Liam Davenport

VIENNA – Individuals born to younger or older parents are at increased risk of developing bipolar disorder, new research suggests.

Results from a meta-analysis of more than 210,000 patients with bipolar disorder and over 13 million healthy individuals showed that children of mothers younger than 20 years had a 23% increased risk for bipolar disorder vs. those whose parents were aged 25-29 years. For participants whose mothers were aged 35-39 years, there was a 10% increased risk for bipolar disorder, which rose to 20% if the mother was aged 40 or older.

Having a father younger than 20 years conferred a 29% increased risk for bipolar disorder, which was the same increase in risk found in individuals whose fathers were aged 45 years or older.

These findings, which are an update of data published in the journal European Pharmacology, were presented at the 35th European College of Neuropsychopharmacology (ECNP) Congress.
 

Fourteen studies included

Previous studies have suggested that parental age at birth is a risk factor for several psychiatric disorders in offspring, including bipolar disorder, and that advanced parental age, specifically, is associated with earlier onset schizophrenia.

To investigate further, the current researchers conducted a systematic review and meta-analysis, searching the PubMed/MEDLINE, EMBASE, Scopus, and PsychINFO databases for relevant studies published to Dec. 1, 2021.

From 712 studies initially identified, 16 met all the inclusion criteria and 14 were included in the quantitative analysis.

Five studies reported only paternal age and risk for bipolar disorder in their offspring, one included just maternal age, and eight reported both maternal and paternal age in relation to the risk for offspring bipolar disorder.

Individuals with a history of any psychiatric disorders were excluded, leaving a total of 13.4 million individuals without bipolar disorder and 217,089 who had received a diagnosis for the disorder.

The investigators also corrected for both socioeconomic status and, when assessing the impact of maternal or paternal age at birth, corrected for the age of the other parent. However, they were unable to correct for the number of children in a family.

Results after stratifying maternal and paternal age showed that, compared with those born to parents aged 25-29 years, there was an increased risk for bipolar disorder in the offspring of both fathers and mothers younger than 20 years of age, with adjusted odds ratios of 1.29 (95% confidence interval, 1.13-1.48) and 1.23 (95% CI, 1.14-1.33), respectively.

Compared with those aged 25-29 years, there was also an increased risk for bipolar disorder in children born to mothers aged 35-39 years (adjusted OR, 1.1; 95% CI, 1.01-1.19) and aged 40 or older (OR, 1.2; 95% CI, 1.02-1.40).

Among fathers, there was increased risk for offspring bipolar disorder in those aged 45 or older vs. those aged 25-29 years (adjusted OR, 1.29; 95% CI, 1.15-1.46).
 

Several hypotheses

There are several hypotheses that could explain the results, lead study author Giovanna Fico, MD, bipolar and depressive disorders unit, Hospital Clínic Barcelona, told this news organization.

In older age, it may be “more related to genetic or epigenetic modification, especially in fathers,” Dr. Fico said. “Some studies have shown that there are de novo mutations in the germ lines, which increase the risk of several diseases, including schizophrenia.”

In younger individuals, there could be a “mixed effect between sociocultural factors, such as substance abuse, low educational status,” and other issues, Dr. Fico noted.

Moreover, as bipolar disorder onset can be as late as 30 years of age, the younger group could include “undiagnosed patients with bipolar disorder, which would increase the risk” of the disease in their offspring, she added.

Dr. Fico noted the investigators are now planning on studying the impact of environmental factors such as pollution, climate change, and urbanization on risk for bipolar disorder, with the aim of being better able to inform parents or to develop prevention strategies.

Psychoeducation is “very common for infertility, birth defects, and Down syndrome, but it’s not so common for psychiatric disorders because we need more data. But I think it’s important that parents know they have an increased risk,” she said.

Nevertheless, “We must stress that this risk is moderate, and it must be kept in perspective,” Dr. Fico said in a news release.
 

‘Exciting’ questions raised

The study “raises several exciting research questions, including the possibility of early prevention and intervention,” Maj Vinberg, MD, PhD, clinical professor, department of clinical medicine, University of Copenhagen, said in the release.

She said she agrees there are likely to be different factors at play at different ages, with the risk for bipolar disorder associated with younger-age parenthood more likely to be related to socioeconomic status.

For older parents, “there has been a lot of speculation around the father’s age especially, which everybody thought didn’t matter,” said Dr. Vinberg, who was not involved with the research.

“But you might have some epigenetic changes as you grow older that might transfer into the next generation,” given that there is 20 years of additional exposure to potential epigenetic changes between a man aged 25 years and one aged 45 years, she noted.

Dr. Vinberg also highlighted that there could be cases of undiagnosed bipolar disorder among the younger parents, and she noted that “men with bipolar disorder tend to have more children,” particularly during manic phases.

She explained that if someone were to get divorced at 35 years of age, then have a new manic episode at 45 “and have a new wife and children, I don’t know whether it’s possible to correct for that.”

The research is supported by a fellowship from “la Caixa” Foundation. The investigators have reported no relevant financial relationships. Dr. Vinberg reported having relationships with Lundbeck and Janssen.

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

VIENNA – Individuals born to younger or older parents are at increased risk of developing bipolar disorder, new research suggests.

Results from a meta-analysis of more than 210,000 patients with bipolar disorder and over 13 million healthy individuals showed that children of mothers younger than 20 years had a 23% increased risk for bipolar disorder vs. those whose parents were aged 25-29 years. For participants whose mothers were aged 35-39 years, there was a 10% increased risk for bipolar disorder, which rose to 20% if the mother was aged 40 or older.

Having a father younger than 20 years conferred a 29% increased risk for bipolar disorder, which was the same increase in risk found in individuals whose fathers were aged 45 years or older.

These findings, which are an update of data published in the journal European Pharmacology, were presented at the 35th European College of Neuropsychopharmacology (ECNP) Congress.
 

Fourteen studies included

Previous studies have suggested that parental age at birth is a risk factor for several psychiatric disorders in offspring, including bipolar disorder, and that advanced parental age, specifically, is associated with earlier onset schizophrenia.

To investigate further, the current researchers conducted a systematic review and meta-analysis, searching the PubMed/MEDLINE, EMBASE, Scopus, and PsychINFO databases for relevant studies published to Dec. 1, 2021.

From 712 studies initially identified, 16 met all the inclusion criteria and 14 were included in the quantitative analysis.

Five studies reported only paternal age and risk for bipolar disorder in their offspring, one included just maternal age, and eight reported both maternal and paternal age in relation to the risk for offspring bipolar disorder.

Individuals with a history of any psychiatric disorders were excluded, leaving a total of 13.4 million individuals without bipolar disorder and 217,089 who had received a diagnosis for the disorder.

The investigators also corrected for both socioeconomic status and, when assessing the impact of maternal or paternal age at birth, corrected for the age of the other parent. However, they were unable to correct for the number of children in a family.

Results after stratifying maternal and paternal age showed that, compared with those born to parents aged 25-29 years, there was an increased risk for bipolar disorder in the offspring of both fathers and mothers younger than 20 years of age, with adjusted odds ratios of 1.29 (95% confidence interval, 1.13-1.48) and 1.23 (95% CI, 1.14-1.33), respectively.

Compared with those aged 25-29 years, there was also an increased risk for bipolar disorder in children born to mothers aged 35-39 years (adjusted OR, 1.1; 95% CI, 1.01-1.19) and aged 40 or older (OR, 1.2; 95% CI, 1.02-1.40).

Among fathers, there was increased risk for offspring bipolar disorder in those aged 45 or older vs. those aged 25-29 years (adjusted OR, 1.29; 95% CI, 1.15-1.46).
 

Several hypotheses

There are several hypotheses that could explain the results, lead study author Giovanna Fico, MD, bipolar and depressive disorders unit, Hospital Clínic Barcelona, told this news organization.

In older age, it may be “more related to genetic or epigenetic modification, especially in fathers,” Dr. Fico said. “Some studies have shown that there are de novo mutations in the germ lines, which increase the risk of several diseases, including schizophrenia.”

In younger individuals, there could be a “mixed effect between sociocultural factors, such as substance abuse, low educational status,” and other issues, Dr. Fico noted.

Moreover, as bipolar disorder onset can be as late as 30 years of age, the younger group could include “undiagnosed patients with bipolar disorder, which would increase the risk” of the disease in their offspring, she added.

Dr. Fico noted the investigators are now planning on studying the impact of environmental factors such as pollution, climate change, and urbanization on risk for bipolar disorder, with the aim of being better able to inform parents or to develop prevention strategies.

Psychoeducation is “very common for infertility, birth defects, and Down syndrome, but it’s not so common for psychiatric disorders because we need more data. But I think it’s important that parents know they have an increased risk,” she said.

Nevertheless, “We must stress that this risk is moderate, and it must be kept in perspective,” Dr. Fico said in a news release.
 

‘Exciting’ questions raised

The study “raises several exciting research questions, including the possibility of early prevention and intervention,” Maj Vinberg, MD, PhD, clinical professor, department of clinical medicine, University of Copenhagen, said in the release.

She said she agrees there are likely to be different factors at play at different ages, with the risk for bipolar disorder associated with younger-age parenthood more likely to be related to socioeconomic status.

For older parents, “there has been a lot of speculation around the father’s age especially, which everybody thought didn’t matter,” said Dr. Vinberg, who was not involved with the research.

“But you might have some epigenetic changes as you grow older that might transfer into the next generation,” given that there is 20 years of additional exposure to potential epigenetic changes between a man aged 25 years and one aged 45 years, she noted.

Dr. Vinberg also highlighted that there could be cases of undiagnosed bipolar disorder among the younger parents, and she noted that “men with bipolar disorder tend to have more children,” particularly during manic phases.

She explained that if someone were to get divorced at 35 years of age, then have a new manic episode at 45 “and have a new wife and children, I don’t know whether it’s possible to correct for that.”

The research is supported by a fellowship from “la Caixa” Foundation. The investigators have reported no relevant financial relationships. Dr. Vinberg reported having relationships with Lundbeck and Janssen.

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

VIENNA – Individuals born to younger or older parents are at increased risk of developing bipolar disorder, new research suggests.

Results from a meta-analysis of more than 210,000 patients with bipolar disorder and over 13 million healthy individuals showed that children of mothers younger than 20 years had a 23% increased risk for bipolar disorder vs. those whose parents were aged 25-29 years. For participants whose mothers were aged 35-39 years, there was a 10% increased risk for bipolar disorder, which rose to 20% if the mother was aged 40 or older.

Having a father younger than 20 years conferred a 29% increased risk for bipolar disorder, which was the same increase in risk found in individuals whose fathers were aged 45 years or older.

These findings, which are an update of data published in the journal European Pharmacology, were presented at the 35th European College of Neuropsychopharmacology (ECNP) Congress.
 

Fourteen studies included

Previous studies have suggested that parental age at birth is a risk factor for several psychiatric disorders in offspring, including bipolar disorder, and that advanced parental age, specifically, is associated with earlier onset schizophrenia.

To investigate further, the current researchers conducted a systematic review and meta-analysis, searching the PubMed/MEDLINE, EMBASE, Scopus, and PsychINFO databases for relevant studies published to Dec. 1, 2021.

From 712 studies initially identified, 16 met all the inclusion criteria and 14 were included in the quantitative analysis.

Five studies reported only paternal age and risk for bipolar disorder in their offspring, one included just maternal age, and eight reported both maternal and paternal age in relation to the risk for offspring bipolar disorder.

Individuals with a history of any psychiatric disorders were excluded, leaving a total of 13.4 million individuals without bipolar disorder and 217,089 who had received a diagnosis for the disorder.

The investigators also corrected for both socioeconomic status and, when assessing the impact of maternal or paternal age at birth, corrected for the age of the other parent. However, they were unable to correct for the number of children in a family.

Results after stratifying maternal and paternal age showed that, compared with those born to parents aged 25-29 years, there was an increased risk for bipolar disorder in the offspring of both fathers and mothers younger than 20 years of age, with adjusted odds ratios of 1.29 (95% confidence interval, 1.13-1.48) and 1.23 (95% CI, 1.14-1.33), respectively.

Compared with those aged 25-29 years, there was also an increased risk for bipolar disorder in children born to mothers aged 35-39 years (adjusted OR, 1.1; 95% CI, 1.01-1.19) and aged 40 or older (OR, 1.2; 95% CI, 1.02-1.40).

Among fathers, there was increased risk for offspring bipolar disorder in those aged 45 or older vs. those aged 25-29 years (adjusted OR, 1.29; 95% CI, 1.15-1.46).
 

Several hypotheses

There are several hypotheses that could explain the results, lead study author Giovanna Fico, MD, bipolar and depressive disorders unit, Hospital Clínic Barcelona, told this news organization.

In older age, it may be “more related to genetic or epigenetic modification, especially in fathers,” Dr. Fico said. “Some studies have shown that there are de novo mutations in the germ lines, which increase the risk of several diseases, including schizophrenia.”

In younger individuals, there could be a “mixed effect between sociocultural factors, such as substance abuse, low educational status,” and other issues, Dr. Fico noted.

Moreover, as bipolar disorder onset can be as late as 30 years of age, the younger group could include “undiagnosed patients with bipolar disorder, which would increase the risk” of the disease in their offspring, she added.

Dr. Fico noted the investigators are now planning on studying the impact of environmental factors such as pollution, climate change, and urbanization on risk for bipolar disorder, with the aim of being better able to inform parents or to develop prevention strategies.

Psychoeducation is “very common for infertility, birth defects, and Down syndrome, but it’s not so common for psychiatric disorders because we need more data. But I think it’s important that parents know they have an increased risk,” she said.

Nevertheless, “We must stress that this risk is moderate, and it must be kept in perspective,” Dr. Fico said in a news release.
 

‘Exciting’ questions raised

The study “raises several exciting research questions, including the possibility of early prevention and intervention,” Maj Vinberg, MD, PhD, clinical professor, department of clinical medicine, University of Copenhagen, said in the release.

She said she agrees there are likely to be different factors at play at different ages, with the risk for bipolar disorder associated with younger-age parenthood more likely to be related to socioeconomic status.

For older parents, “there has been a lot of speculation around the father’s age especially, which everybody thought didn’t matter,” said Dr. Vinberg, who was not involved with the research.

“But you might have some epigenetic changes as you grow older that might transfer into the next generation,” given that there is 20 years of additional exposure to potential epigenetic changes between a man aged 25 years and one aged 45 years, she noted.

Dr. Vinberg also highlighted that there could be cases of undiagnosed bipolar disorder among the younger parents, and she noted that “men with bipolar disorder tend to have more children,” particularly during manic phases.

She explained that if someone were to get divorced at 35 years of age, then have a new manic episode at 45 “and have a new wife and children, I don’t know whether it’s possible to correct for that.”

The research is supported by a fellowship from “la Caixa” Foundation. The investigators have reported no relevant financial relationships. Dr. Vinberg reported having relationships with Lundbeck and Janssen.

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

PARIS – “I thought I was as exhausted, and isolated, and neglected as I could get, and then he came home.”

Those were the words of Kate Washington, PhD, from Sacramento as she gave a moving account of the immense burden she felt as caregiver to her husband with cancer.

She was taking part in the session, “I am FINE: Frustrated * Isolated * Neglected * Emotional,” at the annual meeting of the European Society for Medical Oncology. In that session, speakers assessed the toll of cancer on patients, caregivers, nurses, and doctors.

Dr. Washington, author of “Already Toast: Caregiving and Burnout in America” (Boston: Beacon Press, 2021), explained that she cared for her husband and young family while he was “suffering through two different kinds of lymphoma and really devastating stem cell transplants.”

When her husband was first diagnosed with a rare form of lymphoma in 2015, he was placed on a watch-and-wait protocol. At that point, he seemed fine, Dr. Washington said.

A few months later, he started coughing up blood. After being rushed to the emergency department, doctors found that a slow-growing lung tumor had ruptured.

Three weeks later, he came out of the hospital with a collapsed lung – an effect of his chemotherapy, Dr. Washington said.

But that was hardly the last word. He soon experienced relapse with a “very aggressive” form of his disease, and in 2016, he underwent a stem cell transplant.

“He spent 1½ months in the hospital ... in isolation, not seeing our daughters,” Dr. Washington said. He lost his vision and developed grade 4 graft-versus-host disease, among other problems.

He was alive, just barely, Dr. Washington said.

“As you might imagine, I was pulled between the hospital and the home, taking care of our daughters, who were not seeing him during that time,” she recalled.

But every time someone asked her whether she was okay, she replied: “I am fine.”

“A total lie,” she admitted.

Dr. Washington felt frustrated, not only from the financial strain of out-of-pocket health care costs and lost earnings but also from fast evolving relationships and a feeling of being “unseen and underappreciated.”

Another jarring change: When her husband was discharged from the hospital, Dr. Washington was suddenly thrust into the role of full-time caretaker.

Her husband could not be left alone, his doctor had said. And with two young children, Dr. Washington did not know how she would manage.

The demands of being a full-time caregiver are intense. Caregivers, Dr. Washington explained, can spend 32 hours a week looking after a loved one with cancer.

Like Dr. Washington, most caregivers feel they have no choice but to take on this intense role – one for which they have little or no training or preparation. The nonstop demands leave little time for self-care and can lead to high rates of caregiver injury and illness.

Isolation often creeps in because it can be “hard to ask for help,” she said. About 30% of caregivers report having depression or anxiety, and 21% feel lonely.

“When he was very ill, I found it really difficult to connect with other people and my friends,” Dr. Washington recalled. “I didn’t feel like I could really adequately explain the kind of strain that I was under.”
 

Are patients fine?

Like caregivers, patients often say they are fine when they are not.

The toll cancer takes on patients is immense. Natacha Bolanos Fernandez, from the Lymphoma Coalition Europe, highlighted the physical, mental, and social strain that can affect patients with cancer.

The physical aspects can encompass a host of problems – fatigue, night sweats, weight loss, and the vomiting that accompanies many cancer treatments. Patients may face changes in their mobility and independence as well. The mental side of cancer can include anxiety, depression, and psychological distress, while the social aspects span changing, perhaps strained, relationships with family and friends.

Fatigue, in particular, is an underreported, underdiagnosed, and undertreated problem, Ms. Fernandez noted. According to recent survey data from the Lymphoma Coalition’s Global Patient Survey, 72% of patients reported fatigue. This problem worsened over time, with 59% reporting fatigue after their diagnosis and up to 82% among patients who experienced relapse two or more times.

Fatigue “may be getting worse rather than better over time,” Ms. Fernandez said, and many patients felt that their life had changed completely because of cancer-related fatigue.

To help patients manage, the Lymphoma Coalition has published a report on the impact of cancer-related fatigue and how to improve outcomes. Methods include greater awareness, regular screening, and interventions such as yoga or mindfulness-based cognitive therapy.
 

Are clinicians fine?

Nurses and physicians face challenges caring for patients with cancer.

Although “nurses love their jobs and are extremely committed,” the impact cancer has on a nursing career is often undervalued or “neglected,” said Lena Sharp, RN, PhD, of the Regional Cancer Centre, Stockholm-Gotland.

Burnout, in particular, remains a problem among oncologists and nurses, and it was made worse during the COVID-19 pandemic.

Fatima Cardoso, MD, explained that burnout has an impact on doctors as well as patients because it affects communication with patients and performance. Physicians can, for instance, appear detached, emotional, or tired.

Patients may then feel less inclined to tell their oncologist how they’re feeling, said Dr. Cardoso, director of the breast unit at Champalimaud Clinical Center, Lisbon.

It is important to remember to not just focus on the patient’s disease or treatment but to also ask how they are doing and what is going on in their lives.

Above all, “show that you care,” said Dr. Cardoso.

The Lymphoma Coalition Europe has relationships with Bristol-Myers Squibb, Establishment Labs, Kyowa Kirin, Novartis, Roche, Takeda. Dr. Cardoso has relationships with Amgen, Astellas/Medivation, AstraZeneca, Celgene, Daiichi Sankyo, Eisai, GE Oncology, Genentech, GlaxoSmithKline, and other companies. No other relevant financial relationships were reported.

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

PARIS – “I thought I was as exhausted, and isolated, and neglected as I could get, and then he came home.”

Those were the words of Kate Washington, PhD, from Sacramento as she gave a moving account of the immense burden she felt as caregiver to her husband with cancer.

She was taking part in the session, “I am FINE: Frustrated * Isolated * Neglected * Emotional,” at the annual meeting of the European Society for Medical Oncology. In that session, speakers assessed the toll of cancer on patients, caregivers, nurses, and doctors.

Dr. Washington, author of “Already Toast: Caregiving and Burnout in America” (Boston: Beacon Press, 2021), explained that she cared for her husband and young family while he was “suffering through two different kinds of lymphoma and really devastating stem cell transplants.”

When her husband was first diagnosed with a rare form of lymphoma in 2015, he was placed on a watch-and-wait protocol. At that point, he seemed fine, Dr. Washington said.

A few months later, he started coughing up blood. After being rushed to the emergency department, doctors found that a slow-growing lung tumor had ruptured.

Three weeks later, he came out of the hospital with a collapsed lung – an effect of his chemotherapy, Dr. Washington said.

But that was hardly the last word. He soon experienced relapse with a “very aggressive” form of his disease, and in 2016, he underwent a stem cell transplant.

“He spent 1½ months in the hospital ... in isolation, not seeing our daughters,” Dr. Washington said. He lost his vision and developed grade 4 graft-versus-host disease, among other problems.

He was alive, just barely, Dr. Washington said.

“As you might imagine, I was pulled between the hospital and the home, taking care of our daughters, who were not seeing him during that time,” she recalled.

But every time someone asked her whether she was okay, she replied: “I am fine.”

“A total lie,” she admitted.

