3. Nonpedunculated lesions with high risk of superficial submucosal invasion should be considered for en bloc resection and proper specimen handling.

4. When pathology reports cancer in a lesion that was completely resected endoscopically, the decision to recommend surgery is based on polyp shape, whether there was en bloc resection and adequate histologic assessment, the presence or absence of unfavorable histologic features, the patient’s risk for surgical mortality and morbidity, and patient preferences.

For more information, review the full publication: Endoscopic Recognition and Management Strategies for Malignant Colorectal Polyps: Recommendations of the US Multi-Society Task Force on Colorectal Cancer. The U.S. MSTF recommendations are published jointly in Gastroenterology, The American Journal of Gastroenterology, and Gastrointestinal Endoscopy.

[email protected]

Early identification and removal of cancerous colorectal polyps is critical to preventing the progression of colorectal cancer and improving survival rates. The U.S. Multisociety Task Force (U.S. MSTF) on Colorectal Cancer has released new guidance for endoscopists on how to assess colorectal lesions for features associated with cancer, discuss how these factors guide management and outline when to advise surgery after malignant polyp removal.

Key recommendations from the U.S. Multisociety Task Force on Colorectal Cancer, which is comprised of leading experts representing AGA, ACG and ASGE, include:

1. Management of malignant polyps must begin with a thorough and knowledgeable endoscopic assessment designed to identify features of deep submucosal invasion.

2. In nonpedunculated lesions with features of deep submucosal invasion, endoscopic biopsy and tattooing should be followed by surgical resection.

3. Nonpedunculated lesions with high risk of superficial submucosal invasion should be considered for en bloc resection and proper specimen handling.

4. When pathology reports cancer in a lesion that was completely resected endoscopically, the decision to recommend surgery is based on polyp shape, whether there was en bloc resection and adequate histologic assessment, the presence or absence of unfavorable histologic features, the patient’s risk for surgical mortality and morbidity, and patient preferences.

For more information, review the full publication: Endoscopic Recognition and Management Strategies for Malignant Colorectal Polyps: Recommendations of the US Multi-Society Task Force on Colorectal Cancer. The U.S. MSTF recommendations are published jointly in Gastroenterology, The American Journal of Gastroenterology, and Gastrointestinal Endoscopy.

[email protected]

Early identification and removal of cancerous colorectal polyps is critical to preventing the progression of colorectal cancer and improving survival rates. The U.S. Multisociety Task Force (U.S. MSTF) on Colorectal Cancer has released new guidance for endoscopists on how to assess colorectal lesions for features associated with cancer, discuss how these factors guide management and outline when to advise surgery after malignant polyp removal.

Key recommendations from the U.S. Multisociety Task Force on Colorectal Cancer, which is comprised of leading experts representing AGA, ACG and ASGE, include:

1. Management of malignant polyps must begin with a thorough and knowledgeable endoscopic assessment designed to identify features of deep submucosal invasion.

2. In nonpedunculated lesions with features of deep submucosal invasion, endoscopic biopsy and tattooing should be followed by surgical resection.

3. Nonpedunculated lesions with high risk of superficial submucosal invasion should be considered for en bloc resection and proper specimen handling.

4. When pathology reports cancer in a lesion that was completely resected endoscopically, the decision to recommend surgery is based on polyp shape, whether there was en bloc resection and adequate histologic assessment, the presence or absence of unfavorable histologic features, the patient’s risk for surgical mortality and morbidity, and patient preferences.

For more information, review the full publication: Endoscopic Recognition and Management Strategies for Malignant Colorectal Polyps: Recommendations of the US Multi-Society Task Force on Colorectal Cancer. The U.S. MSTF recommendations are published jointly in Gastroenterology, The American Journal of Gastroenterology, and Gastrointestinal Endoscopy.

[email protected]

Immune checkpoint inhibitor (ICI) therapy does not increase the risk of developing or dying from COVID-19, according to a pair of studies presented at the Society for Immunotherapy of Cancer’s 35th Anniversary Annual Meeting.