Dr. Washington felt frustrated, not only from the financial strain of out-of-pocket health care costs and lost earnings but also from fast evolving relationships and a feeling of being “unseen and underappreciated.”

Another jarring change: When her husband was discharged from the hospital, Dr. Washington was suddenly thrust into the role of full-time caretaker.

Her husband could not be left alone, his doctor had said. And with two young children, Dr. Washington did not know how she would manage.

The demands of being a full-time caregiver are intense. Caregivers, Dr. Washington explained, can spend 32 hours a week looking after a loved one with cancer.

Like Dr. Washington, most caregivers feel they have no choice but to take on this intense role – one for which they have little or no training or preparation. The nonstop demands leave little time for self-care and can lead to high rates of caregiver injury and illness.

Isolation often creeps in because it can be “hard to ask for help,” she said. About 30% of caregivers report having depression or anxiety, and 21% feel lonely.

“When he was very ill, I found it really difficult to connect with other people and my friends,” Dr. Washington recalled. “I didn’t feel like I could really adequately explain the kind of strain that I was under.”
 

Are patients fine?

Like caregivers, patients often say they are fine when they are not.

The toll cancer takes on patients is immense. Natacha Bolanos Fernandez, from the Lymphoma Coalition Europe, highlighted the physical, mental, and social strain that can affect patients with cancer.

The physical aspects can encompass a host of problems – fatigue, night sweats, weight loss, and the vomiting that accompanies many cancer treatments. Patients may face changes in their mobility and independence as well. The mental side of cancer can include anxiety, depression, and psychological distress, while the social aspects span changing, perhaps strained, relationships with family and friends.

Fatigue, in particular, is an underreported, underdiagnosed, and undertreated problem, Ms. Fernandez noted. According to recent survey data from the Lymphoma Coalition’s Global Patient Survey, 72% of patients reported fatigue. This problem worsened over time, with 59% reporting fatigue after their diagnosis and up to 82% among patients who experienced relapse two or more times.

Fatigue “may be getting worse rather than better over time,” Ms. Fernandez said, and many patients felt that their life had changed completely because of cancer-related fatigue.

To help patients manage, the Lymphoma Coalition has published a report on the impact of cancer-related fatigue and how to improve outcomes. Methods include greater awareness, regular screening, and interventions such as yoga or mindfulness-based cognitive therapy.
 

Are clinicians fine?

Nurses and physicians face challenges caring for patients with cancer.

Although “nurses love their jobs and are extremely committed,” the impact cancer has on a nursing career is often undervalued or “neglected,” said Lena Sharp, RN, PhD, of the Regional Cancer Centre, Stockholm-Gotland.

Burnout, in particular, remains a problem among oncologists and nurses, and it was made worse during the COVID-19 pandemic.

Fatima Cardoso, MD, explained that burnout has an impact on doctors as well as patients because it affects communication with patients and performance. Physicians can, for instance, appear detached, emotional, or tired.

Patients may then feel less inclined to tell their oncologist how they’re feeling, said Dr. Cardoso, director of the breast unit at Champalimaud Clinical Center, Lisbon.

It is important to remember to not just focus on the patient’s disease or treatment but to also ask how they are doing and what is going on in their lives.

Above all, “show that you care,” said Dr. Cardoso.

The Lymphoma Coalition Europe has relationships with Bristol-Myers Squibb, Establishment Labs, Kyowa Kirin, Novartis, Roche, Takeda. Dr. Cardoso has relationships with Amgen, Astellas/Medivation, AstraZeneca, Celgene, Daiichi Sankyo, Eisai, GE Oncology, Genentech, GlaxoSmithKline, and other companies. No other relevant financial relationships were reported.

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

PARIS – “I thought I was as exhausted, and isolated, and neglected as I could get, and then he came home.”

Those were the words of Kate Washington, PhD, from Sacramento as she gave a moving account of the immense burden she felt as caregiver to her husband with cancer.

She was taking part in the session, “I am FINE: Frustrated * Isolated * Neglected * Emotional,” at the annual meeting of the European Society for Medical Oncology. In that session, speakers assessed the toll of cancer on patients, caregivers, nurses, and doctors.

Dr. Washington, author of “Already Toast: Caregiving and Burnout in America” (Boston: Beacon Press, 2021), explained that she cared for her husband and young family while he was “suffering through two different kinds of lymphoma and really devastating stem cell transplants.”

When her husband was first diagnosed with a rare form of lymphoma in 2015, he was placed on a watch-and-wait protocol. At that point, he seemed fine, Dr. Washington said.

A few months later, he started coughing up blood. After being rushed to the emergency department, doctors found that a slow-growing lung tumor had ruptured.

Three weeks later, he came out of the hospital with a collapsed lung – an effect of his chemotherapy, Dr. Washington said.

But that was hardly the last word. He soon experienced relapse with a “very aggressive” form of his disease, and in 2016, he underwent a stem cell transplant.

“He spent 1½ months in the hospital ... in isolation, not seeing our daughters,” Dr. Washington said. He lost his vision and developed grade 4 graft-versus-host disease, among other problems.

He was alive, just barely, Dr. Washington said.

“As you might imagine, I was pulled between the hospital and the home, taking care of our daughters, who were not seeing him during that time,” she recalled.

But every time someone asked her whether she was okay, she replied: “I am fine.”

“A total lie,” she admitted.

Dr. Washington felt frustrated, not only from the financial strain of out-of-pocket health care costs and lost earnings but also from fast evolving relationships and a feeling of being “unseen and underappreciated.”

Another jarring change: When her husband was discharged from the hospital, Dr. Washington was suddenly thrust into the role of full-time caretaker.

Her husband could not be left alone, his doctor had said. And with two young children, Dr. Washington did not know how she would manage.

The demands of being a full-time caregiver are intense. Caregivers, Dr. Washington explained, can spend 32 hours a week looking after a loved one with cancer.

Like Dr. Washington, most caregivers feel they have no choice but to take on this intense role – one for which they have little or no training or preparation. The nonstop demands leave little time for self-care and can lead to high rates of caregiver injury and illness.

Isolation often creeps in because it can be “hard to ask for help,” she said. About 30% of caregivers report having depression or anxiety, and 21% feel lonely.

“When he was very ill, I found it really difficult to connect with other people and my friends,” Dr. Washington recalled. “I didn’t feel like I could really adequately explain the kind of strain that I was under.”
 

Are patients fine?

Like caregivers, patients often say they are fine when they are not.

The toll cancer takes on patients is immense. Natacha Bolanos Fernandez, from the Lymphoma Coalition Europe, highlighted the physical, mental, and social strain that can affect patients with cancer.

The physical aspects can encompass a host of problems – fatigue, night sweats, weight loss, and the vomiting that accompanies many cancer treatments. Patients may face changes in their mobility and independence as well. The mental side of cancer can include anxiety, depression, and psychological distress, while the social aspects span changing, perhaps strained, relationships with family and friends.

Fatigue, in particular, is an underreported, underdiagnosed, and undertreated problem, Ms. Fernandez noted. According to recent survey data from the Lymphoma Coalition’s Global Patient Survey, 72% of patients reported fatigue. This problem worsened over time, with 59% reporting fatigue after their diagnosis and up to 82% among patients who experienced relapse two or more times.

Fatigue “may be getting worse rather than better over time,” Ms. Fernandez said, and many patients felt that their life had changed completely because of cancer-related fatigue.

To help patients manage, the Lymphoma Coalition has published a report on the impact of cancer-related fatigue and how to improve outcomes. Methods include greater awareness, regular screening, and interventions such as yoga or mindfulness-based cognitive therapy.
 

Are clinicians fine?

Nurses and physicians face challenges caring for patients with cancer.

Although “nurses love their jobs and are extremely committed,” the impact cancer has on a nursing career is often undervalued or “neglected,” said Lena Sharp, RN, PhD, of the Regional Cancer Centre, Stockholm-Gotland.

Burnout, in particular, remains a problem among oncologists and nurses, and it was made worse during the COVID-19 pandemic.

Fatima Cardoso, MD, explained that burnout has an impact on doctors as well as patients because it affects communication with patients and performance. Physicians can, for instance, appear detached, emotional, or tired.

Patients may then feel less inclined to tell their oncologist how they’re feeling, said Dr. Cardoso, director of the breast unit at Champalimaud Clinical Center, Lisbon.

It is important to remember to not just focus on the patient’s disease or treatment but to also ask how they are doing and what is going on in their lives.

Above all, “show that you care,” said Dr. Cardoso.

The Lymphoma Coalition Europe has relationships with Bristol-Myers Squibb, Establishment Labs, Kyowa Kirin, Novartis, Roche, Takeda. Dr. Cardoso has relationships with Amgen, Astellas/Medivation, AstraZeneca, Celgene, Daiichi Sankyo, Eisai, GE Oncology, Genentech, GlaxoSmithKline, and other companies. No other relevant financial relationships were reported.

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

PARIS – New disappointing results from a trial of adjuvant immunotherapy for patients with renal cell carcinoma who underwent nephrectomy contrast with those from a previous trial that showed benefit with another agent.

The new results, from CheckMate 914, show that adjuvant treatment with the combination of nivolumab (Opdivo) plus ipilimumab (Yervoy) did not improve disease-free survival (DFS), compared with placebo.

The finding was presented at the annual meeting of the European Society for Medical Oncology.

CheckMate 914 “did not meet the primary endpoint,” study presenter Robert J. Motzer, MD, a medical oncologist at Memorial Sloan Kettering Cancer Center, New York, said at a press conference.

The results contrast with those seen with pembrolizumab (Keytruda) in the same setting, where the drug achieved a 32% reduction in risk of recurrence or death over placebo in KEYNOTE-564. This led to the U.S. Food and Drug Administration granting approval for the drug as adjuvant treatment following surgery in patients with renal cell carcinoma at intermediate or high risk for recurrence after nephrectomy or after nephrectomy and resection of metastatic lesions.

Another trial of adjuvant immunotherapy in renal cell carcinoma, also presented at ESMO 2022, the IMmotion010 trial with adjuvant atezolizumab (Tecentriq), also did not show any clinical benefit over placebo.

However, Dr. Motzer said that despite both of these new trials showing no benefit, “I don’t think it takes away from standard of care pembrolizumab” in this setting.

There is a great need for adjuvant therapy for patients who undergo surgery, Dr. Motzer commented. The standard treatment for stage I-III localized nonmetastatic renal cell carcinoma is radical or partial nephrectomy, but there remains a “substantial risk” of relapse after surgery, occurring in up to 50% of patients.

In the past, the standard of care for these patients would be watching and waiting and “hoping that the patient doesn’t relapse,” he said, and if they did, then “we would treat accordingly for metastatic disease.”
 

Differences between trials

When asked about the contrast between the latest trial with the adjuvant nivolumab-ipilimumab combination and the earlier trial with adjuvant pembrolizumab, Dr. Motzer told this news organization that there are differences in the designs of the two studies. “Although they are both global phase 2 trials ... [there are] some differences in the patient population.”

However, the “main differences” are the duration, intensity, and tolerability of the treatment regimens. “I suspect that’s impacted on the outcome of our trial,” he said, as “many of our patients didn’t complete even that 6 months of the more toxic immunotherapy [nivolumab-ipilimumab combination].”

Dr. Motzer also noted that, compared with the metastatic setting, patients “do not tolerate therapy as well” in the adjuvant setting. Consequently, the risk-benefit of a drug is “slightly different ... as we have to be much more concerned about toxicity.”

In addition, he said, “our trial also used these kind-of gross clinical features that were developed years ago” to select patients, but now “there’s other much more refined techniques” that look at the underlying biological signatures “to identify who responds to immunotherapy.”

“So I think we have to do a deep dive into the biology in this trial and in the Merck trial [of pembrolizumab] to see if we can better define who is going to relapse and who is going to benefit,” he said.

Commenting on the new results, Dominik Berthold, MD, Centre Hospitalier Universitaire Vaudois, Lausanne, Switzerland, also wondered whether differences in trial design and study populations could explain the divergent results between the CheckMate and KEYNOTE trials.

“Investigators will need to look in detail at subpopulations and biomarkers to guide treatment decisions and trial design for current and future patients,” he added.

Dr. Berthold said he agrees that pembrolizumab remains standard of care, but “I’m not really sure that we have really to offer all patients” the drug.

He explained that, on the one hand, there is the risk of over-treating many patients, depending on their stage, and on the other hand, “many patients who get pembrolizumab actually do progress.”

In addition, there is the question of the treatment sequence in patients who are already exposed to immunotherapy and when to start tyrosine kinase inhibitors, as well as the much broader issue of the lack of long-term overall survival data with pembrolizumab.

Dr. Berthold noted the issue of whether the high treatment discontinuation rate in CheckMate 914 affected the efficacy of nivolumab plus ipilimumab raises the question of whether, from an immunological point of view, 1 year of pembrolizumab is more effective than 3 months of the combination therapy.

“I think it might be one of the explanations,” he said, adding, however, that these are just “hypotheses” at this stage.
 

Details of the new results

Previous results with the nivolumab-ipilimumab combination, from the CheckMate 214 trial in patients with advanced renal cell carcinoma, had demonstrated that upfront nivolumab plus ipilimumab offered significantly longer treatment-free survival than the VEGF inhibitor sunitinib. The “striking results” from that trial indicated the combination was not only associated with a survival benefit, but also “high response rates, durable responses, complete responses, and even treatment responses that continue after treatment is discontinued,” Dr. Motzer commented.

So his team set out to test the combination in the adjuvant setting in the CheckMate 914 trial, designed in two parts: Part A, comparing nivolumab plus ipilimumab with placebo, and Part B, adding nivolumab monotherapy as another comparator.

Reporting on Part A of the trial, Dr. Motzer explained that they included 816 patients with renal cell carcinoma who had undergone radical or partial nephrectomy with negative surgical margins and had a predominantly clear cell histology.

They also selected patients based on their pathologic TNM staging, choosing “high-risk” individuals, Dr. Motzer explained, but who nevertheless had no evidence of residual disease or distant metastases following nephrectomy.

Between 4 and 12 weeks after surgery, patients were randomized to receive 12 doses of nivolumab plus four doses of ipilimumab or matched placebos for an expected treatment duration of 24 weeks.

The median age of patients was 58-59 years, and approximately 71% were men. By far the most common type of surgery was radical nephrectomy, with 93%, and Dr. Motzer noted that most patients (77%-78%) had pT3 disease without nodal involvement.

After a median follow-up of 37.0 months, there was no significant difference between groups in the primary endpoint of DFS, as assessed by blinded independent central review.

Median DFS was not reached for nivolumab plus ipilimumab versus 50.7 months for placebo, at a hazard ratio of 0.92 (P = .5347). At 24 months, DFS was 76.4% with the combination therapy versus 74.0% for placebo.

Subgroup analysis did not reveal any patient groups that significantly benefitted from the combination therapy, although there was a signal of greater benefit in those with other than pT3 disease.

While tumors with sarcomatoid features appeared to have a significant benefit from nivolumab plus ipilimumab therapy, they represented only 5% of the study population.

During his presentation, Dr. Motzer showed the median duration of therapy was 5.1 months in both groups, but only 57% of nivolumab plus ipilimumab patients completed all doses versus 89% of those assigned to placebo.

In addition, 33% of patients given nivolumab plus ipilimumab discontinued due to study drug toxicity and 29% had a treatment-related adverse event that led to treatment discontinuation. This compared with only 1% of patients for both outcomes with placebo.

The most common treatment-related adverse events in the combination therapy group were pruritus (27%), fatigue (25%), diarrhea (20%), rash (19%), hyperthyroidism (16%), and hypothyroidism (16%), and the vast majority of events were grade 1-2.

Dr. Motzer said that, following these negative results, they are “certainly digging deeper into the details to see which particular groups may have benefited and when toxicity occurred.

Then, more importantly, the team will look out for the results of Part B of the trial to assess the impact of nivolumab monotherapy. “I’m hoping it’s better tolerated,” he said.

Discussant James Larkin, MD, PhD, a consultant medical oncologist at The Royal Marsden, London, said the results from CheckMate 914 came “as a bit of a surprise.”

As did Dr. Motzer, Dr. Larkin singled out the high number of patients who could not complete the full dosing schedule and discontinued treatment.

He added that, while one has to be “cautious” when comparing trials, KEYNOTE-564 was “relatively similar” in design, and it’s “unlikely there’s any significant difference in activity” between the two drugs.

Dr. Larkin also believes data from Part B of CheckMate 914 will be “illuminating.”

There are nevertheless a number of outstanding questions about the results from Part A, he said, the main one being how to better select patients who might respond to the combination, which currently is not possible due to the lack of clinically relevant biomarkers.

The study was funded by Bristol Myers Squibb. Dr. Motzer has disclosed relationships with AstraZeneca, Aveo Pharmaceuticals, Bristol Myers Squibb, Eisai, EMD Serono, Exelixis, Genentech/Roche, Incyte, Lilly Oncology, Merck, Novartis, and Pfizer.

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

PARIS – New disappointing results from a trial of adjuvant immunotherapy for patients with renal cell carcinoma who underwent nephrectomy contrast with those from a previous trial that showed benefit with another agent.

The new results, from CheckMate 914, show that adjuvant treatment with the combination of nivolumab (Opdivo) plus ipilimumab (Yervoy) did not improve disease-free survival (DFS), compared with placebo.

The finding was presented at the annual meeting of the European Society for Medical Oncology.

CheckMate 914 “did not meet the primary endpoint,” study presenter Robert J. Motzer, MD, a medical oncologist at Memorial Sloan Kettering Cancer Center, New York, said at a press conference.

The results contrast with those seen with pembrolizumab (Keytruda) in the same setting, where the drug achieved a 32% reduction in risk of recurrence or death over placebo in KEYNOTE-564. This led to the U.S. Food and Drug Administration granting approval for the drug as adjuvant treatment following surgery in patients with renal cell carcinoma at intermediate or high risk for recurrence after nephrectomy or after nephrectomy and resection of metastatic lesions.

Another trial of adjuvant immunotherapy in renal cell carcinoma, also presented at ESMO 2022, the IMmotion010 trial with adjuvant atezolizumab (Tecentriq), also did not show any clinical benefit over placebo.

However, Dr. Motzer said that despite both of these new trials showing no benefit, “I don’t think it takes away from standard of care pembrolizumab” in this setting.

There is a great need for adjuvant therapy for patients who undergo surgery, Dr. Motzer commented. The standard treatment for stage I-III localized nonmetastatic renal cell carcinoma is radical or partial nephrectomy, but there remains a “substantial risk” of relapse after surgery, occurring in up to 50% of patients.

In the past, the standard of care for these patients would be watching and waiting and “hoping that the patient doesn’t relapse,” he said, and if they did, then “we would treat accordingly for metastatic disease.”
 

Differences between trials

When asked about the contrast between the latest trial with the adjuvant nivolumab-ipilimumab combination and the earlier trial with adjuvant pembrolizumab, Dr. Motzer told this news organization that there are differences in the designs of the two studies. “Although they are both global phase 2 trials ... [there are] some differences in the patient population.”

However, the “main differences” are the duration, intensity, and tolerability of the treatment regimens. “I suspect that’s impacted on the outcome of our trial,” he said, as “many of our patients didn’t complete even that 6 months of the more toxic immunotherapy [nivolumab-ipilimumab combination].”

Dr. Motzer also noted that, compared with the metastatic setting, patients “do not tolerate therapy as well” in the adjuvant setting. Consequently, the risk-benefit of a drug is “slightly different ... as we have to be much more concerned about toxicity.”

In addition, he said, “our trial also used these kind-of gross clinical features that were developed years ago” to select patients, but now “there’s other much more refined techniques” that look at the underlying biological signatures “to identify who responds to immunotherapy.”

“So I think we have to do a deep dive into the biology in this trial and in the Merck trial [of pembrolizumab] to see if we can better define who is going to relapse and who is going to benefit,” he said.

Commenting on the new results, Dominik Berthold, MD, Centre Hospitalier Universitaire Vaudois, Lausanne, Switzerland, also wondered whether differences in trial design and study populations could explain the divergent results between the CheckMate and KEYNOTE trials.

“Investigators will need to look in detail at subpopulations and biomarkers to guide treatment decisions and trial design for current and future patients,” he added.

Dr. Berthold said he agrees that pembrolizumab remains standard of care, but “I’m not really sure that we have really to offer all patients” the drug.

He explained that, on the one hand, there is the risk of over-treating many patients, depending on their stage, and on the other hand, “many patients who get pembrolizumab actually do progress.”

In addition, there is the question of the treatment sequence in patients who are already exposed to immunotherapy and when to start tyrosine kinase inhibitors, as well as the much broader issue of the lack of long-term overall survival data with pembrolizumab.

Dr. Berthold noted the issue of whether the high treatment discontinuation rate in CheckMate 914 affected the efficacy of nivolumab plus ipilimumab raises the question of whether, from an immunological point of view, 1 year of pembrolizumab is more effective than 3 months of the combination therapy.

“I think it might be one of the explanations,” he said, adding, however, that these are just “hypotheses” at this stage.
 

Details of the new results

Previous results with the nivolumab-ipilimumab combination, from the CheckMate 214 trial in patients with advanced renal cell carcinoma, had demonstrated that upfront nivolumab plus ipilimumab offered significantly longer treatment-free survival than the VEGF inhibitor sunitinib. The “striking results” from that trial indicated the combination was not only associated with a survival benefit, but also “high response rates, durable responses, complete responses, and even treatment responses that continue after treatment is discontinued,” Dr. Motzer commented.

So his team set out to test the combination in the adjuvant setting in the CheckMate 914 trial, designed in two parts: Part A, comparing nivolumab plus ipilimumab with placebo, and Part B, adding nivolumab monotherapy as another comparator.

Reporting on Part A of the trial, Dr. Motzer explained that they included 816 patients with renal cell carcinoma who had undergone radical or partial nephrectomy with negative surgical margins and had a predominantly clear cell histology.