Cytokine storm plays a major role in the pathogenesis of COVID-19, according to research published in The Lancet Respiratory Medicine. This has generated concern about using ICIs during the pandemic, given their immunostimulatory activity and the risk of immune-related adverse effects.

However, two retrospective studies suggest ICIs do not increase the risk of developing COVID-19 or dying from the disease.

In a study of 1,545 cancer patients prescribed ICIs and 20,418 matched controls, the incidence of COVID-19 was 1.4% with ICI therapy and 1.0% without it (odds ratio, 1.38; P = .15).

In a case-control study of 50 patients with cancer and COVID-19, 28% of patients who had received ICIs died from COVID-19, compared with 36% of patients who had not received ICIs (OR, 0.36; P = .23).

Vartan Pahalyants and Kevin Tyan, both students in Harvard University’s joint MD/MBA program in Boston, presented these studies at the meeting.
 

COVID-19 incidence with ICIs

Mr. Pahalyants and colleagues analyzed data from cancer patients treated in the Mass General Brigham health care system. The researchers compared 1,545 patients with at least one ICI prescription between July 1, 2019, and Feb. 29, 2020, with 20,418 matched cancer patients not prescribed ICIs. The team assessed COVID-19 incidence based on positive test results through June 19, 2020, from public health data.

The incidence of COVID-19 was low in both groups – 1.4% in the ICI group and 1.0% in the matched control group (P = .16). Among COVID-19–positive patients, the all-cause death rate was 40.9% in the ICI group and 28.6% in the control group (P = .23).

In multivariate analysis, patients prescribed ICIs did not have a significantly elevated risk for COVID-19 relative to peers not prescribed ICIs (OR, 1.38; P = .15). However, risk was significantly increased for female patients (OR, 1.74; P < .001), those living in a town or county with higher COVID-19 positivity rate (OR, 1.59; P < .001), and those with severe comorbidity (vs. mild or moderate; OR, 9.77; P = .02).

Among COVID-19–positive patients, those prescribed ICIs did not have a significantly elevated risk for all-cause mortality (OR, 1.60; P = .71), but male sex and lower income were associated with an increased risk of death.

“We did not identify an increased risk of [COVID-19] diagnosis among patients prescribed ICIs compared to the controls,” Mr. Pahalyants said. “This information may assist patients and their providers in decision-making around continuation of therapy during this protracted pandemic. However, more research needs to be conducted to determine potential behavioral and testing factors that may have affected COVID-19 diagnosis susceptibility among patients included in the study.”

COVID-19 mortality with ICIs

For their study, Mr. Tyan and colleagues identified 25 cancer patients who had received ICIs in the year before a COVID-19 diagnosis between March 20, 2020, and June 3, 2020, at the Dana-Farber Cancer Institute and Mass General Brigham network. The researchers then matched each patient with a cancer patient having a COVID-19 diagnosis who had not received ICIs during the preceding year.

Overall, 28% of patients who had received ICIs before their COVID-19 diagnosis died from COVID-19, compared with 36% of those who had not received ICIs.

In multivariate analysis, ICI therapy did not predict COVID-19 mortality (OR, 0.36; P = .23). However, the risk of death from COVID-19 increased with age (OR, 1.14; P = .01) and for patients with chronic obstructive pulmonary disease (OR, 12.26; P = .01), and risk was lower for statin users (OR, 0.08; P = .02). Findings were similar in an analysis restricted to hospitalized patients in the ICI group and their matched controls.

Two ICI-treated patients with COVID-19 had persistent immune-related adverse events (hypophysitis in both cases), and one ICI-treated patient developed a new immune-related adverse event (hypothyroidism).

At COVID-19 presentation, relative to counterparts who had not received ICIs, patients who had received ICIs had higher platelet counts (P = .017) and higher D-dimer levels (P = .037). In the context of similar levels of other biomarkers, this finding is “of unclear significance, as all deaths in the cohort were due to respiratory failure as opposed to hypercoagulability,” Mr. Tyan said.

The patients treated with ICIs were more likely to die from COVID-19 if they had elevated troponin levels (P = .01), whereas no such association was seen for those not treated with ICIs.

“We found that ICI therapy is not associated with greater risk for COVID-19 mortality. Our period of follow-up was relatively short, but we did not observe a high incidence of new or persistent immune-related adverse events among our patients taking ICIs,” Mr. Tyan said.

“While larger prospective trials are needed to evaluate long-term safety in the context of COVID-19 infection, our findings support the continuation of ICI therapy during the pandemic as it does not appear to worsen outcomes for cancer patients,” he concluded.
 

ICI therapy can continue, with precautions

“The question of susceptibility to COVID-19 has been unclear as ICIs do not necessarily cause immunosuppression but certainly result in modulation of a patient’s immune system,” said Deborah Doroshow, MD, PhD, assistant professor at the Tisch Cancer Institute Icahn School of Medicine at Mount Sinai, New York. She was not involved in these studies.

“The findings of the study by Pahalyants and colleagues, which used a very large sample size, appear to convincingly demonstrate that ICI receipt is not associated with an increased susceptibility to COVID-19,” Dr. Doroshow said in an interview.

SOURCE: Pahalyants V et al. SITC 2020, Abstract 826. Tyan K et al. SITC 2020, Abstract 481.

Immune checkpoint inhibitor (ICI) therapy does not increase the risk of developing or dying from COVID-19, according to a pair of studies presented at the Society for Immunotherapy of Cancer’s 35th Anniversary Annual Meeting.

Cytokine storm plays a major role in the pathogenesis of COVID-19, according to research published in The Lancet Respiratory Medicine. This has generated concern about using ICIs during the pandemic, given their immunostimulatory activity and the risk of immune-related adverse effects.

However, two retrospective studies suggest ICIs do not increase the risk of developing COVID-19 or dying from the disease.

In a study of 1,545 cancer patients prescribed ICIs and 20,418 matched controls, the incidence of COVID-19 was 1.4% with ICI therapy and 1.0% without it (odds ratio, 1.38; P = .15).

In a case-control study of 50 patients with cancer and COVID-19, 28% of patients who had received ICIs died from COVID-19, compared with 36% of patients who had not received ICIs (OR, 0.36; P = .23).

Vartan Pahalyants and Kevin Tyan, both students in Harvard University’s joint MD/MBA program in Boston, presented these studies at the meeting.
 

COVID-19 incidence with ICIs

Mr. Pahalyants and colleagues analyzed data from cancer patients treated in the Mass General Brigham health care system. The researchers compared 1,545 patients with at least one ICI prescription between July 1, 2019, and Feb. 29, 2020, with 20,418 matched cancer patients not prescribed ICIs. The team assessed COVID-19 incidence based on positive test results through June 19, 2020, from public health data.

The incidence of COVID-19 was low in both groups – 1.4% in the ICI group and 1.0% in the matched control group (P = .16). Among COVID-19–positive patients, the all-cause death rate was 40.9% in the ICI group and 28.6% in the control group (P = .23).

In multivariate analysis, patients prescribed ICIs did not have a significantly elevated risk for COVID-19 relative to peers not prescribed ICIs (OR, 1.38; P = .15). However, risk was significantly increased for female patients (OR, 1.74; P < .001), those living in a town or county with higher COVID-19 positivity rate (OR, 1.59; P < .001), and those with severe comorbidity (vs. mild or moderate; OR, 9.77; P = .02).

Among COVID-19–positive patients, those prescribed ICIs did not have a significantly elevated risk for all-cause mortality (OR, 1.60; P = .71), but male sex and lower income were associated with an increased risk of death.

“We did not identify an increased risk of [COVID-19] diagnosis among patients prescribed ICIs compared to the controls,” Mr. Pahalyants said. “This information may assist patients and their providers in decision-making around continuation of therapy during this protracted pandemic. However, more research needs to be conducted to determine potential behavioral and testing factors that may have affected COVID-19 diagnosis susceptibility among patients included in the study.”