They also selected patients based on their pathologic TNM staging, choosing “high-risk” individuals, Dr. Motzer explained, but who nevertheless had no evidence of residual disease or distant metastases following nephrectomy.

Between 4 and 12 weeks after surgery, patients were randomized to receive 12 doses of nivolumab plus four doses of ipilimumab or matched placebos for an expected treatment duration of 24 weeks.

The median age of patients was 58-59 years, and approximately 71% were men. By far the most common type of surgery was radical nephrectomy, with 93%, and Dr. Motzer noted that most patients (77%-78%) had pT3 disease without nodal involvement.

After a median follow-up of 37.0 months, there was no significant difference between groups in the primary endpoint of DFS, as assessed by blinded independent central review.

Median DFS was not reached for nivolumab plus ipilimumab versus 50.7 months for placebo, at a hazard ratio of 0.92 (P = .5347). At 24 months, DFS was 76.4% with the combination therapy versus 74.0% for placebo.

Subgroup analysis did not reveal any patient groups that significantly benefitted from the combination therapy, although there was a signal of greater benefit in those with other than pT3 disease.

While tumors with sarcomatoid features appeared to have a significant benefit from nivolumab plus ipilimumab therapy, they represented only 5% of the study population.

During his presentation, Dr. Motzer showed the median duration of therapy was 5.1 months in both groups, but only 57% of nivolumab plus ipilimumab patients completed all doses versus 89% of those assigned to placebo.

In addition, 33% of patients given nivolumab plus ipilimumab discontinued due to study drug toxicity and 29% had a treatment-related adverse event that led to treatment discontinuation. This compared with only 1% of patients for both outcomes with placebo.

The most common treatment-related adverse events in the combination therapy group were pruritus (27%), fatigue (25%), diarrhea (20%), rash (19%), hyperthyroidism (16%), and hypothyroidism (16%), and the vast majority of events were grade 1-2.

Dr. Motzer said that, following these negative results, they are “certainly digging deeper into the details to see which particular groups may have benefited and when toxicity occurred.

Then, more importantly, the team will look out for the results of Part B of the trial to assess the impact of nivolumab monotherapy. “I’m hoping it’s better tolerated,” he said.

Discussant James Larkin, MD, PhD, a consultant medical oncologist at The Royal Marsden, London, said the results from CheckMate 914 came “as a bit of a surprise.”

As did Dr. Motzer, Dr. Larkin singled out the high number of patients who could not complete the full dosing schedule and discontinued treatment.

He added that, while one has to be “cautious” when comparing trials, KEYNOTE-564 was “relatively similar” in design, and it’s “unlikely there’s any significant difference in activity” between the two drugs.

Dr. Larkin also believes data from Part B of CheckMate 914 will be “illuminating.”

There are nevertheless a number of outstanding questions about the results from Part A, he said, the main one being how to better select patients who might respond to the combination, which currently is not possible due to the lack of clinically relevant biomarkers.

The study was funded by Bristol Myers Squibb. Dr. Motzer has disclosed relationships with AstraZeneca, Aveo Pharmaceuticals, Bristol Myers Squibb, Eisai, EMD Serono, Exelixis, Genentech/Roche, Incyte, Lilly Oncology, Merck, Novartis, and Pfizer.

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

PARIS – New disappointing results from a trial of adjuvant immunotherapy for patients with renal cell carcinoma who underwent nephrectomy contrast with those from a previous trial that showed benefit with another agent.

The new results, from CheckMate 914, show that adjuvant treatment with the combination of nivolumab (Opdivo) plus ipilimumab (Yervoy) did not improve disease-free survival (DFS), compared with placebo.

The finding was presented at the annual meeting of the European Society for Medical Oncology.

CheckMate 914 “did not meet the primary endpoint,” study presenter Robert J. Motzer, MD, a medical oncologist at Memorial Sloan Kettering Cancer Center, New York, said at a press conference.

The results contrast with those seen with pembrolizumab (Keytruda) in the same setting, where the drug achieved a 32% reduction in risk of recurrence or death over placebo in KEYNOTE-564. This led to the U.S. Food and Drug Administration granting approval for the drug as adjuvant treatment following surgery in patients with renal cell carcinoma at intermediate or high risk for recurrence after nephrectomy or after nephrectomy and resection of metastatic lesions.

Another trial of adjuvant immunotherapy in renal cell carcinoma, also presented at ESMO 2022, the IMmotion010 trial with adjuvant atezolizumab (Tecentriq), also did not show any clinical benefit over placebo.

However, Dr. Motzer said that despite both of these new trials showing no benefit, “I don’t think it takes away from standard of care pembrolizumab” in this setting.

There is a great need for adjuvant therapy for patients who undergo surgery, Dr. Motzer commented. The standard treatment for stage I-III localized nonmetastatic renal cell carcinoma is radical or partial nephrectomy, but there remains a “substantial risk” of relapse after surgery, occurring in up to 50% of patients.

In the past, the standard of care for these patients would be watching and waiting and “hoping that the patient doesn’t relapse,” he said, and if they did, then “we would treat accordingly for metastatic disease.”
 

Differences between trials

When asked about the contrast between the latest trial with the adjuvant nivolumab-ipilimumab combination and the earlier trial with adjuvant pembrolizumab, Dr. Motzer told this news organization that there are differences in the designs of the two studies. “Although they are both global phase 2 trials ... [there are] some differences in the patient population.”

However, the “main differences” are the duration, intensity, and tolerability of the treatment regimens. “I suspect that’s impacted on the outcome of our trial,” he said, as “many of our patients didn’t complete even that 6 months of the more toxic immunotherapy [nivolumab-ipilimumab combination].”

Dr. Motzer also noted that, compared with the metastatic setting, patients “do not tolerate therapy as well” in the adjuvant setting. Consequently, the risk-benefit of a drug is “slightly different ... as we have to be much more concerned about toxicity.”

In addition, he said, “our trial also used these kind-of gross clinical features that were developed years ago” to select patients, but now “there’s other much more refined techniques” that look at the underlying biological signatures “to identify who responds to immunotherapy.”

“So I think we have to do a deep dive into the biology in this trial and in the Merck trial [of pembrolizumab] to see if we can better define who is going to relapse and who is going to benefit,” he said.

Commenting on the new results, Dominik Berthold, MD, Centre Hospitalier Universitaire Vaudois, Lausanne, Switzerland, also wondered whether differences in trial design and study populations could explain the divergent results between the CheckMate and KEYNOTE trials.

“Investigators will need to look in detail at subpopulations and biomarkers to guide treatment decisions and trial design for current and future patients,” he added.

Dr. Berthold said he agrees that pembrolizumab remains standard of care, but “I’m not really sure that we have really to offer all patients” the drug.

He explained that, on the one hand, there is the risk of over-treating many patients, depending on their stage, and on the other hand, “many patients who get pembrolizumab actually do progress.”

In addition, there is the question of the treatment sequence in patients who are already exposed to immunotherapy and when to start tyrosine kinase inhibitors, as well as the much broader issue of the lack of long-term overall survival data with pembrolizumab.

Dr. Berthold noted the issue of whether the high treatment discontinuation rate in CheckMate 914 affected the efficacy of nivolumab plus ipilimumab raises the question of whether, from an immunological point of view, 1 year of pembrolizumab is more effective than 3 months of the combination therapy.

“I think it might be one of the explanations,” he said, adding, however, that these are just “hypotheses” at this stage.
 

Details of the new results

Previous results with the nivolumab-ipilimumab combination, from the CheckMate 214 trial in patients with advanced renal cell carcinoma, had demonstrated that upfront nivolumab plus ipilimumab offered significantly longer treatment-free survival than the VEGF inhibitor sunitinib. The “striking results” from that trial indicated the combination was not only associated with a survival benefit, but also “high response rates, durable responses, complete responses, and even treatment responses that continue after treatment is discontinued,” Dr. Motzer commented.

So his team set out to test the combination in the adjuvant setting in the CheckMate 914 trial, designed in two parts: Part A, comparing nivolumab plus ipilimumab with placebo, and Part B, adding nivolumab monotherapy as another comparator.

Reporting on Part A of the trial, Dr. Motzer explained that they included 816 patients with renal cell carcinoma who had undergone radical or partial nephrectomy with negative surgical margins and had a predominantly clear cell histology.

They also selected patients based on their pathologic TNM staging, choosing “high-risk” individuals, Dr. Motzer explained, but who nevertheless had no evidence of residual disease or distant metastases following nephrectomy.

Between 4 and 12 weeks after surgery, patients were randomized to receive 12 doses of nivolumab plus four doses of ipilimumab or matched placebos for an expected treatment duration of 24 weeks.

The median age of patients was 58-59 years, and approximately 71% were men. By far the most common type of surgery was radical nephrectomy, with 93%, and Dr. Motzer noted that most patients (77%-78%) had pT3 disease without nodal involvement.

After a median follow-up of 37.0 months, there was no significant difference between groups in the primary endpoint of DFS, as assessed by blinded independent central review.

Median DFS was not reached for nivolumab plus ipilimumab versus 50.7 months for placebo, at a hazard ratio of 0.92 (P = .5347). At 24 months, DFS was 76.4% with the combination therapy versus 74.0% for placebo.

Subgroup analysis did not reveal any patient groups that significantly benefitted from the combination therapy, although there was a signal of greater benefit in those with other than pT3 disease.

While tumors with sarcomatoid features appeared to have a significant benefit from nivolumab plus ipilimumab therapy, they represented only 5% of the study population.

During his presentation, Dr. Motzer showed the median duration of therapy was 5.1 months in both groups, but only 57% of nivolumab plus ipilimumab patients completed all doses versus 89% of those assigned to placebo.

In addition, 33% of patients given nivolumab plus ipilimumab discontinued due to study drug toxicity and 29% had a treatment-related adverse event that led to treatment discontinuation. This compared with only 1% of patients for both outcomes with placebo.

The most common treatment-related adverse events in the combination therapy group were pruritus (27%), fatigue (25%), diarrhea (20%), rash (19%), hyperthyroidism (16%), and hypothyroidism (16%), and the vast majority of events were grade 1-2.

Dr. Motzer said that, following these negative results, they are “certainly digging deeper into the details to see which particular groups may have benefited and when toxicity occurred.

Then, more importantly, the team will look out for the results of Part B of the trial to assess the impact of nivolumab monotherapy. “I’m hoping it’s better tolerated,” he said.

Discussant James Larkin, MD, PhD, a consultant medical oncologist at The Royal Marsden, London, said the results from CheckMate 914 came “as a bit of a surprise.”

As did Dr. Motzer, Dr. Larkin singled out the high number of patients who could not complete the full dosing schedule and discontinued treatment.

He added that, while one has to be “cautious” when comparing trials, KEYNOTE-564 was “relatively similar” in design, and it’s “unlikely there’s any significant difference in activity” between the two drugs.

Dr. Larkin also believes data from Part B of CheckMate 914 will be “illuminating.”

There are nevertheless a number of outstanding questions about the results from Part A, he said, the main one being how to better select patients who might respond to the combination, which currently is not possible due to the lack of clinically relevant biomarkers.

The study was funded by Bristol Myers Squibb. Dr. Motzer has disclosed relationships with AstraZeneca, Aveo Pharmaceuticals, Bristol Myers Squibb, Eisai, EMD Serono, Exelixis, Genentech/Roche, Incyte, Lilly Oncology, Merck, Novartis, and Pfizer.

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

The level of remission in patients with remitting inflammatory bowel disease (IBD) appears to play a major role in whether they will relapse after treatment when biologic therapies are discontinued, according to a new prospective study.

Patients with complete endoscopic healing have half the rate of relapse after withdrawal of anti-tumor necrosis factor alpha (anti-TNF) treatment than those with only partial healing, according to a study published online in Clinical Gastroenterology and Hepatology.

“Applying strict criteria for endoscopic healing and mesalamine treatment ... may lower the risk of relapse after withdrawal of anti-TNF treatment,” write Bas Oldenburg, MD, PhD, a professor at University Medical Center Utrecht, the Netherlands, and colleagues in their analysis of 81 patients.

De-escalation of anti-TNF treatment in IBD patients in remission has the potential to “reduce side effects, including risks of serious infections and malignancies, decrease health care expenditures, and meet patients’ preferences,” they note.

However, withdrawal of the drugs increases the risk of relapse by 30%-45% at 12 months. When patients relapse, reintroduction of anti-TNF therapy returns over 80% to remission.

Although no consensus exists on how to select patients for therapy de-escalation, evidence suggests that persistent inflammation affects outcomes and that the “depth” of endoscopic healing is a key indicator, the authors note.
 

Study details

To further the knowledge base, they conducted a prospective study of patients in remission to determine the relapse rate following de-escalation of anti-TNF therapy; evaluate relapse factors, including degree of endoscopic healing; and assess outcomes after reintroduction of anti-TNF therapy.

The study was limited to adult patients with IBD with at least 6 months of corticosteroid-free clinical remission, confirmed baseline clinical remission and endoscopic healing, no current hospitalization, and no pregnancy.

The patients underwent elective discontinuation of anti-TNF therapy between 2018 and 2020. The recommended protocol was to measure C-reactive protein (CRP) and fecal calprotectin at 3, 6, 12, and 24 months and to perform endoscopy at 12 months.

Patients also completed questionnaires at baseline and at 3, 6, 12, and 24 months. The authors selected the patient–Harvey-Bradshaw Index for patients with Crohn’s disease and the patient–Simple Clinical Colitis Activity Index for patients with ulcerative colitis and unclassified IBD, as well as the short IBD Quality of Life measure.

Of the 81 patients from 13 centers who took part, 51% had Crohn’s disease. The median duration of remission at baseline was 3.5 years, and the median disease duration was 9.1 years.

All patients had evidence of endoscopic healing, and 88% met the strict criteria for complete endoscopic healing. In 34%, trough levels of anti-TNF treatments were judged to be subtherapeutic.

After withdrawal of the drugs, 25.9% of patients continued on immunomodulators.

Over a median follow-up of 2 years, 49% of patients relapsed, which was confirmed via endoscopy, fecal calprotectin, or CRP in 83% of cases and inferred from treatment escalation for clinical flare in 17%. Rates of relapse were comparable between patients with Crohn’s disease and ulcerative colitis or unclassified IBD and between those discontinuing adalimumab and those stopping infliximab.
 

Better healing, better outcomes

However, analysis showed that partial endoscopic healing was independently associated with a higher risk of relapse, at an adjusted hazard ratio versus complete endoscopic healing of 3.28.

At 12 months, 70% of patients with partial endoscopic healing had relapsed versus 35% of those with complete endoscopic healing.

Treatment with the anti-inflammatory agent mesalamine (multiple brands) was independently associated with a reduced risk of relapse, at an adjusted hazard ratio of 0.08. No other potential predictors of relapse were identified.

Of the patients who relapsed, 75% restarted anti-TNF treatment, and the majority (87%) were restarted on the same agent at a median of 0.9 years since its withdrawal and a median of 24 days since the onset of relapse.

Clinical remission was achieved at 3 months in 73% of patients who restarted anti-TNF therapy, which was found to restore quality of life and well-being in relapsed patients, the authors report.
 

Reluctance remains

Stephen B. Hanauer, MD, professor of medicine (gastroenterology and hepatology) at Northwestern University Feinberg School of Medicine, Chicago, said the findings “reinforce the benefits of the maintenance versus the withdrawal of therapy” and “the deeper the remission” the more likely it is to be sustained.

The 35% relapse rate at 12 months, even in patients with compete endoscopic healing, indicates that treatment should be maintained, Dr. Hanauer said.

“What is also relevant, but was not evaluated, is the additional endpoint of histologic healing, which is likely to sustain remissions even longer,” he added.

Nevertheless, Dr. Hanauer said, the “observed relapse rate is important to discuss in shared decision-making with patients.”

The findings are interesting, but the study didn’t follow the patients for long enough to understand why 35% of those with complete endoscopic healing relapsed, Miguel Regueiro, MD, chair of the Cleveland Clinic’s Digestive Disease & Surgery Institute, told this news organization.

“Are there predictors, factors, or other treatments that could be used to reduce that 35% risk of relapse further?” he questioned.

Although the study didn’t clear up that question for Dr. Regueiro, he found it compelling that mesalamine continuation resulted in higher rates of sustained remission after anti-TNF withdrawal among patients with ulcerative colitis.

Dr. Regueiro said that he will not begin recommending withdrawal of advanced therapies, including anti-TNF drugs, in patients who have achieved a stable remission.

“We have not yet found the cure for IBD, and my concern is that patients may relapse with more severe disease than previously and that recurrence of inflammation could have potential risks for complications,” he said.

“Nonetheless, this study is intriguing and important, and at least prompts the discussion of withdrawing therapy in those who have achieved a deep endoscopic remission for a sustained period of time,” Dr. Regueiro added.

The study received support from the Dutch Health Insurance Innovation Fund.

Dr. Oldenburg declares relationships with AbbVie, Celltrion, Ferring, Takeda, Galapagos, Pfizer, Cablon, PBMS, Janssen, and MSD. Other authors also declare numerous relationships. The full list can be found with the original article. Dr. Hanauer declares relationships with AbbVie, Janssen, Pfizer, and Boehringer Ingelheim. Dr. Regueiro declares relationships with AbbVie, Janssen, UCB, Takeda, Pfizer, Miraca Labs, Amgen, Celgene, Seres, Allergan, Genentech, Gilead, Salix, Prometheus, Lilly, TARGET Pharma Solutions, ALFASIGMA, S.p.A., BMS, CME Outfitters, Imedex, GI Health Foundation, Cornerstones, Remedy, MJH Life Sciences, Medscape, MDEducation, WebMD, and HMPGlobal.

Help your patients better understand their IBD treatment options by sharing AGA’s patient education, “Living with IBD,” in the AGA GI Patient Center at www.gastro.org/IBD. 

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

The level of remission in patients with remitting inflammatory bowel disease (IBD) appears to play a major role in whether they will relapse after treatment when biologic therapies are discontinued, according to a new prospective study.

Patients with complete endoscopic healing have half the rate of relapse after withdrawal of anti-tumor necrosis factor alpha (anti-TNF) treatment than those with only partial healing, according to a study published online in Clinical Gastroenterology and Hepatology.

“Applying strict criteria for endoscopic healing and mesalamine treatment ... may lower the risk of relapse after withdrawal of anti-TNF treatment,” write Bas Oldenburg, MD, PhD, a professor at University Medical Center Utrecht, the Netherlands, and colleagues in their analysis of 81 patients.

De-escalation of anti-TNF treatment in IBD patients in remission has the potential to “reduce side effects, including risks of serious infections and malignancies, decrease health care expenditures, and meet patients’ preferences,” they note.

However, withdrawal of the drugs increases the risk of relapse by 30%-45% at 12 months. When patients relapse, reintroduction of anti-TNF therapy returns over 80% to remission.

Although no consensus exists on how to select patients for therapy de-escalation, evidence suggests that persistent inflammation affects outcomes and that the “depth” of endoscopic healing is a key indicator, the authors note.
 

Study details

To further the knowledge base, they conducted a prospective study of patients in remission to determine the relapse rate following de-escalation of anti-TNF therapy; evaluate relapse factors, including degree of endoscopic healing; and assess outcomes after reintroduction of anti-TNF therapy.

The study was limited to adult patients with IBD with at least 6 months of corticosteroid-free clinical remission, confirmed baseline clinical remission and endoscopic healing, no current hospitalization, and no pregnancy.

The patients underwent elective discontinuation of anti-TNF therapy between 2018 and 2020. The recommended protocol was to measure C-reactive protein (CRP) and fecal calprotectin at 3, 6, 12, and 24 months and to perform endoscopy at 12 months.

Patients also completed questionnaires at baseline and at 3, 6, 12, and 24 months. The authors selected the patient–Harvey-Bradshaw Index for patients with Crohn’s disease and the patient–Simple Clinical Colitis Activity Index for patients with ulcerative colitis and unclassified IBD, as well as the short IBD Quality of Life measure.

Of the 81 patients from 13 centers who took part, 51% had Crohn’s disease. The median duration of remission at baseline was 3.5 years, and the median disease duration was 9.1 years.

All patients had evidence of endoscopic healing, and 88% met the strict criteria for complete endoscopic healing. In 34%, trough levels of anti-TNF treatments were judged to be subtherapeutic.

After withdrawal of the drugs, 25.9% of patients continued on immunomodulators.

Over a median follow-up of 2 years, 49% of patients relapsed, which was confirmed via endoscopy, fecal calprotectin, or CRP in 83% of cases and inferred from treatment escalation for clinical flare in 17%. Rates of relapse were comparable between patients with Crohn’s disease and ulcerative colitis or unclassified IBD and between those discontinuing adalimumab and those stopping infliximab.
 

Better healing, better outcomes

However, analysis showed that partial endoscopic healing was independently associated with a higher risk of relapse, at an adjusted hazard ratio versus complete endoscopic healing of 3.28.

At 12 months, 70% of patients with partial endoscopic healing had relapsed versus 35% of those with complete endoscopic healing.

Treatment with the anti-inflammatory agent mesalamine (multiple brands) was independently associated with a reduced risk of relapse, at an adjusted hazard ratio of 0.08. No other potential predictors of relapse were identified.

Of the patients who relapsed, 75% restarted anti-TNF treatment, and the majority (87%) were restarted on the same agent at a median of 0.9 years since its withdrawal and a median of 24 days since the onset of relapse.

Clinical remission was achieved at 3 months in 73% of patients who restarted anti-TNF therapy, which was found to restore quality of life and well-being in relapsed patients, the authors report.
 