COVID-19 mortality with ICIs

For their study, Mr. Tyan and colleagues identified 25 cancer patients who had received ICIs in the year before a COVID-19 diagnosis between March 20, 2020, and June 3, 2020, at the Dana-Farber Cancer Institute and Mass General Brigham network. The researchers then matched each patient with a cancer patient having a COVID-19 diagnosis who had not received ICIs during the preceding year.

Overall, 28% of patients who had received ICIs before their COVID-19 diagnosis died from COVID-19, compared with 36% of those who had not received ICIs.

In multivariate analysis, ICI therapy did not predict COVID-19 mortality (OR, 0.36; P = .23). However, the risk of death from COVID-19 increased with age (OR, 1.14; P = .01) and for patients with chronic obstructive pulmonary disease (OR, 12.26; P = .01), and risk was lower for statin users (OR, 0.08; P = .02). Findings were similar in an analysis restricted to hospitalized patients in the ICI group and their matched controls.

Two ICI-treated patients with COVID-19 had persistent immune-related adverse events (hypophysitis in both cases), and one ICI-treated patient developed a new immune-related adverse event (hypothyroidism).

At COVID-19 presentation, relative to counterparts who had not received ICIs, patients who had received ICIs had higher platelet counts (P = .017) and higher D-dimer levels (P = .037). In the context of similar levels of other biomarkers, this finding is “of unclear significance, as all deaths in the cohort were due to respiratory failure as opposed to hypercoagulability,” Mr. Tyan said.

The patients treated with ICIs were more likely to die from COVID-19 if they had elevated troponin levels (P = .01), whereas no such association was seen for those not treated with ICIs.

“We found that ICI therapy is not associated with greater risk for COVID-19 mortality. Our period of follow-up was relatively short, but we did not observe a high incidence of new or persistent immune-related adverse events among our patients taking ICIs,” Mr. Tyan said.

“While larger prospective trials are needed to evaluate long-term safety in the context of COVID-19 infection, our findings support the continuation of ICI therapy during the pandemic as it does not appear to worsen outcomes for cancer patients,” he concluded.
 

ICI therapy can continue, with precautions

“The question of susceptibility to COVID-19 has been unclear as ICIs do not necessarily cause immunosuppression but certainly result in modulation of a patient’s immune system,” said Deborah Doroshow, MD, PhD, assistant professor at the Tisch Cancer Institute Icahn School of Medicine at Mount Sinai, New York. She was not involved in these studies.

“The findings of the study by Pahalyants and colleagues, which used a very large sample size, appear to convincingly demonstrate that ICI receipt is not associated with an increased susceptibility to COVID-19,” Dr. Doroshow said in an interview.

SOURCE: Pahalyants V et al. SITC 2020, Abstract 826. Tyan K et al. SITC 2020, Abstract 481.

Immune checkpoint inhibitor (ICI) therapy does not increase the risk of developing or dying from COVID-19, according to a pair of studies presented at the Society for Immunotherapy of Cancer’s 35th Anniversary Annual Meeting.

Cytokine storm plays a major role in the pathogenesis of COVID-19, according to research published in The Lancet Respiratory Medicine. This has generated concern about using ICIs during the pandemic, given their immunostimulatory activity and the risk of immune-related adverse effects.

However, two retrospective studies suggest ICIs do not increase the risk of developing COVID-19 or dying from the disease.

In a study of 1,545 cancer patients prescribed ICIs and 20,418 matched controls, the incidence of COVID-19 was 1.4% with ICI therapy and 1.0% without it (odds ratio, 1.38; P = .15).

In a case-control study of 50 patients with cancer and COVID-19, 28% of patients who had received ICIs died from COVID-19, compared with 36% of patients who had not received ICIs (OR, 0.36; P = .23).

Vartan Pahalyants and Kevin Tyan, both students in Harvard University’s joint MD/MBA program in Boston, presented these studies at the meeting.
 

COVID-19 incidence with ICIs

Mr. Pahalyants and colleagues analyzed data from cancer patients treated in the Mass General Brigham health care system. The researchers compared 1,545 patients with at least one ICI prescription between July 1, 2019, and Feb. 29, 2020, with 20,418 matched cancer patients not prescribed ICIs. The team assessed COVID-19 incidence based on positive test results through June 19, 2020, from public health data.

The incidence of COVID-19 was low in both groups – 1.4% in the ICI group and 1.0% in the matched control group (P = .16). Among COVID-19–positive patients, the all-cause death rate was 40.9% in the ICI group and 28.6% in the control group (P = .23).

In multivariate analysis, patients prescribed ICIs did not have a significantly elevated risk for COVID-19 relative to peers not prescribed ICIs (OR, 1.38; P = .15). However, risk was significantly increased for female patients (OR, 1.74; P < .001), those living in a town or county with higher COVID-19 positivity rate (OR, 1.59; P < .001), and those with severe comorbidity (vs. mild or moderate; OR, 9.77; P = .02).

Among COVID-19–positive patients, those prescribed ICIs did not have a significantly elevated risk for all-cause mortality (OR, 1.60; P = .71), but male sex and lower income were associated with an increased risk of death.

“We did not identify an increased risk of [COVID-19] diagnosis among patients prescribed ICIs compared to the controls,” Mr. Pahalyants said. “This information may assist patients and their providers in decision-making around continuation of therapy during this protracted pandemic. However, more research needs to be conducted to determine potential behavioral and testing factors that may have affected COVID-19 diagnosis susceptibility among patients included in the study.”

COVID-19 mortality with ICIs

For their study, Mr. Tyan and colleagues identified 25 cancer patients who had received ICIs in the year before a COVID-19 diagnosis between March 20, 2020, and June 3, 2020, at the Dana-Farber Cancer Institute and Mass General Brigham network. The researchers then matched each patient with a cancer patient having a COVID-19 diagnosis who had not received ICIs during the preceding year.

Overall, 28% of patients who had received ICIs before their COVID-19 diagnosis died from COVID-19, compared with 36% of those who had not received ICIs.

In multivariate analysis, ICI therapy did not predict COVID-19 mortality (OR, 0.36; P = .23). However, the risk of death from COVID-19 increased with age (OR, 1.14; P = .01) and for patients with chronic obstructive pulmonary disease (OR, 12.26; P = .01), and risk was lower for statin users (OR, 0.08; P = .02). Findings were similar in an analysis restricted to hospitalized patients in the ICI group and their matched controls.

Two ICI-treated patients with COVID-19 had persistent immune-related adverse events (hypophysitis in both cases), and one ICI-treated patient developed a new immune-related adverse event (hypothyroidism).

At COVID-19 presentation, relative to counterparts who had not received ICIs, patients who had received ICIs had higher platelet counts (P = .017) and higher D-dimer levels (P = .037). In the context of similar levels of other biomarkers, this finding is “of unclear significance, as all deaths in the cohort were due to respiratory failure as opposed to hypercoagulability,” Mr. Tyan said.

The patients treated with ICIs were more likely to die from COVID-19 if they had elevated troponin levels (P = .01), whereas no such association was seen for those not treated with ICIs.

“We found that ICI therapy is not associated with greater risk for COVID-19 mortality. Our period of follow-up was relatively short, but we did not observe a high incidence of new or persistent immune-related adverse events among our patients taking ICIs,” Mr. Tyan said.

“While larger prospective trials are needed to evaluate long-term safety in the context of COVID-19 infection, our findings support the continuation of ICI therapy during the pandemic as it does not appear to worsen outcomes for cancer patients,” he concluded.
 

ICI therapy can continue, with precautions

“The question of susceptibility to COVID-19 has been unclear as ICIs do not necessarily cause immunosuppression but certainly result in modulation of a patient’s immune system,” said Deborah Doroshow, MD, PhD, assistant professor at the Tisch Cancer Institute Icahn School of Medicine at Mount Sinai, New York. She was not involved in these studies.

“The findings of the study by Pahalyants and colleagues, which used a very large sample size, appear to convincingly demonstrate that ICI receipt is not associated with an increased susceptibility to COVID-19,” Dr. Doroshow said in an interview.

SOURCE: Pahalyants V et al. SITC 2020, Abstract 826. Tyan K et al. SITC 2020, Abstract 481.