Reluctance remains

Stephen B. Hanauer, MD, professor of medicine (gastroenterology and hepatology) at Northwestern University Feinberg School of Medicine, Chicago, said the findings “reinforce the benefits of the maintenance versus the withdrawal of therapy” and “the deeper the remission” the more likely it is to be sustained.

The 35% relapse rate at 12 months, even in patients with compete endoscopic healing, indicates that treatment should be maintained, Dr. Hanauer said.

“What is also relevant, but was not evaluated, is the additional endpoint of histologic healing, which is likely to sustain remissions even longer,” he added.

Nevertheless, Dr. Hanauer said, the “observed relapse rate is important to discuss in shared decision-making with patients.”

The findings are interesting, but the study didn’t follow the patients for long enough to understand why 35% of those with complete endoscopic healing relapsed, Miguel Regueiro, MD, chair of the Cleveland Clinic’s Digestive Disease & Surgery Institute, told this news organization.

“Are there predictors, factors, or other treatments that could be used to reduce that 35% risk of relapse further?” he questioned.

Although the study didn’t clear up that question for Dr. Regueiro, he found it compelling that mesalamine continuation resulted in higher rates of sustained remission after anti-TNF withdrawal among patients with ulcerative colitis.

Dr. Regueiro said that he will not begin recommending withdrawal of advanced therapies, including anti-TNF drugs, in patients who have achieved a stable remission.

“We have not yet found the cure for IBD, and my concern is that patients may relapse with more severe disease than previously and that recurrence of inflammation could have potential risks for complications,” he said.

“Nonetheless, this study is intriguing and important, and at least prompts the discussion of withdrawing therapy in those who have achieved a deep endoscopic remission for a sustained period of time,” Dr. Regueiro added.

The study received support from the Dutch Health Insurance Innovation Fund.

Dr. Oldenburg declares relationships with AbbVie, Celltrion, Ferring, Takeda, Galapagos, Pfizer, Cablon, PBMS, Janssen, and MSD. Other authors also declare numerous relationships. The full list can be found with the original article. Dr. Hanauer declares relationships with AbbVie, Janssen, Pfizer, and Boehringer Ingelheim. Dr. Regueiro declares relationships with AbbVie, Janssen, UCB, Takeda, Pfizer, Miraca Labs, Amgen, Celgene, Seres, Allergan, Genentech, Gilead, Salix, Prometheus, Lilly, TARGET Pharma Solutions, ALFASIGMA, S.p.A., BMS, CME Outfitters, Imedex, GI Health Foundation, Cornerstones, Remedy, MJH Life Sciences, Medscape, MDEducation, WebMD, and HMPGlobal.

Help your patients better understand their IBD treatment options by sharing AGA’s patient education, “Living with IBD,” in the AGA GI Patient Center at www.gastro.org/IBD. 

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

The level of remission in patients with remitting inflammatory bowel disease (IBD) appears to play a major role in whether they will relapse after treatment when biologic therapies are discontinued, according to a new prospective study.

Patients with complete endoscopic healing have half the rate of relapse after withdrawal of anti-tumor necrosis factor alpha (anti-TNF) treatment than those with only partial healing, according to a study published online in Clinical Gastroenterology and Hepatology.

“Applying strict criteria for endoscopic healing and mesalamine treatment ... may lower the risk of relapse after withdrawal of anti-TNF treatment,” write Bas Oldenburg, MD, PhD, a professor at University Medical Center Utrecht, the Netherlands, and colleagues in their analysis of 81 patients.

De-escalation of anti-TNF treatment in IBD patients in remission has the potential to “reduce side effects, including risks of serious infections and malignancies, decrease health care expenditures, and meet patients’ preferences,” they note.

However, withdrawal of the drugs increases the risk of relapse by 30%-45% at 12 months. When patients relapse, reintroduction of anti-TNF therapy returns over 80% to remission.

Although no consensus exists on how to select patients for therapy de-escalation, evidence suggests that persistent inflammation affects outcomes and that the “depth” of endoscopic healing is a key indicator, the authors note.
 

Study details

To further the knowledge base, they conducted a prospective study of patients in remission to determine the relapse rate following de-escalation of anti-TNF therapy; evaluate relapse factors, including degree of endoscopic healing; and assess outcomes after reintroduction of anti-TNF therapy.

The study was limited to adult patients with IBD with at least 6 months of corticosteroid-free clinical remission, confirmed baseline clinical remission and endoscopic healing, no current hospitalization, and no pregnancy.

The patients underwent elective discontinuation of anti-TNF therapy between 2018 and 2020. The recommended protocol was to measure C-reactive protein (CRP) and fecal calprotectin at 3, 6, 12, and 24 months and to perform endoscopy at 12 months.

Patients also completed questionnaires at baseline and at 3, 6, 12, and 24 months. The authors selected the patient–Harvey-Bradshaw Index for patients with Crohn’s disease and the patient–Simple Clinical Colitis Activity Index for patients with ulcerative colitis and unclassified IBD, as well as the short IBD Quality of Life measure.

Of the 81 patients from 13 centers who took part, 51% had Crohn’s disease. The median duration of remission at baseline was 3.5 years, and the median disease duration was 9.1 years.

All patients had evidence of endoscopic healing, and 88% met the strict criteria for complete endoscopic healing. In 34%, trough levels of anti-TNF treatments were judged to be subtherapeutic.

After withdrawal of the drugs, 25.9% of patients continued on immunomodulators.

Over a median follow-up of 2 years, 49% of patients relapsed, which was confirmed via endoscopy, fecal calprotectin, or CRP in 83% of cases and inferred from treatment escalation for clinical flare in 17%. Rates of relapse were comparable between patients with Crohn’s disease and ulcerative colitis or unclassified IBD and between those discontinuing adalimumab and those stopping infliximab.
 

Better healing, better outcomes

However, analysis showed that partial endoscopic healing was independently associated with a higher risk of relapse, at an adjusted hazard ratio versus complete endoscopic healing of 3.28.

At 12 months, 70% of patients with partial endoscopic healing had relapsed versus 35% of those with complete endoscopic healing.

Treatment with the anti-inflammatory agent mesalamine (multiple brands) was independently associated with a reduced risk of relapse, at an adjusted hazard ratio of 0.08. No other potential predictors of relapse were identified.

Of the patients who relapsed, 75% restarted anti-TNF treatment, and the majority (87%) were restarted on the same agent at a median of 0.9 years since its withdrawal and a median of 24 days since the onset of relapse.

Clinical remission was achieved at 3 months in 73% of patients who restarted anti-TNF therapy, which was found to restore quality of life and well-being in relapsed patients, the authors report.
 

Reluctance remains

Stephen B. Hanauer, MD, professor of medicine (gastroenterology and hepatology) at Northwestern University Feinberg School of Medicine, Chicago, said the findings “reinforce the benefits of the maintenance versus the withdrawal of therapy” and “the deeper the remission” the more likely it is to be sustained.

The 35% relapse rate at 12 months, even in patients with compete endoscopic healing, indicates that treatment should be maintained, Dr. Hanauer said.

“What is also relevant, but was not evaluated, is the additional endpoint of histologic healing, which is likely to sustain remissions even longer,” he added.

Nevertheless, Dr. Hanauer said, the “observed relapse rate is important to discuss in shared decision-making with patients.”

The findings are interesting, but the study didn’t follow the patients for long enough to understand why 35% of those with complete endoscopic healing relapsed, Miguel Regueiro, MD, chair of the Cleveland Clinic’s Digestive Disease & Surgery Institute, told this news organization.

“Are there predictors, factors, or other treatments that could be used to reduce that 35% risk of relapse further?” he questioned.

Although the study didn’t clear up that question for Dr. Regueiro, he found it compelling that mesalamine continuation resulted in higher rates of sustained remission after anti-TNF withdrawal among patients with ulcerative colitis.

Dr. Regueiro said that he will not begin recommending withdrawal of advanced therapies, including anti-TNF drugs, in patients who have achieved a stable remission.

“We have not yet found the cure for IBD, and my concern is that patients may relapse with more severe disease than previously and that recurrence of inflammation could have potential risks for complications,” he said.

“Nonetheless, this study is intriguing and important, and at least prompts the discussion of withdrawing therapy in those who have achieved a deep endoscopic remission for a sustained period of time,” Dr. Regueiro added.

The study received support from the Dutch Health Insurance Innovation Fund.

Dr. Oldenburg declares relationships with AbbVie, Celltrion, Ferring, Takeda, Galapagos, Pfizer, Cablon, PBMS, Janssen, and MSD. Other authors also declare numerous relationships. The full list can be found with the original article. Dr. Hanauer declares relationships with AbbVie, Janssen, Pfizer, and Boehringer Ingelheim. Dr. Regueiro declares relationships with AbbVie, Janssen, UCB, Takeda, Pfizer, Miraca Labs, Amgen, Celgene, Seres, Allergan, Genentech, Gilead, Salix, Prometheus, Lilly, TARGET Pharma Solutions, ALFASIGMA, S.p.A., BMS, CME Outfitters, Imedex, GI Health Foundation, Cornerstones, Remedy, MJH Life Sciences, Medscape, MDEducation, WebMD, and HMPGlobal.

Help your patients better understand their IBD treatment options by sharing AGA’s patient education, “Living with IBD,” in the AGA GI Patient Center at www.gastro.org/IBD. 

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

The level of remission in patients with remitting inflammatory bowel disease (IBD) appears to play a major role in whether they will relapse after treatment when biologic therapies are discontinued, according to a new prospective study.

Patients with complete endoscopic healing have half the rate of relapse after withdrawal of anti-tumor necrosis factor alpha (anti-TNF) treatment than those with only partial healing, according to a study published online in Clinical Gastroenterology and Hepatology.

“Applying strict criteria for endoscopic healing and mesalamine treatment ... may lower the risk of relapse after withdrawal of anti-TNF treatment,” write Bas Oldenburg, MD, PhD, a professor at University Medical Center Utrecht, the Netherlands, and colleagues in their analysis of 81 patients.

De-escalation of anti-TNF treatment in IBD patients in remission has the potential to “reduce side effects, including risks of serious infections and malignancies, decrease health care expenditures, and meet patients’ preferences,” they note.

However, withdrawal of the drugs increases the risk of relapse by 30%-45% at 12 months. When patients relapse, reintroduction of anti-TNF therapy returns over 80% to remission.

Although no consensus exists on how to select patients for therapy de-escalation, evidence suggests that persistent inflammation affects outcomes and that the “depth” of endoscopic healing is a key indicator, the authors note.
 

Study details

To further the knowledge base, they conducted a prospective study of patients in remission to determine the relapse rate following de-escalation of anti-TNF therapy; evaluate relapse factors, including degree of endoscopic healing; and assess outcomes after reintroduction of anti-TNF therapy.

The study was limited to adult patients with IBD with at least 6 months of corticosteroid-free clinical remission, confirmed baseline clinical remission and endoscopic healing, no current hospitalization, and no pregnancy.

The patients underwent elective discontinuation of anti-TNF therapy between 2018 and 2020. The recommended protocol was to measure C-reactive protein (CRP) and fecal calprotectin at 3, 6, 12, and 24 months and to perform endoscopy at 12 months.

Patients also completed questionnaires at baseline and at 3, 6, 12, and 24 months. The authors selected the patient–Harvey-Bradshaw Index for patients with Crohn’s disease and the patient–Simple Clinical Colitis Activity Index for patients with ulcerative colitis and unclassified IBD, as well as the short IBD Quality of Life measure.

Of the 81 patients from 13 centers who took part, 51% had Crohn’s disease. The median duration of remission at baseline was 3.5 years, and the median disease duration was 9.1 years.

All patients had evidence of endoscopic healing, and 88% met the strict criteria for complete endoscopic healing. In 34%, trough levels of anti-TNF treatments were judged to be subtherapeutic.

After withdrawal of the drugs, 25.9% of patients continued on immunomodulators.

Over a median follow-up of 2 years, 49% of patients relapsed, which was confirmed via endoscopy, fecal calprotectin, or CRP in 83% of cases and inferred from treatment escalation for clinical flare in 17%. Rates of relapse were comparable between patients with Crohn’s disease and ulcerative colitis or unclassified IBD and between those discontinuing adalimumab and those stopping infliximab.
 

Better healing, better outcomes

However, analysis showed that partial endoscopic healing was independently associated with a higher risk of relapse, at an adjusted hazard ratio versus complete endoscopic healing of 3.28.

At 12 months, 70% of patients with partial endoscopic healing had relapsed versus 35% of those with complete endoscopic healing.

Treatment with the anti-inflammatory agent mesalamine (multiple brands) was independently associated with a reduced risk of relapse, at an adjusted hazard ratio of 0.08. No other potential predictors of relapse were identified.

Of the patients who relapsed, 75% restarted anti-TNF treatment, and the majority (87%) were restarted on the same agent at a median of 0.9 years since its withdrawal and a median of 24 days since the onset of relapse.

Clinical remission was achieved at 3 months in 73% of patients who restarted anti-TNF therapy, which was found to restore quality of life and well-being in relapsed patients, the authors report.
 

Reluctance remains

Stephen B. Hanauer, MD, professor of medicine (gastroenterology and hepatology) at Northwestern University Feinberg School of Medicine, Chicago, said the findings “reinforce the benefits of the maintenance versus the withdrawal of therapy” and “the deeper the remission” the more likely it is to be sustained.

The 35% relapse rate at 12 months, even in patients with compete endoscopic healing, indicates that treatment should be maintained, Dr. Hanauer said.

“What is also relevant, but was not evaluated, is the additional endpoint of histologic healing, which is likely to sustain remissions even longer,” he added.

Nevertheless, Dr. Hanauer said, the “observed relapse rate is important to discuss in shared decision-making with patients.”

The findings are interesting, but the study didn’t follow the patients for long enough to understand why 35% of those with complete endoscopic healing relapsed, Miguel Regueiro, MD, chair of the Cleveland Clinic’s Digestive Disease & Surgery Institute, told this news organization.

“Are there predictors, factors, or other treatments that could be used to reduce that 35% risk of relapse further?” he questioned.

Although the study didn’t clear up that question for Dr. Regueiro, he found it compelling that mesalamine continuation resulted in higher rates of sustained remission after anti-TNF withdrawal among patients with ulcerative colitis.

Dr. Regueiro said that he will not begin recommending withdrawal of advanced therapies, including anti-TNF drugs, in patients who have achieved a stable remission.

“We have not yet found the cure for IBD, and my concern is that patients may relapse with more severe disease than previously and that recurrence of inflammation could have potential risks for complications,” he said.

“Nonetheless, this study is intriguing and important, and at least prompts the discussion of withdrawing therapy in those who have achieved a deep endoscopic remission for a sustained period of time,” Dr. Regueiro added.

The study received support from the Dutch Health Insurance Innovation Fund.

Dr. Oldenburg declares relationships with AbbVie, Celltrion, Ferring, Takeda, Galapagos, Pfizer, Cablon, PBMS, Janssen, and MSD. Other authors also declare numerous relationships. The full list can be found with the original article. Dr. Hanauer declares relationships with AbbVie, Janssen, Pfizer, and Boehringer Ingelheim. Dr. Regueiro declares relationships with AbbVie, Janssen, UCB, Takeda, Pfizer, Miraca Labs, Amgen, Celgene, Seres, Allergan, Genentech, Gilead, Salix, Prometheus, Lilly, TARGET Pharma Solutions, ALFASIGMA, S.p.A., BMS, CME Outfitters, Imedex, GI Health Foundation, Cornerstones, Remedy, MJH Life Sciences, Medscape, MDEducation, WebMD, and HMPGlobal.

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

The level of remission in patients with remitting inflammatory bowel disease (IBD) appears to play a major role in whether they will relapse after treatment when biologic therapies are discontinued, according to a new prospective study.

Patients with complete endoscopic healing have half the rate of relapse after withdrawal of anti-tumor necrosis factor alpha (anti-TNF) treatment than those with only partial healing, according to a study published online in Clinical Gastroenterology and Hepatology.

“Applying strict criteria for endoscopic healing and mesalamine treatment ... may lower the risk of relapse after withdrawal of anti-TNF treatment,” write Bas Oldenburg, MD, PhD, a professor at University Medical Center Utrecht, the Netherlands, and colleagues in their analysis of 81 patients.

De-escalation of anti-TNF treatment in IBD patients in remission has the potential to “reduce side effects, including risks of serious infections and malignancies, decrease health care expenditures, and meet patients’ preferences,” they note.

However, withdrawal of the drugs increases the risk of relapse by 30%-45% at 12 months. When patients relapse, reintroduction of anti-TNF therapy returns over 80% to remission.

Although no consensus exists on how to select patients for therapy de-escalation, evidence suggests that persistent inflammation affects outcomes and that the “depth” of endoscopic healing is a key indicator, the authors note.
 

Study details

To further the knowledge base, they conducted a prospective study of patients in remission to determine the relapse rate following de-escalation of anti-TNF therapy; evaluate relapse factors, including degree of endoscopic healing; and assess outcomes after reintroduction of anti-TNF therapy.

The study was limited to adult patients with IBD with at least 6 months of corticosteroid-free clinical remission, confirmed baseline clinical remission and endoscopic healing, no current hospitalization, and no pregnancy.

The patients underwent elective discontinuation of anti-TNF therapy between 2018 and 2020. The recommended protocol was to measure C-reactive protein (CRP) and fecal calprotectin at 3, 6, 12, and 24 months and to perform endoscopy at 12 months.

Patients also completed questionnaires at baseline and at 3, 6, 12, and 24 months. The authors selected the patient–Harvey-Bradshaw Index for patients with Crohn’s disease and the patient–Simple Clinical Colitis Activity Index for patients with ulcerative colitis and unclassified IBD, as well as the short IBD Quality of Life measure.

Of the 81 patients from 13 centers who took part, 51% had Crohn’s disease. The median duration of remission at baseline was 3.5 years, and the median disease duration was 9.1 years.

All patients had evidence of endoscopic healing, and 88% met the strict criteria for complete endoscopic healing. In 34%, trough levels of anti-TNF treatments were judged to be subtherapeutic.

After withdrawal of the drugs, 25.9% of patients continued on immunomodulators.

Over a median follow-up of 2 years, 49% of patients relapsed, which was confirmed via endoscopy, fecal calprotectin, or CRP in 83% of cases and inferred from treatment escalation for clinical flare in 17%. Rates of relapse were comparable between patients with Crohn’s disease and ulcerative colitis or unclassified IBD and between those discontinuing adalimumab and those stopping infliximab.
 

Better healing, better outcomes

However, analysis showed that partial endoscopic healing was independently associated with a higher risk of relapse, at an adjusted hazard ratio versus complete endoscopic healing of 3.28.

At 12 months, 70% of patients with partial endoscopic healing had relapsed versus 35% of those with complete endoscopic healing.

Treatment with the anti-inflammatory agent mesalamine (multiple brands) was independently associated with a reduced risk of relapse, at an adjusted hazard ratio of 0.08. No other potential predictors of relapse were identified.

Of the patients who relapsed, 75% restarted anti-TNF treatment, and the majority (87%) were restarted on the same agent at a median of 0.9 years since its withdrawal and a median of 24 days since the onset of relapse.

Clinical remission was achieved at 3 months in 73% of patients who restarted anti-TNF therapy, which was found to restore quality of life and well-being in relapsed patients, the authors report.
 

Reluctance remains

Stephen B. Hanauer, MD, professor of medicine (gastroenterology and hepatology) at Northwestern University Feinberg School of Medicine, Chicago, said the findings “reinforce the benefits of the maintenance versus the withdrawal of therapy” and “the deeper the remission” the more likely it is to be sustained.

The 35% relapse rate at 12 months, even in patients with compete endoscopic healing, indicates that treatment should be maintained, Dr. Hanauer said.

“What is also relevant, but was not evaluated, is the additional endpoint of histologic healing, which is likely to sustain remissions even longer,” he added.

Nevertheless, Dr. Hanauer said, the “observed relapse rate is important to discuss in shared decision-making with patients.”

The findings are interesting, but the study didn’t follow the patients for long enough to understand why 35% of those with complete endoscopic healing relapsed, Miguel Regueiro, MD, chair of the Cleveland Clinic’s Digestive Disease & Surgery Institute, told this news organization.

“Are there predictors, factors, or other treatments that could be used to reduce that 35% risk of relapse further?” he questioned.

Although the study didn’t clear up that question for Dr. Regueiro, he found it compelling that mesalamine continuation resulted in higher rates of sustained remission after anti-TNF withdrawal among patients with ulcerative colitis.

Dr. Regueiro said that he will not begin recommending withdrawal of advanced therapies, including anti-TNF drugs, in patients who have achieved a stable remission.

“We have not yet found the cure for IBD, and my concern is that patients may relapse with more severe disease than previously and that recurrence of inflammation could have potential risks for complications,” he said.

“Nonetheless, this study is intriguing and important, and at least prompts the discussion of withdrawing therapy in those who have achieved a deep endoscopic remission for a sustained period of time,” Dr. Regueiro added.

The study received support from the Dutch Health Insurance Innovation Fund.

Dr. Oldenburg declares relationships with AbbVie, Celltrion, Ferring, Takeda, Galapagos, Pfizer, Cablon, PBMS, Janssen, and MSD. Other authors also declare numerous relationships. The full list can be found with the original article. Dr. Hanauer declares relationships with AbbVie, Janssen, Pfizer, and Boehringer Ingelheim. Dr. Regueiro declares relationships with AbbVie, Janssen, UCB, Takeda, Pfizer, Miraca Labs, Amgen, Celgene, Seres, Allergan, Genentech, Gilead, Salix, Prometheus, Lilly, TARGET Pharma Solutions, ALFASIGMA, S.p.A., BMS, CME Outfitters, Imedex, GI Health Foundation, Cornerstones, Remedy, MJH Life Sciences, Medscape, MDEducation, WebMD, and HMPGlobal.

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

The level of remission in patients with remitting inflammatory bowel disease (IBD) appears to play a major role in whether they will relapse after treatment when biologic therapies are discontinued, according to a new prospective study.

Patients with complete endoscopic healing have half the rate of relapse after withdrawal of anti-tumor necrosis factor alpha (anti-TNF) treatment than those with only partial healing, according to a study published online in Clinical Gastroenterology and Hepatology.

“Applying strict criteria for endoscopic healing and mesalamine treatment ... may lower the risk of relapse after withdrawal of anti-TNF treatment,” write Bas Oldenburg, MD, PhD, a professor at University Medical Center Utrecht, the Netherlands, and colleagues in their analysis of 81 patients.

De-escalation of anti-TNF treatment in IBD patients in remission has the potential to “reduce side effects, including risks of serious infections and malignancies, decrease health care expenditures, and meet patients’ preferences,” they note.

However, withdrawal of the drugs increases the risk of relapse by 30%-45% at 12 months. When patients relapse, reintroduction of anti-TNF therapy returns over 80% to remission.

Although no consensus exists on how to select patients for therapy de-escalation, evidence suggests that persistent inflammation affects outcomes and that the “depth” of endoscopic healing is a key indicator, the authors note.
 

Study details

To further the knowledge base, they conducted a prospective study of patients in remission to determine the relapse rate following de-escalation of anti-TNF therapy; evaluate relapse factors, including degree of endoscopic healing; and assess outcomes after reintroduction of anti-TNF therapy.

The study was limited to adult patients with IBD with at least 6 months of corticosteroid-free clinical remission, confirmed baseline clinical remission and endoscopic healing, no current hospitalization, and no pregnancy.

The patients underwent elective discontinuation of anti-TNF therapy between 2018 and 2020. The recommended protocol was to measure C-reactive protein (CRP) and fecal calprotectin at 3, 6, 12, and 24 months and to perform endoscopy at 12 months.

Patients also completed questionnaires at baseline and at 3, 6, 12, and 24 months. The authors selected the patient–Harvey-Bradshaw Index for patients with Crohn’s disease and the patient–Simple Clinical Colitis Activity Index for patients with ulcerative colitis and unclassified IBD, as well as the short IBD Quality of Life measure.

Of the 81 patients from 13 centers who took part, 51% had Crohn’s disease. The median duration of remission at baseline was 3.5 years, and the median disease duration was 9.1 years.

All patients had evidence of endoscopic healing, and 88% met the strict criteria for complete endoscopic healing. In 34%, trough levels of anti-TNF treatments were judged to be subtherapeutic.

After withdrawal of the drugs, 25.9% of patients continued on immunomodulators.

Over a median follow-up of 2 years, 49% of patients relapsed, which was confirmed via endoscopy, fecal calprotectin, or CRP in 83% of cases and inferred from treatment escalation for clinical flare in 17%. Rates of relapse were comparable between patients with Crohn’s disease and ulcerative colitis or unclassified IBD and between those discontinuing adalimumab and those stopping infliximab.
 

Better healing, better outcomes

However, analysis showed that partial endoscopic healing was independently associated with a higher risk of relapse, at an adjusted hazard ratio versus complete endoscopic healing of 3.28.

At 12 months, 70% of patients with partial endoscopic healing had relapsed versus 35% of those with complete endoscopic healing.

Treatment with the anti-inflammatory agent mesalamine (multiple brands) was independently associated with a reduced risk of relapse, at an adjusted hazard ratio of 0.08. No other potential predictors of relapse were identified.

Of the patients who relapsed, 75% restarted anti-TNF treatment, and the majority (87%) were restarted on the same agent at a median of 0.9 years since its withdrawal and a median of 24 days since the onset of relapse.

Clinical remission was achieved at 3 months in 73% of patients who restarted anti-TNF therapy, which was found to restore quality of life and well-being in relapsed patients, the authors report.
 

Reluctance remains

Stephen B. Hanauer, MD, professor of medicine (gastroenterology and hepatology) at Northwestern University Feinberg School of Medicine, Chicago, said the findings “reinforce the benefits of the maintenance versus the withdrawal of therapy” and “the deeper the remission” the more likely it is to be sustained.

The 35% relapse rate at 12 months, even in patients with compete endoscopic healing, indicates that treatment should be maintained, Dr. Hanauer said.

“What is also relevant, but was not evaluated, is the additional endpoint of histologic healing, which is likely to sustain remissions even longer,” he added.

Nevertheless, Dr. Hanauer said, the “observed relapse rate is important to discuss in shared decision-making with patients.”

The findings are interesting, but the study didn’t follow the patients for long enough to understand why 35% of those with complete endoscopic healing relapsed, Miguel Regueiro, MD, chair of the Cleveland Clinic’s Digestive Disease & Surgery Institute, told this news organization.

“Are there predictors, factors, or other treatments that could be used to reduce that 35% risk of relapse further?” he questioned.

Although the study didn’t clear up that question for Dr. Regueiro, he found it compelling that mesalamine continuation resulted in higher rates of sustained remission after anti-TNF withdrawal among patients with ulcerative colitis.

Dr. Regueiro said that he will not begin recommending withdrawal of advanced therapies, including anti-TNF drugs, in patients who have achieved a stable remission.

“We have not yet found the cure for IBD, and my concern is that patients may relapse with more severe disease than previously and that recurrence of inflammation could have potential risks for complications,” he said.

“Nonetheless, this study is intriguing and important, and at least prompts the discussion of withdrawing therapy in those who have achieved a deep endoscopic remission for a sustained period of time,” Dr. Regueiro added.

The study received support from the Dutch Health Insurance Innovation Fund.

Dr. Oldenburg declares relationships with AbbVie, Celltrion, Ferring, Takeda, Galapagos, Pfizer, Cablon, PBMS, Janssen, and MSD. Other authors also declare numerous relationships. The full list can be found with the original article. Dr. Hanauer declares relationships with AbbVie, Janssen, Pfizer, and Boehringer Ingelheim. Dr. Regueiro declares relationships with AbbVie, Janssen, UCB, Takeda, Pfizer, Miraca Labs, Amgen, Celgene, Seres, Allergan, Genentech, Gilead, Salix, Prometheus, Lilly, TARGET Pharma Solutions, ALFASIGMA, S.p.A., BMS, CME Outfitters, Imedex, GI Health Foundation, Cornerstones, Remedy, MJH Life Sciences, Medscape, MDEducation, WebMD, and HMPGlobal.

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

The immune checkpoint inhibitor nivolumab (Opdivo) appears to prevent the transformation of oral proliferative leukoplakia (PL), a high-risk precancerous disease, into oral cancer, suggest the results from a phase 2 study.

“We think that immunotherapy as a preventative strategy, either as first-line or even secondary prevention, should be further explored,” said lead researcher Glenn J. Hanna, MD, director, Center for Salivary and Rare Head and Neck Cancers, Dana-Farber Cancer Institute, Boston.

The research was presented at the European Society for Medical Oncology Annual Congress in Paris.

Oral leukoplakia refers to a white plaque of “questionable cancer risk” that affects about  4% of the global population, Dr. Hanna explained. However, about 5% of leukoplakia cases develop into oral proliferative leukoplakia, an aggressive form of the disease characterized by multifocal lesions. It has a high risk of transformation to oral squamous cell carcinoma (OSCC), at approaching 10% per year, and the 5-year cancer-free survival rate is estimated to be 47%.

While there are no effective therapies to prevent progression to oral cancer, the condition does have a “rich immune microenvironment,” potentially making it amenable to programmed death (PD)-1 blockade, Dr. Hanna said.

His team conducted a single-arm, phase 2 trial involving 33 patients with proliferative leukoplakia with greater than or equal to 2 multifocal lesions, or contiguous lesions of greater than or equal to 3 cm, or a single lesion greater than or equal to 4 cm with any degree of epithelial dysplasia. The median age was 63.2 years, and 55% were women. Just over half (52%) were never smokers.

The main disease subsite was the oral tongue in 39% of participants, followed by the buccal gingiva in 30%, and 24% of patients had a prior diagnosis of OSCC.

Following a pretreatment biopsy at one to three sites, the patients received four doses of nivolumab every 28 days, followed by rebiopsy. At each visit, the patients had intraoral photographs taken of the lesions and measurements taken.

The median time from study registration to the first dose of nivolumab was 9 days. The majority (88%) of patients completed all four doses of nivolumab.

The median time from the first dose of nivolumab to the posttreatment biopsy was 115 days and ranged from 29 to 171 days.

The overall response rate, defined as a greater than or equal to 40% decrease in a composite score combining the size and degree of dysplasia between the pre- and posttreatment assessments, was observed in 36.4% of patients.

After a median follow-up of 14.7 months, the median cancer-free survival was not reached, with cancer events recorded in 21.2% of patients. The median time from the last dose of nivolumab to the first OSCC event was 3.7 months.

Cancer-free survival at 1 year was calculated to be 77.7%, which was unchanged at 2 years. At the final follow-up, all patients were still alive.

Additional analysis of the biopsies revealed that the lesions had programmed death ligand 1 (PD-L1) combined positive scores that ranged from 0 to 80, with 66.7% of patients having a score of greater than or equal to 1. A cutoff score of greater than or equal to 20 did not reveal any significant differences in cancer-free survival rates.

Turning to safety, Dr. Hanna said that nivolumab was associated with “acceptable toxicity” in this “non-cancer population,” with 21.2% of patients experiencing a grade 3-4 adverse event.

The most common adverse events of any grade were fatigue (55%), diarrhea (27%), elevated alanine transaminase levels (18%), elevated aspartate transaminase levels (18%), and other skin disorders (18%).

With a relatively low rate of adverse events and a “clinical benefit” in up to a third of patients, Dr. Hanna said that this was the “first study to our knowledge to demonstrate the potential efficacy of anti–PD-L1 blockade among patients with a high-risk oral precancerous disease.”

Discussing this study at the meeting, Amanda Psyrri, MD, PhD, professor of medical oncology, Attikon University Hospital, Athens, who was not involved in the research, said these data were “very interesting,” but she expressed some reservations over the way the study was conducted.

She said that the composite score to measure response rates was “defined arbitrarily,” its prognostic value “has not been demonstrated,” and also pointed out that mixed responses by lesions within the same patient led to changes in scores.

In addition, the time interval between the end of treatment and lesion rebiopsy was “highly variable,” and the follow-up period was short.

Consequently, Dr. Psyrri believes the importance of the findings is “unclear,” especially as several patients who responded to nivolumab went on to develop cancer anyway, a finding that needs further investigation.

The study was funded by Bristol Myers Squibb.

Dr. Hanna declared relationships with BMS, Bicara, Exicure, Gateway for Cancer Research, GSK, Kite, NantKwest, Regeneron, Sanofi Genzyme, Maverick, and Merck.

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

The immune checkpoint inhibitor nivolumab (Opdivo) appears to prevent the transformation of oral proliferative leukoplakia (PL), a high-risk precancerous disease, into oral cancer, suggest the results from a phase 2 study.

“We think that immunotherapy as a preventative strategy, either as first-line or even secondary prevention, should be further explored,” said lead researcher Glenn J. Hanna, MD, director, Center for Salivary and Rare Head and Neck Cancers, Dana-Farber Cancer Institute, Boston.

The research was presented at the European Society for Medical Oncology Annual Congress in Paris.

Oral leukoplakia refers to a white plaque of “questionable cancer risk” that affects about  4% of the global population, Dr. Hanna explained. However, about 5% of leukoplakia cases develop into oral proliferative leukoplakia, an aggressive form of the disease characterized by multifocal lesions. It has a high risk of transformation to oral squamous cell carcinoma (OSCC), at approaching 10% per year, and the 5-year cancer-free survival rate is estimated to be 47%.

While there are no effective therapies to prevent progression to oral cancer, the condition does have a “rich immune microenvironment,” potentially making it amenable to programmed death (PD)-1 blockade, Dr. Hanna said.

His team conducted a single-arm, phase 2 trial involving 33 patients with proliferative leukoplakia with greater than or equal to 2 multifocal lesions, or contiguous lesions of greater than or equal to 3 cm, or a single lesion greater than or equal to 4 cm with any degree of epithelial dysplasia. The median age was 63.2 years, and 55% were women. Just over half (52%) were never smokers.

The main disease subsite was the oral tongue in 39% of participants, followed by the buccal gingiva in 30%, and 24% of patients had a prior diagnosis of OSCC.

Following a pretreatment biopsy at one to three sites, the patients received four doses of nivolumab every 28 days, followed by rebiopsy. At each visit, the patients had intraoral photographs taken of the lesions and measurements taken.

The median time from study registration to the first dose of nivolumab was 9 days. The majority (88%) of patients completed all four doses of nivolumab.

The median time from the first dose of nivolumab to the posttreatment biopsy was 115 days and ranged from 29 to 171 days.

The overall response rate, defined as a greater than or equal to 40% decrease in a composite score combining the size and degree of dysplasia between the pre- and posttreatment assessments, was observed in 36.4% of patients.

After a median follow-up of 14.7 months, the median cancer-free survival was not reached, with cancer events recorded in 21.2% of patients. The median time from the last dose of nivolumab to the first OSCC event was 3.7 months.

Cancer-free survival at 1 year was calculated to be 77.7%, which was unchanged at 2 years. At the final follow-up, all patients were still alive.

Additional analysis of the biopsies revealed that the lesions had programmed death ligand 1 (PD-L1) combined positive scores that ranged from 0 to 80, with 66.7% of patients having a score of greater than or equal to 1. A cutoff score of greater than or equal to 20 did not reveal any significant differences in cancer-free survival rates.

Turning to safety, Dr. Hanna said that nivolumab was associated with “acceptable toxicity” in this “non-cancer population,” with 21.2% of patients experiencing a grade 3-4 adverse event.

The most common adverse events of any grade were fatigue (55%), diarrhea (27%), elevated alanine transaminase levels (18%), elevated aspartate transaminase levels (18%), and other skin disorders (18%).

With a relatively low rate of adverse events and a “clinical benefit” in up to a third of patients, Dr. Hanna said that this was the “first study to our knowledge to demonstrate the potential efficacy of anti–PD-L1 blockade among patients with a high-risk oral precancerous disease.”

Discussing this study at the meeting, Amanda Psyrri, MD, PhD, professor of medical oncology, Attikon University Hospital, Athens, who was not involved in the research, said these data were “very interesting,” but she expressed some reservations over the way the study was conducted.

She said that the composite score to measure response rates was “defined arbitrarily,” its prognostic value “has not been demonstrated,” and also pointed out that mixed responses by lesions within the same patient led to changes in scores.

In addition, the time interval between the end of treatment and lesion rebiopsy was “highly variable,” and the follow-up period was short.

Consequently, Dr. Psyrri believes the importance of the findings is “unclear,” especially as several patients who responded to nivolumab went on to develop cancer anyway, a finding that needs further investigation.

The study was funded by Bristol Myers Squibb.

Dr. Hanna declared relationships with BMS, Bicara, Exicure, Gateway for Cancer Research, GSK, Kite, NantKwest, Regeneron, Sanofi Genzyme, Maverick, and Merck.

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

The immune checkpoint inhibitor nivolumab (Opdivo) appears to prevent the transformation of oral proliferative leukoplakia (PL), a high-risk precancerous disease, into oral cancer, suggest the results from a phase 2 study.

“We think that immunotherapy as a preventative strategy, either as first-line or even secondary prevention, should be further explored,” said lead researcher Glenn J. Hanna, MD, director, Center for Salivary and Rare Head and Neck Cancers, Dana-Farber Cancer Institute, Boston.

The research was presented at the European Society for Medical Oncology Annual Congress in Paris.

Oral leukoplakia refers to a white plaque of “questionable cancer risk” that affects about  4% of the global population, Dr. Hanna explained. However, about 5% of leukoplakia cases develop into oral proliferative leukoplakia, an aggressive form of the disease characterized by multifocal lesions. It has a high risk of transformation to oral squamous cell carcinoma (OSCC), at approaching 10% per year, and the 5-year cancer-free survival rate is estimated to be 47%.

While there are no effective therapies to prevent progression to oral cancer, the condition does have a “rich immune microenvironment,” potentially making it amenable to programmed death (PD)-1 blockade, Dr. Hanna said.

His team conducted a single-arm, phase 2 trial involving 33 patients with proliferative leukoplakia with greater than or equal to 2 multifocal lesions, or contiguous lesions of greater than or equal to 3 cm, or a single lesion greater than or equal to 4 cm with any degree of epithelial dysplasia. The median age was 63.2 years, and 55% were women. Just over half (52%) were never smokers.

The main disease subsite was the oral tongue in 39% of participants, followed by the buccal gingiva in 30%, and 24% of patients had a prior diagnosis of OSCC.

Following a pretreatment biopsy at one to three sites, the patients received four doses of nivolumab every 28 days, followed by rebiopsy. At each visit, the patients had intraoral photographs taken of the lesions and measurements taken.

The median time from study registration to the first dose of nivolumab was 9 days. The majority (88%) of patients completed all four doses of nivolumab.

The median time from the first dose of nivolumab to the posttreatment biopsy was 115 days and ranged from 29 to 171 days.

The overall response rate, defined as a greater than or equal to 40% decrease in a composite score combining the size and degree of dysplasia between the pre- and posttreatment assessments, was observed in 36.4% of patients.

After a median follow-up of 14.7 months, the median cancer-free survival was not reached, with cancer events recorded in 21.2% of patients. The median time from the last dose of nivolumab to the first OSCC event was 3.7 months.

Cancer-free survival at 1 year was calculated to be 77.7%, which was unchanged at 2 years. At the final follow-up, all patients were still alive.

Additional analysis of the biopsies revealed that the lesions had programmed death ligand 1 (PD-L1) combined positive scores that ranged from 0 to 80, with 66.7% of patients having a score of greater than or equal to 1. A cutoff score of greater than or equal to 20 did not reveal any significant differences in cancer-free survival rates.

Turning to safety, Dr. Hanna said that nivolumab was associated with “acceptable toxicity” in this “non-cancer population,” with 21.2% of patients experiencing a grade 3-4 adverse event.

The most common adverse events of any grade were fatigue (55%), diarrhea (27%), elevated alanine transaminase levels (18%), elevated aspartate transaminase levels (18%), and other skin disorders (18%).

With a relatively low rate of adverse events and a “clinical benefit” in up to a third of patients, Dr. Hanna said that this was the “first study to our knowledge to demonstrate the potential efficacy of anti–PD-L1 blockade among patients with a high-risk oral precancerous disease.”

Discussing this study at the meeting, Amanda Psyrri, MD, PhD, professor of medical oncology, Attikon University Hospital, Athens, who was not involved in the research, said these data were “very interesting,” but she expressed some reservations over the way the study was conducted.

She said that the composite score to measure response rates was “defined arbitrarily,” its prognostic value “has not been demonstrated,” and also pointed out that mixed responses by lesions within the same patient led to changes in scores.

In addition, the time interval between the end of treatment and lesion rebiopsy was “highly variable,” and the follow-up period was short.

Consequently, Dr. Psyrri believes the importance of the findings is “unclear,” especially as several patients who responded to nivolumab went on to develop cancer anyway, a finding that needs further investigation.

The study was funded by Bristol Myers Squibb.

Dr. Hanna declared relationships with BMS, Bicara, Exicure, Gateway for Cancer Research, GSK, Kite, NantKwest, Regeneron, Sanofi Genzyme, Maverick, and Merck.

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

PARIS – “Unprecedented” pathologic responses were seen after a neoadjuvant 4-week course of ipilimumab (Yervoy) plus nivolumab (Opdivo) was given before surgery to patients with DNA mismatch repair deficient (dMMR) colon cancer, say researchers reporting new results from the NICHE-2 trial.

The trial involved 112 patients with dMMR colon cancer who were given one cycle of low-dose ipilimumab and two cycles of nivolumab followed by surgery.

The results show that 95% of patients had a major pathologic response (MPR), and 67% had a pathologic complete response (pCR) to immunotherapy.

To date, none of these patients have had disease recurrence after a median follow-up of 13.1 months.

Study presenter Myriam Chalabi, MD, an oncologist at the Netherlands Cancer Institute, Amsterdam, described the findings as “unprecedented,” especially as many of the patients had stage 3 and high-risk disease, and the expected disease recurrence rate with standard-of-care adjuvant chemotherapy in these patients would usually have been around 15%.

“Importantly, this treatment was very well-tolerated,” she added.

Dr. Chalabi presented the new results during a presidential session at the European Society for Medical Oncology Congress 2022, held in Paris.

Neoadjuvant immunotherapy “has the potential to become standard of care” in these patients, she said, adding that the “future has never been brighter” for dMMR colon cancer.

Around 10%-15% of colon cancers are dMMR, and around 33% of these are associated with Lynch syndrome, she noted.

She also urged pharmaceutical companies to seek approval for immunotherapy in this patient population, to warm applause from the audience.

Commenting on the results, Andrés Cervantes, MD, PhD, professor of medicine at the University of Valencia, Spain, said in an ESMO press release that the “innovative” study “questions the need for surgery and postoperative chemotherapy in all patients in whom the primary tumor has disappeared.”

He observed that adjuvant chemotherapy has remained standard of care, “despite the fact that chemotherapy is not so active, and a complete disappearance of the tumor in the surgical specimen is not observed.”

Overall, Dr. Cervantes said that dMMR status is a “strong predictor of the positive effect observed with this short-course immunotherapy,” adding that “determining dMMR can be easily done by immunohistochemistry in the conventional pathology lab, without the need for complex molecular testing.”

The “minimal toxicity” seen in the study “may also facilitate the implementation of this strategy, potentially sparing patients from surgery.”
 

Details of the new results

For the NICHE-2 study, patients with stage cT3 dMMR colon cancer and/or nodal involvement but without metastases and no signs of obstruction received one dose of ipilimumab 1 mg/kg and two doses of nivolumab 3 mg/kg before undergoing surgery within 6 weeks of enrollment.

The 112 participants were a median age of 60 years, and just over half were women. High-risk stage 3 disease was present in 74% of patients, which included 64% of patients with clinical T4a or T4b tumors and 62% with radiologic N2 stage cancer.

Median time from the first immunotherapy dose to surgery was 5.4 weeks.

Immune-related adverse events were seen in 61% of patients, but just 4% of patients experienced grade 3-4 immune-related adverse events, and 2% consequently had a delay in surgery, meaning the study met its primary safety endpoint.

In the end, all patients underwent surgery, with 100% having R0 resections.

A pathologic response was seen in 99% of patients, with 95% having an MPR, defined as less than or equal to 10% residual viable tumor, and 4% a partial response, defined as 10% to less than or equal to 50% residual viable tumor. A pCR, which included both the tumor bed and lymph nodes, was seen in 67% of participants.

There was a borderline significant difference in pCR patients between the 66 patients with sporadic tumors and the 32 with Lynch syndrome, at 58% versus 78% (P = .056).

At the meeting, discussant James Larkin, MD, PhD, consultant medical oncologist, The Royal Marsden, London, who was not involved with the study, agreed that the results were “striking,” with “brief treatment ... [showing] a major effect.”

However, he emphasized that it will be “important” to see the prespecified 3-year disease-free survival data, and he questioned whether the single low dose of ipilimumab was, in fact, necessary.

Dr. Larkin also emphasized that organ-sparing strategies in colon cancer are less “clear cut” than they are in rectal cancer and would require ongoing follow-up with colonoscopies and, potentially, biopsies. He also said it is “critical” to get patients’ views on the desirability of organ sparing.

The study was funded by Bristol Myers Squibb. Dr. Chalabi has reported no financial interests. Disclosures for the other authors are listed with the abstract. Dr. Larkin has declared relationships with Eisai, Novartis, Merck, Pfizer, BMS, iOnctura, Debiopharm, Incyte, MSD, Pierre Fabre, Ibsen, Roche, EUSA Pharma, AstraZeneca, GSK, Calithera, Ultimovacs, Seagen, and Nektar Therapeutics.

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

PARIS – “Unprecedented” pathologic responses were seen after a neoadjuvant 4-week course of ipilimumab (Yervoy) plus nivolumab (Opdivo) was given before surgery to patients with DNA mismatch repair deficient (dMMR) colon cancer, say researchers reporting new results from the NICHE-2 trial.

The trial involved 112 patients with dMMR colon cancer who were given one cycle of low-dose ipilimumab and two cycles of nivolumab followed by surgery.

The results show that 95% of patients had a major pathologic response (MPR), and 67% had a pathologic complete response (pCR) to immunotherapy.

To date, none of these patients have had disease recurrence after a median follow-up of 13.1 months.

Study presenter Myriam Chalabi, MD, an oncologist at the Netherlands Cancer Institute, Amsterdam, described the findings as “unprecedented,” especially as many of the patients had stage 3 and high-risk disease, and the expected disease recurrence rate with standard-of-care adjuvant chemotherapy in these patients would usually have been around 15%.

“Importantly, this treatment was very well-tolerated,” she added.

Dr. Chalabi presented the new results during a presidential session at the European Society for Medical Oncology Congress 2022, held in Paris.

Neoadjuvant immunotherapy “has the potential to become standard of care” in these patients, she said, adding that the “future has never been brighter” for dMMR colon cancer.

Around 10%-15% of colon cancers are dMMR, and around 33% of these are associated with Lynch syndrome, she noted.

She also urged pharmaceutical companies to seek approval for immunotherapy in this patient population, to warm applause from the audience.

Commenting on the results, Andrés Cervantes, MD, PhD, professor of medicine at the University of Valencia, Spain, said in an ESMO press release that the “innovative” study “questions the need for surgery and postoperative chemotherapy in all patients in whom the primary tumor has disappeared.”

He observed that adjuvant chemotherapy has remained standard of care, “despite the fact that chemotherapy is not so active, and a complete disappearance of the tumor in the surgical specimen is not observed.”

Overall, Dr. Cervantes said that dMMR status is a “strong predictor of the positive effect observed with this short-course immunotherapy,” adding that “determining dMMR can be easily done by immunohistochemistry in the conventional pathology lab, without the need for complex molecular testing.”

The “minimal toxicity” seen in the study “may also facilitate the implementation of this strategy, potentially sparing patients from surgery.”
 

Details of the new results

For the NICHE-2 study, patients with stage cT3 dMMR colon cancer and/or nodal involvement but without metastases and no signs of obstruction received one dose of ipilimumab 1 mg/kg and two doses of nivolumab 3 mg/kg before undergoing surgery within 6 weeks of enrollment.

The 112 participants were a median age of 60 years, and just over half were women. High-risk stage 3 disease was present in 74% of patients, which included 64% of patients with clinical T4a or T4b tumors and 62% with radiologic N2 stage cancer.

Median time from the first immunotherapy dose to surgery was 5.4 weeks.

Immune-related adverse events were seen in 61% of patients, but just 4% of patients experienced grade 3-4 immune-related adverse events, and 2% consequently had a delay in surgery, meaning the study met its primary safety endpoint.

In the end, all patients underwent surgery, with 100% having R0 resections.

A pathologic response was seen in 99% of patients, with 95% having an MPR, defined as less than or equal to 10% residual viable tumor, and 4% a partial response, defined as 10% to less than or equal to 50% residual viable tumor. A pCR, which included both the tumor bed and lymph nodes, was seen in 67% of participants.

There was a borderline significant difference in pCR patients between the 66 patients with sporadic tumors and the 32 with Lynch syndrome, at 58% versus 78% (P = .056).

At the meeting, discussant James Larkin, MD, PhD, consultant medical oncologist, The Royal Marsden, London, who was not involved with the study, agreed that the results were “striking,” with “brief treatment ... [showing] a major effect.”

However, he emphasized that it will be “important” to see the prespecified 3-year disease-free survival data, and he questioned whether the single low dose of ipilimumab was, in fact, necessary.

Dr. Larkin also emphasized that organ-sparing strategies in colon cancer are less “clear cut” than they are in rectal cancer and would require ongoing follow-up with colonoscopies and, potentially, biopsies. He also said it is “critical” to get patients’ views on the desirability of organ sparing.

The study was funded by Bristol Myers Squibb. Dr. Chalabi has reported no financial interests. Disclosures for the other authors are listed with the abstract. Dr. Larkin has declared relationships with Eisai, Novartis, Merck, Pfizer, BMS, iOnctura, Debiopharm, Incyte, MSD, Pierre Fabre, Ibsen, Roche, EUSA Pharma, AstraZeneca, GSK, Calithera, Ultimovacs, Seagen, and Nektar Therapeutics.

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

PARIS – “Unprecedented” pathologic responses were seen after a neoadjuvant 4-week course of ipilimumab (Yervoy) plus nivolumab (Opdivo) was given before surgery to patients with DNA mismatch repair deficient (dMMR) colon cancer, say researchers reporting new results from the NICHE-2 trial.

The trial involved 112 patients with dMMR colon cancer who were given one cycle of low-dose ipilimumab and two cycles of nivolumab followed by surgery.

The results show that 95% of patients had a major pathologic response (MPR), and 67% had a pathologic complete response (pCR) to immunotherapy.

To date, none of these patients have had disease recurrence after a median follow-up of 13.1 months.

Study presenter Myriam Chalabi, MD, an oncologist at the Netherlands Cancer Institute, Amsterdam, described the findings as “unprecedented,” especially as many of the patients had stage 3 and high-risk disease, and the expected disease recurrence rate with standard-of-care adjuvant chemotherapy in these patients would usually have been around 15%.

“Importantly, this treatment was very well-tolerated,” she added.

Dr. Chalabi presented the new results during a presidential session at the European Society for Medical Oncology Congress 2022, held in Paris.

Neoadjuvant immunotherapy “has the potential to become standard of care” in these patients, she said, adding that the “future has never been brighter” for dMMR colon cancer.

Around 10%-15% of colon cancers are dMMR, and around 33% of these are associated with Lynch syndrome, she noted.

She also urged pharmaceutical companies to seek approval for immunotherapy in this patient population, to warm applause from the audience.

Commenting on the results, Andrés Cervantes, MD, PhD, professor of medicine at the University of Valencia, Spain, said in an ESMO press release that the “innovative” study “questions the need for surgery and postoperative chemotherapy in all patients in whom the primary tumor has disappeared.”

He observed that adjuvant chemotherapy has remained standard of care, “despite the fact that chemotherapy is not so active, and a complete disappearance of the tumor in the surgical specimen is not observed.”

Overall, Dr. Cervantes said that dMMR status is a “strong predictor of the positive effect observed with this short-course immunotherapy,” adding that “determining dMMR can be easily done by immunohistochemistry in the conventional pathology lab, without the need for complex molecular testing.”

The “minimal toxicity” seen in the study “may also facilitate the implementation of this strategy, potentially sparing patients from surgery.”
 

Details of the new results

For the NICHE-2 study, patients with stage cT3 dMMR colon cancer and/or nodal involvement but without metastases and no signs of obstruction received one dose of ipilimumab 1 mg/kg and two doses of nivolumab 3 mg/kg before undergoing surgery within 6 weeks of enrollment.

The 112 participants were a median age of 60 years, and just over half were women. High-risk stage 3 disease was present in 74% of patients, which included 64% of patients with clinical T4a or T4b tumors and 62% with radiologic N2 stage cancer.

Median time from the first immunotherapy dose to surgery was 5.4 weeks.

Immune-related adverse events were seen in 61% of patients, but just 4% of patients experienced grade 3-4 immune-related adverse events, and 2% consequently had a delay in surgery, meaning the study met its primary safety endpoint.

In the end, all patients underwent surgery, with 100% having R0 resections.

A pathologic response was seen in 99% of patients, with 95% having an MPR, defined as less than or equal to 10% residual viable tumor, and 4% a partial response, defined as 10% to less than or equal to 50% residual viable tumor. A pCR, which included both the tumor bed and lymph nodes, was seen in 67% of participants.

There was a borderline significant difference in pCR patients between the 66 patients with sporadic tumors and the 32 with Lynch syndrome, at 58% versus 78% (P = .056).

At the meeting, discussant James Larkin, MD, PhD, consultant medical oncologist, The Royal Marsden, London, who was not involved with the study, agreed that the results were “striking,” with “brief treatment ... [showing] a major effect.”

However, he emphasized that it will be “important” to see the prespecified 3-year disease-free survival data, and he questioned whether the single low dose of ipilimumab was, in fact, necessary.

Dr. Larkin also emphasized that organ-sparing strategies in colon cancer are less “clear cut” than they are in rectal cancer and would require ongoing follow-up with colonoscopies and, potentially, biopsies. He also said it is “critical” to get patients’ views on the desirability of organ sparing.

The study was funded by Bristol Myers Squibb. Dr. Chalabi has reported no financial interests. Disclosures for the other authors are listed with the abstract. Dr. Larkin has declared relationships with Eisai, Novartis, Merck, Pfizer, BMS, iOnctura, Debiopharm, Incyte, MSD, Pierre Fabre, Ibsen, Roche, EUSA Pharma, AstraZeneca, GSK, Calithera, Ultimovacs, Seagen, and Nektar Therapeutics.

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

PARIS – Adding cabozantinib (Cabometyx, Exelixis) to standard-of-care immunotherapy with nivolumab (Opdivo, Bristol Myers Squibb) plus ipilimumab (Yervoy) markedly improved progression-free survival (PFS) in advanced renal cell carcinoma (aRCC), particularly in intermediate-risk patients, suggest results from the COSMIC-313 trial.

At present, dual checkpoint inhibition with nivolumab and ipilimumab is a standard of care for first-line treatment of aRCC that is deemed to be of intermediate or poor risk on the International Metastatic RCC Database Consortium (IMDC) risk score.

Cabozantinib, a tyrosine kinase inhibitor (TKI), is also a standard of care in aRCC, both as a single agent and in combination with nivolumab.

The new study investigated the use of the three drugs together as upfront first-line treatment and suggests that this triplet may become a new standard of care, especially in patients with intermediate-risk disease.

The research was presented at the European Society for Medical Oncology Congress in Paris.

The trial involved 855 previously untreated patients with aRCC, all of whom received dual immunotherapy with nivolumab and ipilimumab, who were randomly assigned to also receive either cabozantinib or matched placebo.

Patients given the triplet therapy had a significant 27% reduction in the risk for progression versus the doublet in the overall patient population.

The difference increased to 37% in patients with intermediate-risk disease on the IMDC risk score.

However, patients with poor-risk disease appeared not to derive any benefit from adding cabozantinib to nivolumab plus ipilimumab.

In addition, grade 3 or 4 treatment-related adverse events were more common with the triplet therapy.

The results suggest that adding cabozantinib results in a “statistically significant and clinically meaningful” PFS benefit, study presenter Toni Choueiri, MD, director of the Lank Center for Genitourinary Oncology at the Dana-Farber Cancer Institute, Boston, told a press conference.

He added that the safety profile of the triplet therapy was “generally manageable” and “consistent with the profiles of the treatment components.”

“The study will continue to the next analysis of overall survival, as this secondary endpoint was not met at first interim analysis,” Dr. Choueiri commented.

He told this news organization that, based on the current results, the triplet combination “may end up in intermediate-risk” patients, although it is not clear why there is a difference in response between risk groups, and the finding is “quite intriguing.”

Asked which therapy to choose now for first-line treatment of aRCC, given that there are now so many options, he said that there is now such “an embarrassment of riches of trials in the first-line” that it is perhaps easier to talk about which therapies “not to use.”

“We cannot use single TKIs anymore, so you have to use doublets and possibly now triplets,” he said.

“In my practice, patients that are progressing rapidly ... need a VEGF [vascular endothelial growth factor]–based combination. In patients that can wait and ... do not have a heavy disease burden, I still believe in nivolumab and ipilimumab, which has the longest follow-up, and the responses are durable.”

Approached for comment, Dominik Berthold, MD, Centre hospitalier universitaire vaudois, Lausanne, Switzerland, said that this is a “really important study” because it has a “modern” study comparator in the control arm.

He said in an interview, however, that the question now is “obviously” how much treatment should be escalated to triple therapy “upfront versus the sequencing of active drugs.” The answer, he said, is currently unclear, and overall survival data are awaited.

Alongside the potential “challenge” of the toxicity to patients of the triplet therapy, Dr. Berthold also highlighted that it is “currently a challenge for health systems to imagine giving such expensive combinations.”

So though it is “really interesting data” and potentially represents a “step forward” in the field, the combination of cabozantinib and nivolumab plus ipilimumab is “not for everybody.”

Dr. Choueiri said that he does “agree” that adding a third drug to an already expensive doublet therapy can mean that the costs end up being “exorbitant.”

However, he noted that in aRCC, “the paradigm is sequential, so if we’re able to delay the second line, and give drugs later, especially if there is some quality of life [benefit], I’m not sure it is more expensive” to give the three-drug combination.

Commenting for ESMO, Viktor Grünwald, MD, West German Cancer Center, University Hospital Essen, Germany, noted that this is the “first study” to report “successful treatment intensification” in metastatic RCC through the use of triple therapy.

“However, treatment intensification is rarely seen without additional risks. Patients experienced the benefit of superior disease control but also additional toxicities, treatment pauses and discontinuations,” he pointed out.

“The triplet may compete in the clinical landscape with recommended life-prolonging immune doublets but mature overall survival data is needed for it to become a novel standard of care,” Dr. Grünwald commented.
 

Details of the new results

The phase 3 COSMIC-313 trial enrolled intermediate- or poor-risk patients with aRCC and good performance status who had received no prior systemic therapy and had a clear cell component on histology, which, Dr. Choueiri noted, represents around 80% of patients.

They were randomly assigned to cabozantinib or a matched placebo against a background of four cycles of nivolumab plus ipilimumab followed by nivolumab for up to 2 years. No crossover was allowed between the two arms. Tumor assessment was performed every 8 weeks.

Overall, 855 patients were randomly assigned, 75% of whom had an intermediate risk on the IDMC risk score, and 25% had a poor risk. The median age of the patients was around 60 years, and between 73% and 76% were men. Prior nephrectomy had been performed in 65%.

The study met its primary endpoint of a significant improvement in PFS as assessed by blinded independent central review. The median PFS was not reached for the triplet versus 11.3 months for patients given the doublet, at a hazard ratio of 0.73 (P = 0.013).

At 12 months, 57% of patients in the triplet-therapy arm remained disease-free versus 49% of those on dual immunotherapy.

Moreover, there was a higher objective response rate with the triplet therapy, at 43% versus 36% for the doublet, and the median duration of response was not reached in either group.

Prespecified subgroup analysis suggested that most subgroups responded similarly to the overall patient population.

However, breaking the results down by IMDC risk group, Dr. Choueiri showed that PFS benefit was even greater in intermediate-risk patients, at an HR for the triplet versus the doublet therapy of 0.63 (95% confidence interval, 047-0.85), and a similar response rate as in the overall analysis.

But the benefit of adding cabozantinib to nivolumab plus ipilimumab appeared to be lost in poor-risk patients, at an HR for the triplet versus the doublet of 1.04 (95% CI, 0.65-1.69). And in this subgroup, the objective response rates were similar: 37% with the triplet and 38% with the doublet.

Also, the triplet had a higher rate of adverse events. Grade 3 or 4 treatment-related adverse events were observed in 73% of patients on the triplet versus 41% with the doublet; 1% of patients in each group had a grade 5 event.

Treatment-related adverse events leading to discontinuation of all treatment components occurred in 12% of patients receiving triplet therapy and in 5% of those assigned to placebo and nivolumab plus ipilimumab.

Dr. Choueiri highlighted that some adverse events, including elevated liver transaminases, diarrhea, and skin toxicity, were markedly more frequent with cabozantinib and nivolumab plus ipilimumab than with the doublet therapy. Discussing the study, Sumanta K. Pal, MD, co-director of the Kidney Cancer Program at City of Hope, Irvine, Calif., said that ESMO Congress 2022 has been a “high watermark” for trials in the RCC field and congratulated the researchers of COSMIC-313 for the number of “firsts” that it achieved.

However, he continued, the “elephant in the room” is the current lack of overall survival, and he pointed out that those hotly anticipated results could have a major impact on the future use of the triplet combination.

Dr. Pal questioned whether, in the meantime, it is even possible to make a decision about the combination and urged investigators of all trials to make overall survival data available sooner.

He also highlighted the high rates of elevated liver transaminases, and the apparent overlapping toxicities between the TKI and the immune checkpoint inhibitors, asking: “Does toxicity stand in the way of treatment?”

In conclusion, Dr. Pal acknowledged that the study did meet its PFS primary endpoint but asked whether a risk-adapted approach could be used to optimize delivery of triplet therapy.

He also called for investment into biomarker studies for regimens that are “actually used in the clinic” and wondered whether there could be a shift toward using drugs with novel modes of action that do not yield overlapping toxicities.

The study was funded by Exelixis.

Dr. Choueiri reports relationships with Bristol-Myers Squibb; Pfizer; Lilly; Merck; Exelixis; AstraZeneca; EMD Serono; Calithera; Ipsen; Infinity; Surface Oncology; Analysis Group; ww2.peerview.com; gotoper.com; researchtopractice.com; ResearchToPractice; National Association of Managed Care; Orien Network; Aptitude Health; Advent health; UAE Society of Onc; MJH life sciences; MDACC; Cancernet; Kidney Cancer Association; Springer; WebMed; ASiM, Caribou Publishing; Aravive; Roche, and others.

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

PARIS – Adding cabozantinib (Cabometyx, Exelixis) to standard-of-care immunotherapy with nivolumab (Opdivo, Bristol Myers Squibb) plus ipilimumab (Yervoy) markedly improved progression-free survival (PFS) in advanced renal cell carcinoma (aRCC), particularly in intermediate-risk patients, suggest results from the COSMIC-313 trial.

At present, dual checkpoint inhibition with nivolumab and ipilimumab is a standard of care for first-line treatment of aRCC that is deemed to be of intermediate or poor risk on the International Metastatic RCC Database Consortium (IMDC) risk score.

Cabozantinib, a tyrosine kinase inhibitor (TKI), is also a standard of care in aRCC, both as a single agent and in combination with nivolumab.

The new study investigated the use of the three drugs together as upfront first-line treatment and suggests that this triplet may become a new standard of care, especially in patients with intermediate-risk disease.

The research was presented at the European Society for Medical Oncology Congress in Paris.

The trial involved 855 previously untreated patients with aRCC, all of whom received dual immunotherapy with nivolumab and ipilimumab, who were randomly assigned to also receive either cabozantinib or matched placebo.

Patients given the triplet therapy had a significant 27% reduction in the risk for progression versus the doublet in the overall patient population.

The difference increased to 37% in patients with intermediate-risk disease on the IMDC risk score.

However, patients with poor-risk disease appeared not to derive any benefit from adding cabozantinib to nivolumab plus ipilimumab.

In addition, grade 3 or 4 treatment-related adverse events were more common with the triplet therapy.

The results suggest that adding cabozantinib results in a “statistically significant and clinically meaningful” PFS benefit, study presenter Toni Choueiri, MD, director of the Lank Center for Genitourinary Oncology at the Dana-Farber Cancer Institute, Boston, told a press conference.

He added that the safety profile of the triplet therapy was “generally manageable” and “consistent with the profiles of the treatment components.”

“The study will continue to the next analysis of overall survival, as this secondary endpoint was not met at first interim analysis,” Dr. Choueiri commented.

He told this news organization that, based on the current results, the triplet combination “may end up in intermediate-risk” patients, although it is not clear why there is a difference in response between risk groups, and the finding is “quite intriguing.”

Asked which therapy to choose now for first-line treatment of aRCC, given that there are now so many options, he said that there is now such “an embarrassment of riches of trials in the first-line” that it is perhaps easier to talk about which therapies “not to use.”

“We cannot use single TKIs anymore, so you have to use doublets and possibly now triplets,” he said.

“In my practice, patients that are progressing rapidly ... need a VEGF [vascular endothelial growth factor]–based combination. In patients that can wait and ... do not have a heavy disease burden, I still believe in nivolumab and ipilimumab, which has the longest follow-up, and the responses are durable.”

Approached for comment, Dominik Berthold, MD, Centre hospitalier universitaire vaudois, Lausanne, Switzerland, said that this is a “really important study” because it has a “modern” study comparator in the control arm.

He said in an interview, however, that the question now is “obviously” how much treatment should be escalated to triple therapy “upfront versus the sequencing of active drugs.” The answer, he said, is currently unclear, and overall survival data are awaited.

Alongside the potential “challenge” of the toxicity to patients of the triplet therapy, Dr. Berthold also highlighted that it is “currently a challenge for health systems to imagine giving such expensive combinations.”

So though it is “really interesting data” and potentially represents a “step forward” in the field, the combination of cabozantinib and nivolumab plus ipilimumab is “not for everybody.”

Dr. Choueiri said that he does “agree” that adding a third drug to an already expensive doublet therapy can mean that the costs end up being “exorbitant.”

However, he noted that in aRCC, “the paradigm is sequential, so if we’re able to delay the second line, and give drugs later, especially if there is some quality of life [benefit], I’m not sure it is more expensive” to give the three-drug combination.

Commenting for ESMO, Viktor Grünwald, MD, West German Cancer Center, University Hospital Essen, Germany, noted that this is the “first study” to report “successful treatment intensification” in metastatic RCC through the use of triple therapy.

“However, treatment intensification is rarely seen without additional risks. Patients experienced the benefit of superior disease control but also additional toxicities, treatment pauses and discontinuations,” he pointed out.

“The triplet may compete in the clinical landscape with recommended life-prolonging immune doublets but mature overall survival data is needed for it to become a novel standard of care,” Dr. Grünwald commented.
 

Details of the new results

The phase 3 COSMIC-313 trial enrolled intermediate- or poor-risk patients with aRCC and good performance status who had received no prior systemic therapy and had a clear cell component on histology, which, Dr. Choueiri noted, represents around 80% of patients.

They were randomly assigned to cabozantinib or a matched placebo against a background of four cycles of nivolumab plus ipilimumab followed by nivolumab for up to 2 years. No crossover was allowed between the two arms. Tumor assessment was performed every 8 weeks.

Overall, 855 patients were randomly assigned, 75% of whom had an intermediate risk on the IDMC risk score, and 25% had a poor risk. The median age of the patients was around 60 years, and between 73% and 76% were men. Prior nephrectomy had been performed in 65%.

The study met its primary endpoint of a significant improvement in PFS as assessed by blinded independent central review. The median PFS was not reached for the triplet versus 11.3 months for patients given the doublet, at a hazard ratio of 0.73 (P = 0.013).

At 12 months, 57% of patients in the triplet-therapy arm remained disease-free versus 49% of those on dual immunotherapy.

Moreover, there was a higher objective response rate with the triplet therapy, at 43% versus 36% for the doublet, and the median duration of response was not reached in either group.

Prespecified subgroup analysis suggested that most subgroups responded similarly to the overall patient population.

However, breaking the results down by IMDC risk group, Dr. Choueiri showed that PFS benefit was even greater in intermediate-risk patients, at an HR for the triplet versus the doublet therapy of 0.63 (95% confidence interval, 047-0.85), and a similar response rate as in the overall analysis.

But the benefit of adding cabozantinib to nivolumab plus ipilimumab appeared to be lost in poor-risk patients, at an HR for the triplet versus the doublet of 1.04 (95% CI, 0.65-1.69). And in this subgroup, the objective response rates were similar: 37% with the triplet and 38% with the doublet.

Also, the triplet had a higher rate of adverse events. Grade 3 or 4 treatment-related adverse events were observed in 73% of patients on the triplet versus 41% with the doublet; 1% of patients in each group had a grade 5 event.

Treatment-related adverse events leading to discontinuation of all treatment components occurred in 12% of patients receiving triplet therapy and in 5% of those assigned to placebo and nivolumab plus ipilimumab.

Dr. Choueiri highlighted that some adverse events, including elevated liver transaminases, diarrhea, and skin toxicity, were markedly more frequent with cabozantinib and nivolumab plus ipilimumab than with the doublet therapy. Discussing the study, Sumanta K. Pal, MD, co-director of the Kidney Cancer Program at City of Hope, Irvine, Calif., said that ESMO Congress 2022 has been a “high watermark” for trials in the RCC field and congratulated the researchers of COSMIC-313 for the number of “firsts” that it achieved.

However, he continued, the “elephant in the room” is the current lack of overall survival, and he pointed out that those hotly anticipated results could have a major impact on the future use of the triplet combination.

Dr. Pal questioned whether, in the meantime, it is even possible to make a decision about the combination and urged investigators of all trials to make overall survival data available sooner.

He also highlighted the high rates of elevated liver transaminases, and the apparent overlapping toxicities between the TKI and the immune checkpoint inhibitors, asking: “Does toxicity stand in the way of treatment?”

In conclusion, Dr. Pal acknowledged that the study did meet its PFS primary endpoint but asked whether a risk-adapted approach could be used to optimize delivery of triplet therapy.

He also called for investment into biomarker studies for regimens that are “actually used in the clinic” and wondered whether there could be a shift toward using drugs with novel modes of action that do not yield overlapping toxicities.

The study was funded by Exelixis.

Dr. Choueiri reports relationships with Bristol-Myers Squibb; Pfizer; Lilly; Merck; Exelixis; AstraZeneca; EMD Serono; Calithera; Ipsen; Infinity; Surface Oncology; Analysis Group; ww2.peerview.com; gotoper.com; researchtopractice.com; ResearchToPractice; National Association of Managed Care; Orien Network; Aptitude Health; Advent health; UAE Society of Onc; MJH life sciences; MDACC; Cancernet; Kidney Cancer Association; Springer; WebMed; ASiM, Caribou Publishing; Aravive; Roche, and others.

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

PARIS – Adding cabozantinib (Cabometyx, Exelixis) to standard-of-care immunotherapy with nivolumab (Opdivo, Bristol Myers Squibb) plus ipilimumab (Yervoy) markedly improved progression-free survival (PFS) in advanced renal cell carcinoma (aRCC), particularly in intermediate-risk patients, suggest results from the COSMIC-313 trial.

At present, dual checkpoint inhibition with nivolumab and ipilimumab is a standard of care for first-line treatment of aRCC that is deemed to be of intermediate or poor risk on the International Metastatic RCC Database Consortium (IMDC) risk score.

Cabozantinib, a tyrosine kinase inhibitor (TKI), is also a standard of care in aRCC, both as a single agent and in combination with nivolumab.

The new study investigated the use of the three drugs together as upfront first-line treatment and suggests that this triplet may become a new standard of care, especially in patients with intermediate-risk disease.

The research was presented at the European Society for Medical Oncology Congress in Paris.

The trial involved 855 previously untreated patients with aRCC, all of whom received dual immunotherapy with nivolumab and ipilimumab, who were randomly assigned to also receive either cabozantinib or matched placebo.

Patients given the triplet therapy had a significant 27% reduction in the risk for progression versus the doublet in the overall patient population.

The difference increased to 37% in patients with intermediate-risk disease on the IMDC risk score.

However, patients with poor-risk disease appeared not to derive any benefit from adding cabozantinib to nivolumab plus ipilimumab.

In addition, grade 3 or 4 treatment-related adverse events were more common with the triplet therapy.

The results suggest that adding cabozantinib results in a “statistically significant and clinically meaningful” PFS benefit, study presenter Toni Choueiri, MD, director of the Lank Center for Genitourinary Oncology at the Dana-Farber Cancer Institute, Boston, told a press conference.

He added that the safety profile of the triplet therapy was “generally manageable” and “consistent with the profiles of the treatment components.”

“The study will continue to the next analysis of overall survival, as this secondary endpoint was not met at first interim analysis,” Dr. Choueiri commented.

He told this news organization that, based on the current results, the triplet combination “may end up in intermediate-risk” patients, although it is not clear why there is a difference in response between risk groups, and the finding is “quite intriguing.”

Asked which therapy to choose now for first-line treatment of aRCC, given that there are now so many options, he said that there is now such “an embarrassment of riches of trials in the first-line” that it is perhaps easier to talk about which therapies “not to use.”

“We cannot use single TKIs anymore, so you have to use doublets and possibly now triplets,” he said.

“In my practice, patients that are progressing rapidly ... need a VEGF [vascular endothelial growth factor]–based combination. In patients that can wait and ... do not have a heavy disease burden, I still believe in nivolumab and ipilimumab, which has the longest follow-up, and the responses are durable.”

Approached for comment, Dominik Berthold, MD, Centre hospitalier universitaire vaudois, Lausanne, Switzerland, said that this is a “really important study” because it has a “modern” study comparator in the control arm.

He said in an interview, however, that the question now is “obviously” how much treatment should be escalated to triple therapy “upfront versus the sequencing of active drugs.” The answer, he said, is currently unclear, and overall survival data are awaited.

Alongside the potential “challenge” of the toxicity to patients of the triplet therapy, Dr. Berthold also highlighted that it is “currently a challenge for health systems to imagine giving such expensive combinations.”

So though it is “really interesting data” and potentially represents a “step forward” in the field, the combination of cabozantinib and nivolumab plus ipilimumab is “not for everybody.”

Dr. Choueiri said that he does “agree” that adding a third drug to an already expensive doublet therapy can mean that the costs end up being “exorbitant.”

However, he noted that in aRCC, “the paradigm is sequential, so if we’re able to delay the second line, and give drugs later, especially if there is some quality of life [benefit], I’m not sure it is more expensive” to give the three-drug combination.

Commenting for ESMO, Viktor Grünwald, MD, West German Cancer Center, University Hospital Essen, Germany, noted that this is the “first study” to report “successful treatment intensification” in metastatic RCC through the use of triple therapy.

“However, treatment intensification is rarely seen without additional risks. Patients experienced the benefit of superior disease control but also additional toxicities, treatment pauses and discontinuations,” he pointed out.

“The triplet may compete in the clinical landscape with recommended life-prolonging immune doublets but mature overall survival data is needed for it to become a novel standard of care,” Dr. Grünwald commented.
 

Details of the new results

The phase 3 COSMIC-313 trial enrolled intermediate- or poor-risk patients with aRCC and good performance status who had received no prior systemic therapy and had a clear cell component on histology, which, Dr. Choueiri noted, represents around 80% of patients.

They were randomly assigned to cabozantinib or a matched placebo against a background of four cycles of nivolumab plus ipilimumab followed by nivolumab for up to 2 years. No crossover was allowed between the two arms. Tumor assessment was performed every 8 weeks.

Overall, 855 patients were randomly assigned, 75% of whom had an intermediate risk on the IDMC risk score, and 25% had a poor risk. The median age of the patients was around 60 years, and between 73% and 76% were men. Prior nephrectomy had been performed in 65%.

The study met its primary endpoint of a significant improvement in PFS as assessed by blinded independent central review. The median PFS was not reached for the triplet versus 11.3 months for patients given the doublet, at a hazard ratio of 0.73 (P = 0.013).

At 12 months, 57% of patients in the triplet-therapy arm remained disease-free versus 49% of those on dual immunotherapy.

Moreover, there was a higher objective response rate with the triplet therapy, at 43% versus 36% for the doublet, and the median duration of response was not reached in either group.

Prespecified subgroup analysis suggested that most subgroups responded similarly to the overall patient population.

However, breaking the results down by IMDC risk group, Dr. Choueiri showed that PFS benefit was even greater in intermediate-risk patients, at an HR for the triplet versus the doublet therapy of 0.63 (95% confidence interval, 047-0.85), and a similar response rate as in the overall analysis.

But the benefit of adding cabozantinib to nivolumab plus ipilimumab appeared to be lost in poor-risk patients, at an HR for the triplet versus the doublet of 1.04 (95% CI, 0.65-1.69). And in this subgroup, the objective response rates were similar: 37% with the triplet and 38% with the doublet.

Also, the triplet had a higher rate of adverse events. Grade 3 or 4 treatment-related adverse events were observed in 73% of patients on the triplet versus 41% with the doublet; 1% of patients in each group had a grade 5 event.

Treatment-related adverse events leading to discontinuation of all treatment components occurred in 12% of patients receiving triplet therapy and in 5% of those assigned to placebo and nivolumab plus ipilimumab.

Dr. Choueiri highlighted that some adverse events, including elevated liver transaminases, diarrhea, and skin toxicity, were markedly more frequent with cabozantinib and nivolumab plus ipilimumab than with the doublet therapy. Discussing the study, Sumanta K. Pal, MD, co-director of the Kidney Cancer Program at City of Hope, Irvine, Calif., said that ESMO Congress 2022 has been a “high watermark” for trials in the RCC field and congratulated the researchers of COSMIC-313 for the number of “firsts” that it achieved.

However, he continued, the “elephant in the room” is the current lack of overall survival, and he pointed out that those hotly anticipated results could have a major impact on the future use of the triplet combination.

Dr. Pal questioned whether, in the meantime, it is even possible to make a decision about the combination and urged investigators of all trials to make overall survival data available sooner.

He also highlighted the high rates of elevated liver transaminases, and the apparent overlapping toxicities between the TKI and the immune checkpoint inhibitors, asking: “Does toxicity stand in the way of treatment?”

In conclusion, Dr. Pal acknowledged that the study did meet its PFS primary endpoint but asked whether a risk-adapted approach could be used to optimize delivery of triplet therapy.

He also called for investment into biomarker studies for regimens that are “actually used in the clinic” and wondered whether there could be a shift toward using drugs with novel modes of action that do not yield overlapping toxicities.

The study was funded by Exelixis.

Dr. Choueiri reports relationships with Bristol-Myers Squibb; Pfizer; Lilly; Merck; Exelixis; AstraZeneca; EMD Serono; Calithera; Ipsen; Infinity; Surface Oncology; Analysis Group; ww2.peerview.com; gotoper.com; researchtopractice.com; ResearchToPractice; National Association of Managed Care; Orien Network; Aptitude Health; Advent health; UAE Society of Onc; MJH life sciences; MDACC; Cancernet; Kidney Cancer Association; Springer; WebMed; ASiM, Caribou Publishing; Aravive; Roche, and others.

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

PARIS – Desmoid tumors are rare, locally aggressive, soft-tissue tumors for which there is no approved systemic therapy – but a novel drug may become the first.

Nirogacestat, under development by Connecticut-based SpringWorks Therapeutics, is an oral, selective, small-molecule gamma secretase inhibitor that targets the Notch signaling pathway, which is involved in cell differentiation. Desmoid tumors express high levels of Notch, so there is a “clear mechanistic rationale” for using such drugs in these patients.

Now, nirogacestat has shown a significant improvement in progression-free survival (PFS) and also a reduction in symptoms and better quality of life, when compared with placebo in the phase 3 DeFi trial.

The company has said that, by the end of this year, it will file these data for U.S. Food and Drug Administration approval of the drug for use in desmoid tumors.

Trial results were presented at the annual meeting of the European Society for Medical Oncology.

Overall, nirogacestat demonstrated “rapid, sustained, and statistically significant improvements in all primary and secondary endpoints,” study presenter Bernd Kasper, MD, PhD, sarcoma unit, Mannheim (Germany) Cancer Center, told a press conference.

There were “really impressive” reductions in pain scores and symptom burden, as well as improvements in health-related quality of life.

Dr. Kasper highlighted that this is the “first phase 3 trial … to demonstrate a clinical benefit with a gamma secretase inhibitor in any indication.”

With the drug showing a “manageable safety profile,” despite a high rate of ovarian dysfunction, Dr. Kasper believes it “has the potential to become the standard of care for patients with desmoid tumors requiring systemic treatment.”

Asked how long patients could take the drug, he replied, “Usually you take a drug as long as the patient benefits” from it.

“That means as long as there is no progression,” Dr. Kasper said, noting that there are patients from the earlier phase trials of nirogacestat who have been taking the drug “for years.”

However, there is a “very important question that is not answered” by the current study: “How long should we treat our patients?”

Dr. Kasper said to answer that question will require further trials, including those focused on treatment discontinuation.
 

Large trial in rare cancer

DeFi is a “unique study” and “very important in many aspects,” commented Jean-Yves Blay, MD, PhD, professor of medicine at the University Claude Bernard in Lyon, France, in an ESMO press release. Dr. Blay was not involved with the DeFi research.

“The results show benefit for the first time with a novel treatment with a new mode of action in patients where treatment options are currently limited,” he said, adding that the findings are “practice changing.”

Dr. Blay also praised the study for being “smart,” as it showed that large, placebo-controlled trials can be conducted in a rare cancer, and demonstrated the “importance of targeting the right patients with right drug.”

“The success of this study puts even more emphasis on the concept of having patients with rare cancers referred into reference centers, where clinical studies can be accomplished in record times, with the potential to deliver new treatments to patients with orphan diseases,” he said.

Discussing the results following their presentation, Dr. Blay said there are nevertheless a number of different treatment options for desmoid tumors, including sorafenib (Nexavar), and it is not clear whether patients with nonprogressive disease would experience any symptomatic benefit with nirogacestat.

Biomarkers of treatment efficacy and resistance are also required, he continued, and the drug’s long-term toxicity profile needs to be understood. In addition, its impact on ovarian dysfunction, as well as on future pregnancies, is currently unclear.
 

Details of the results

Presenting the study, Dr. Kasper explained that desmoid tumors have a variable presentation and an “unpredictable disease course,” and this together with the lack of approved therapies means they are “challenging to manage.”

Moreover, “due to local and aggressive growth, desmoid tumors can cause pain, disfigurement, and functional problems that can be a real burden for patients,” Dr. Kasper stressed.

Treatment should therefore be individualized to each patient to “optimize tumor control and improve the symptom burden,” he told the audience, including the impact on pain, physical function, and overall quality of life.

Indeed, a recent global consensus-based guideline for the management of desmoid tumors recommended a five-step model for treatment selection based on the level of evidence, overall response rate, PFS rate, ease of administration, and expected toxicity.

The DeFi trial enrolled patients with progressive desmoid tumors, stratified by target tumor location (intra-/extra-abdominal), who either were treatment-naive and not amenable to surgery, or were treatment refractory, or had recurrent disease after one prior line of therapy.

Dr. Kasper said in an interview that they required the patient to have at least 20% disease progression at the tumor sites so that they would include only those “who are in need of treatment.”

He explained that requirement was “quite strict” to ensure they excluded patients with “smaller-scale disease” and those with spontaneous regression, which can occur in desmoid tumors.

In all, 142 patients from 37 sites worldwide were randomly assigned to receive either nirogacestat 150 mg or placebo twice daily in 28-day cycles until radiographic progression, at which point patients were moved into an open-label phase and placebo patients could switch to nirogacestat.

The median age of the patients was 34 years, and two-thirds were female. Dr. Kasper underlined that there was a “rather high” prevalence of multifocal disease, at around 40%.

At the data cutoff for the primary analysis on April 7, nirogacestat was associated with a significant reduction in disease progression, at a median PFS that was not reached vs. 15.1 months for placebo, or a hazard ratio of 0.29 (P < .001).

This effect was seen across all subgroups included in the analysis, including when stratifying patients by age, gender, tumor characteristics, and prior treatment.

The objective response rate was also significantly higher with nirogacestat, at 41% vs. 8% in patients assigned to placebo (P < .001). A complete response was seen in 7% of patients given active treatment vs. 0% of those in the placebo group.

The median time to response was 5.6 months with nirogacestat and 11.1 months for patients given placebo.

Dr. Kasper also showed that nirogacestat was associated with significant reductions in pain severity, compared with placebo at treatment cycle 10, as measured on the Brief Pain Index-Short Form of –1.5 (P < .001).

There were also significant improvements with nirogacestat over placebo in the DT Symptom and DT Impact Scales (P < .001 for both), and on the global health status/quality of life scale (P = .007), physical functioning scale (P < .001), and role functioning scale (P < .001) of the EORTC Quality of Life Questionnaire-Core 30.

After a median exposure of 20.6 months, grade 3 or higher treatment-emergent adverse events were observed in 57% of patients treated with nirogacestat vs. 17% of those given placebo, who had a median treatment exposure of 11.4 months.

The most commonly reported adverse events of any grade with the active drug were diarrhea (84%), nausea (54%), fatigue (51%), and hypophosphatemia (42%), but Dr. Kasper noted that 95% of treatment-emergent adverse events were grade 1 or 2, with the first onset typically during cycle 1.

Ovarian dysfunction was observed in 75% of women of childbearing age, at a median onset at 9 weeks and a median duration of 21 weeks. However, the dysfunction resolved in 74% of patients, including those who continued active therapy.

The study was funded by SpringWorks Therapeutics. Dr. Kasper declares relationships with Bayer, Blueprint, Boehringer Ingelheim, SpringWorks, GSK, PharmaMar, and Ayala.

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

PARIS – Desmoid tumors are rare, locally aggressive, soft-tissue tumors for which there is no approved systemic therapy – but a novel drug may become the first.

Nirogacestat, under development by Connecticut-based SpringWorks Therapeutics, is an oral, selective, small-molecule gamma secretase inhibitor that targets the Notch signaling pathway, which is involved in cell differentiation. Desmoid tumors express high levels of Notch, so there is a “clear mechanistic rationale” for using such drugs in these patients.

Now, nirogacestat has shown a significant improvement in progression-free survival (PFS) and also a reduction in symptoms and better quality of life, when compared with placebo in the phase 3 DeFi trial.

The company has said that, by the end of this year, it will file these data for U.S. Food and Drug Administration approval of the drug for use in desmoid tumors.

Trial results were presented at the annual meeting of the European Society for Medical Oncology.

Overall, nirogacestat demonstrated “rapid, sustained, and statistically significant improvements in all primary and secondary endpoints,” study presenter Bernd Kasper, MD, PhD, sarcoma unit, Mannheim (Germany) Cancer Center, told a press conference.

There were “really impressive” reductions in pain scores and symptom burden, as well as improvements in health-related quality of life.

Dr. Kasper highlighted that this is the “first phase 3 trial … to demonstrate a clinical benefit with a gamma secretase inhibitor in any indication.”

With the drug showing a “manageable safety profile,” despite a high rate of ovarian dysfunction, Dr. Kasper believes it “has the potential to become the standard of care for patients with desmoid tumors requiring systemic treatment.”

Asked how long patients could take the drug, he replied, “Usually you take a drug as long as the patient benefits” from it.

“That means as long as there is no progression,” Dr. Kasper said, noting that there are patients from the earlier phase trials of nirogacestat who have been taking the drug “for years.”

However, there is a “very important question that is not answered” by the current study: “How long should we treat our patients?”

Dr. Kasper said to answer that question will require further trials, including those focused on treatment discontinuation.
 

Large trial in rare cancer

DeFi is a “unique study” and “very important in many aspects,” commented Jean-Yves Blay, MD, PhD, professor of medicine at the University Claude Bernard in Lyon, France, in an ESMO press release. Dr. Blay was not involved with the DeFi research.

“The results show benefit for the first time with a novel treatment with a new mode of action in patients where treatment options are currently limited,” he said, adding that the findings are “practice changing.”

Dr. Blay also praised the study for being “smart,” as it showed that large, placebo-controlled trials can be conducted in a rare cancer, and demonstrated the “importance of targeting the right patients with right drug.”

“The success of this study puts even more emphasis on the concept of having patients with rare cancers referred into reference centers, where clinical studies can be accomplished in record times, with the potential to deliver new treatments to patients with orphan diseases,” he said.

Discussing the results following their presentation, Dr. Blay said there are nevertheless a number of different treatment options for desmoid tumors, including sorafenib (Nexavar), and it is not clear whether patients with nonprogressive disease would experience any symptomatic benefit with nirogacestat.

Biomarkers of treatment efficacy and resistance are also required, he continued, and the drug’s long-term toxicity profile needs to be understood. In addition, its impact on ovarian dysfunction, as well as on future pregnancies, is currently unclear.
 

Details of the results

Presenting the study, Dr. Kasper explained that desmoid tumors have a variable presentation and an “unpredictable disease course,” and this together with the lack of approved therapies means they are “challenging to manage.”

Moreover, “due to local and aggressive growth, desmoid tumors can cause pain, disfigurement, and functional problems that can be a real burden for patients,” Dr. Kasper stressed.

Treatment should therefore be individualized to each patient to “optimize tumor control and improve the symptom burden,” he told the audience, including the impact on pain, physical function, and overall quality of life.

Indeed, a recent global consensus-based guideline for the management of desmoid tumors recommended a five-step model for treatment selection based on the level of evidence, overall response rate, PFS rate, ease of administration, and expected toxicity.

The DeFi trial enrolled patients with progressive desmoid tumors, stratified by target tumor location (intra-/extra-abdominal), who either were treatment-naive and not amenable to surgery, or were treatment refractory, or had recurrent disease after one prior line of therapy.

Dr. Kasper said in an interview that they required the patient to have at least 20% disease progression at the tumor sites so that they would include only those “who are in need of treatment.”

He explained that requirement was “quite strict” to ensure they excluded patients with “smaller-scale disease” and those with spontaneous regression, which can occur in desmoid tumors.

In all, 142 patients from 37 sites worldwide were randomly assigned to receive either nirogacestat 150 mg or placebo twice daily in 28-day cycles until radiographic progression, at which point patients were moved into an open-label phase and placebo patients could switch to nirogacestat.

The median age of the patients was 34 years, and two-thirds were female. Dr. Kasper underlined that there was a “rather high” prevalence of multifocal disease, at around 40%.

At the data cutoff for the primary analysis on April 7, nirogacestat was associated with a significant reduction in disease progression, at a median PFS that was not reached vs. 15.1 months for placebo, or a hazard ratio of 0.29 (P < .001).

This effect was seen across all subgroups included in the analysis, including when stratifying patients by age, gender, tumor characteristics, and prior treatment.

The objective response rate was also significantly higher with nirogacestat, at 41% vs. 8% in patients assigned to placebo (P < .001). A complete response was seen in 7% of patients given active treatment vs. 0% of those in the placebo group.

The median time to response was 5.6 months with nirogacestat and 11.1 months for patients given placebo.

Dr. Kasper also showed that nirogacestat was associated with significant reductions in pain severity, compared with placebo at treatment cycle 10, as measured on the Brief Pain Index-Short Form of –1.5 (P < .001).

There were also significant improvements with nirogacestat over placebo in the DT Symptom and DT Impact Scales (P < .001 for both), and on the global health status/quality of life scale (P = .007), physical functioning scale (P < .001), and role functioning scale (P < .001) of the EORTC Quality of Life Questionnaire-Core 30.

After a median exposure of 20.6 months, grade 3 or higher treatment-emergent adverse events were observed in 57% of patients treated with nirogacestat vs. 17% of those given placebo, who had a median treatment exposure of 11.4 months.

The most commonly reported adverse events of any grade with the active drug were diarrhea (84%), nausea (54%), fatigue (51%), and hypophosphatemia (42%), but Dr. Kasper noted that 95% of treatment-emergent adverse events were grade 1 or 2, with the first onset typically during cycle 1.

Ovarian dysfunction was observed in 75% of women of childbearing age, at a median onset at 9 weeks and a median duration of 21 weeks. However, the dysfunction resolved in 74% of patients, including those who continued active therapy.

The study was funded by SpringWorks Therapeutics. Dr. Kasper declares relationships with Bayer, Blueprint, Boehringer Ingelheim, SpringWorks, GSK, PharmaMar, and Ayala.

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

PARIS – Desmoid tumors are rare, locally aggressive, soft-tissue tumors for which there is no approved systemic therapy – but a novel drug may become the first.

Nirogacestat, under development by Connecticut-based SpringWorks Therapeutics, is an oral, selective, small-molecule gamma secretase inhibitor that targets the Notch signaling pathway, which is involved in cell differentiation. Desmoid tumors express high levels of Notch, so there is a “clear mechanistic rationale” for using such drugs in these patients.

Now, nirogacestat has shown a significant improvement in progression-free survival (PFS) and also a reduction in symptoms and better quality of life, when compared with placebo in the phase 3 DeFi trial.

The company has said that, by the end of this year, it will file these data for U.S. Food and Drug Administration approval of the drug for use in desmoid tumors.

Trial results were presented at the annual meeting of the European Society for Medical Oncology.

Overall, nirogacestat demonstrated “rapid, sustained, and statistically significant improvements in all primary and secondary endpoints,” study presenter Bernd Kasper, MD, PhD, sarcoma unit, Mannheim (Germany) Cancer Center, told a press conference.

There were “really impressive” reductions in pain scores and symptom burden, as well as improvements in health-related quality of life.

Dr. Kasper highlighted that this is the “first phase 3 trial … to demonstrate a clinical benefit with a gamma secretase inhibitor in any indication.”

With the drug showing a “manageable safety profile,” despite a high rate of ovarian dysfunction, Dr. Kasper believes it “has the potential to become the standard of care for patients with desmoid tumors requiring systemic treatment.”

Asked how long patients could take the drug, he replied, “Usually you take a drug as long as the patient benefits” from it.

“That means as long as there is no progression,” Dr. Kasper said, noting that there are patients from the earlier phase trials of nirogacestat who have been taking the drug “for years.”

However, there is a “very important question that is not answered” by the current study: “How long should we treat our patients?”

Dr. Kasper said to answer that question will require further trials, including those focused on treatment discontinuation.
 

Large trial in rare cancer

DeFi is a “unique study” and “very important in many aspects,” commented Jean-Yves Blay, MD, PhD, professor of medicine at the University Claude Bernard in Lyon, France, in an ESMO press release. Dr. Blay was not involved with the DeFi research.

“The results show benefit for the first time with a novel treatment with a new mode of action in patients where treatment options are currently limited,” he said, adding that the findings are “practice changing.”

Dr. Blay also praised the study for being “smart,” as it showed that large, placebo-controlled trials can be conducted in a rare cancer, and demonstrated the “importance of targeting the right patients with right drug.”

“The success of this study puts even more emphasis on the concept of having patients with rare cancers referred into reference centers, where clinical studies can be accomplished in record times, with the potential to deliver new treatments to patients with orphan diseases,” he said.

Discussing the results following their presentation, Dr. Blay said there are nevertheless a number of different treatment options for desmoid tumors, including sorafenib (Nexavar), and it is not clear whether patients with nonprogressive disease would experience any symptomatic benefit with nirogacestat.

Biomarkers of treatment efficacy and resistance are also required, he continued, and the drug’s long-term toxicity profile needs to be understood. In addition, its impact on ovarian dysfunction, as well as on future pregnancies, is currently unclear.
 

Details of the results

Presenting the study, Dr. Kasper explained that desmoid tumors have a variable presentation and an “unpredictable disease course,” and this together with the lack of approved therapies means they are “challenging to manage.”

Moreover, “due to local and aggressive growth, desmoid tumors can cause pain, disfigurement, and functional problems that can be a real burden for patients,” Dr. Kasper stressed.

Treatment should therefore be individualized to each patient to “optimize tumor control and improve the symptom burden,” he told the audience, including the impact on pain, physical function, and overall quality of life.

Indeed, a recent global consensus-based guideline for the management of desmoid tumors recommended a five-step model for treatment selection based on the level of evidence, overall response rate, PFS rate, ease of administration, and expected toxicity.

The DeFi trial enrolled patients with progressive desmoid tumors, stratified by target tumor location (intra-/extra-abdominal), who either were treatment-naive and not amenable to surgery, or were treatment refractory, or had recurrent disease after one prior line of therapy.

Dr. Kasper said in an interview that they required the patient to have at least 20% disease progression at the tumor sites so that they would include only those “who are in need of treatment.”

He explained that requirement was “quite strict” to ensure they excluded patients with “smaller-scale disease” and those with spontaneous regression, which can occur in desmoid tumors.

In all, 142 patients from 37 sites worldwide were randomly assigned to receive either nirogacestat 150 mg or placebo twice daily in 28-day cycles until radiographic progression, at which point patients were moved into an open-label phase and placebo patients could switch to nirogacestat.

The median age of the patients was 34 years, and two-thirds were female. Dr. Kasper underlined that there was a “rather high” prevalence of multifocal disease, at around 40%.

At the data cutoff for the primary analysis on April 7, nirogacestat was associated with a significant reduction in disease progression, at a median PFS that was not reached vs. 15.1 months for placebo, or a hazard ratio of 0.29 (P < .001).

This effect was seen across all subgroups included in the analysis, including when stratifying patients by age, gender, tumor characteristics, and prior treatment.

The objective response rate was also significantly higher with nirogacestat, at 41% vs. 8% in patients assigned to placebo (P < .001). A complete response was seen in 7% of patients given active treatment vs. 0% of those in the placebo group.

The median time to response was 5.6 months with nirogacestat and 11.1 months for patients given placebo.

Dr. Kasper also showed that nirogacestat was associated with significant reductions in pain severity, compared with placebo at treatment cycle 10, as measured on the Brief Pain Index-Short Form of –1.5 (P < .001).

There were also significant improvements with nirogacestat over placebo in the DT Symptom and DT Impact Scales (P < .001 for both), and on the global health status/quality of life scale (P = .007), physical functioning scale (P < .001), and role functioning scale (P < .001) of the EORTC Quality of Life Questionnaire-Core 30.

After a median exposure of 20.6 months, grade 3 or higher treatment-emergent adverse events were observed in 57% of patients treated with nirogacestat vs. 17% of those given placebo, who had a median treatment exposure of 11.4 months.

The most commonly reported adverse events of any grade with the active drug were diarrhea (84%), nausea (54%), fatigue (51%), and hypophosphatemia (42%), but Dr. Kasper noted that 95% of treatment-emergent adverse events were grade 1 or 2, with the first onset typically during cycle 1.

Ovarian dysfunction was observed in 75% of women of childbearing age, at a median onset at 9 weeks and a median duration of 21 weeks. However, the dysfunction resolved in 74% of patients, including those who continued active therapy.

The study was funded by SpringWorks Therapeutics. Dr. Kasper declares relationships with Bayer, Blueprint, Boehringer Ingelheim, SpringWorks, GSK, PharmaMar, and Ayala.

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

Patients with prurigo nodularis (PN) who had severe itch and high lesion counts and whose condition was inadequately controlled with prior therapies experienced significant improvements with dupilumab (Dupixent), indicate results from the phase 2 LIBERTY-PN PRIME trial.

The research was presented at the annual Congress of the European Academy of Dermatology and Venereology.

More than 150 patients with severe PN whose quality of life was impaired were randomly assigned to receive dupilumab (Dupixent) or placebo for 24 weeks. Use of the monoclonal antibody was associated with significant improvements in itch scores.

The researchers also found that the percentage of patients who had no or few PN lesions increased substantially with use of dupilumab, and there were no new safety signals, confirming results from previous studies. Dupilumab, an interleukin-4 receptor alpha antagonist administered by injection, was initially approved by the U.S. Food and Drug Administration for treating atopic dermatitis in 2022.

Study presenter Gil Yosipovitch, MD, professor of dermatology at the University of Miami, emphasized that the improvements in itch and skin lesions seen in these patients were “clinically meaningful.”

Among 151 patients in the study, the mean age was 50.1 years, and 66.2% were women. The majority (53.0%) were White; 7.3% were Black; and 35.8% were Asian; 40.4% of patients had a history of atopy. The mean WI-NRS was 8.5, and the mean skin pain score on a 10-point scale was 7.2.

The Investigator’s Global Assessment for PN stage of disease (IGA PN-S) was also employed in the trial. That measure uses a 5-point scale to assess disease severity, with 0 indicating no lesions and 4 indicating more than 100 lesions. At baseline, 28.7% of patients had a score of 4, and the remainder had a score of 3, indicating the presence of 20-100 PN lesions.

Dr. Yosipovitch said that quality of life for these patients was “low” and that scores on the Hospital Anxiety and Depression scale indicated that the participants, many of whom had previously received topical and systemic medications for their PN, indicated they were depressed.

He showed that at week 24, the proportion of patients who had experienced an improvement in the WI-NRS score of greater than or equal to 4 (the study’s primary endpoint) was significantly greater with dupilumab, at 60.0% versus 18.4% among patients given placebo (P < .0001).

Moreover, the proportion of patients at week 24 with an IGA PN-S score of 0 or 1 (the secondary endpoint) was 48.0% in the active treatment group, versus 18.4% with placebo (P =.0004).

With regard to safety, rates of any treatment-emergent adverse events were similar between the groups, at 70.7% for dupilumab and 62.7% for placebo, as were rates for severe treatment-emergent adverse events, at 6.7% and 10.7%, respectively.

Rates of treatment-emergent adverse events of interest, such as skin infections, conjunctivitis, herpes viral infections, and injection site reactions, also suggested that there was no increased risk with active treatment.

Dupilumab is currently under review at the FDA and in Europe for the treatment of PN, according to dupilumab manufacturers Regeneron and Sanofi.

The study was sponsored by Sanofi in collaboration with Regeneron Pharmaceuticals. Dr. Yosipovitch has relationships with Arcutis Biotherapeutics, Bellus Health, Eli Lilly, Galderma, GSK, Kiniksa Pharmaceuticals, LEO Pharma, Novartis, Pfizer, Regeneron Pharmaceuticals, Sanofi, and Trevi Therapeutics.

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

Patients with prurigo nodularis (PN) who had severe itch and high lesion counts and whose condition was inadequately controlled with prior therapies experienced significant improvements with dupilumab (Dupixent), indicate results from the phase 2 LIBERTY-PN PRIME trial.

The research was presented at the annual Congress of the European Academy of Dermatology and Venereology.

More than 150 patients with severe PN whose quality of life was impaired were randomly assigned to receive dupilumab (Dupixent) or placebo for 24 weeks. Use of the monoclonal antibody was associated with significant improvements in itch scores.

The researchers also found that the percentage of patients who had no or few PN lesions increased substantially with use of dupilumab, and there were no new safety signals, confirming results from previous studies. Dupilumab, an interleukin-4 receptor alpha antagonist administered by injection, was initially approved by the U.S. Food and Drug Administration for treating atopic dermatitis in 2022.

Study presenter Gil Yosipovitch, MD, professor of dermatology at the University of Miami, emphasized that the improvements in itch and skin lesions seen in these patients were “clinically meaningful.”

Among 151 patients in the study, the mean age was 50.1 years, and 66.2% were women. The majority (53.0%) were White; 7.3% were Black; and 35.8% were Asian; 40.4% of patients had a history of atopy. The mean WI-NRS was 8.5, and the mean skin pain score on a 10-point scale was 7.2.

The Investigator’s Global Assessment for PN stage of disease (IGA PN-S) was also employed in the trial. That measure uses a 5-point scale to assess disease severity, with 0 indicating no lesions and 4 indicating more than 100 lesions. At baseline, 28.7% of patients had a score of 4, and the remainder had a score of 3, indicating the presence of 20-100 PN lesions.

Dr. Yosipovitch said that quality of life for these patients was “low” and that scores on the Hospital Anxiety and Depression scale indicated that the participants, many of whom had previously received topical and systemic medications for their PN, indicated they were depressed.

He showed that at week 24, the proportion of patients who had experienced an improvement in the WI-NRS score of greater than or equal to 4 (the study’s primary endpoint) was significantly greater with dupilumab, at 60.0% versus 18.4% among patients given placebo (P < .0001).

Moreover, the proportion of patients at week 24 with an IGA PN-S score of 0 or 1 (the secondary endpoint) was 48.0% in the active treatment group, versus 18.4% with placebo (P =.0004).

With regard to safety, rates of any treatment-emergent adverse events were similar between the groups, at 70.7% for dupilumab and 62.7% for placebo, as were rates for severe treatment-emergent adverse events, at 6.7% and 10.7%, respectively.

Rates of treatment-emergent adverse events of interest, such as skin infections, conjunctivitis, herpes viral infections, and injection site reactions, also suggested that there was no increased risk with active treatment.

Dupilumab is currently under review at the FDA and in Europe for the treatment of PN, according to dupilumab manufacturers Regeneron and Sanofi.

The study was sponsored by Sanofi in collaboration with Regeneron Pharmaceuticals. Dr. Yosipovitch has relationships with Arcutis Biotherapeutics, Bellus Health, Eli Lilly, Galderma, GSK, Kiniksa Pharmaceuticals, LEO Pharma, Novartis, Pfizer, Regeneron Pharmaceuticals, Sanofi, and Trevi Therapeutics.

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

Patients with prurigo nodularis (PN) who had severe itch and high lesion counts and whose condition was inadequately controlled with prior therapies experienced significant improvements with dupilumab (Dupixent), indicate results from the phase 2 LIBERTY-PN PRIME trial.

The research was presented at the annual Congress of the European Academy of Dermatology and Venereology.

More than 150 patients with severe PN whose quality of life was impaired were randomly assigned to receive dupilumab (Dupixent) or placebo for 24 weeks. Use of the monoclonal antibody was associated with significant improvements in itch scores.

The researchers also found that the percentage of patients who had no or few PN lesions increased substantially with use of dupilumab, and there were no new safety signals, confirming results from previous studies. Dupilumab, an interleukin-4 receptor alpha antagonist administered by injection, was initially approved by the U.S. Food and Drug Administration for treating atopic dermatitis in 2022.

Study presenter Gil Yosipovitch, MD, professor of dermatology at the University of Miami, emphasized that the improvements in itch and skin lesions seen in these patients were “clinically meaningful.”

Among 151 patients in the study, the mean age was 50.1 years, and 66.2% were women. The majority (53.0%) were White; 7.3% were Black; and 35.8% were Asian; 40.4% of patients had a history of atopy. The mean WI-NRS was 8.5, and the mean skin pain score on a 10-point scale was 7.2.

The Investigator’s Global Assessment for PN stage of disease (IGA PN-S) was also employed in the trial. That measure uses a 5-point scale to assess disease severity, with 0 indicating no lesions and 4 indicating more than 100 lesions. At baseline, 28.7% of patients had a score of 4, and the remainder had a score of 3, indicating the presence of 20-100 PN lesions.

Dr. Yosipovitch said that quality of life for these patients was “low” and that scores on the Hospital Anxiety and Depression scale indicated that the participants, many of whom had previously received topical and systemic medications for their PN, indicated they were depressed.

He showed that at week 24, the proportion of patients who had experienced an improvement in the WI-NRS score of greater than or equal to 4 (the study’s primary endpoint) was significantly greater with dupilumab, at 60.0% versus 18.4% among patients given placebo (P < .0001).

Moreover, the proportion of patients at week 24 with an IGA PN-S score of 0 or 1 (the secondary endpoint) was 48.0% in the active treatment group, versus 18.4% with placebo (P =.0004).

With regard to safety, rates of any treatment-emergent adverse events were similar between the groups, at 70.7% for dupilumab and 62.7% for placebo, as were rates for severe treatment-emergent adverse events, at 6.7% and 10.7%, respectively.

Rates of treatment-emergent adverse events of interest, such as skin infections, conjunctivitis, herpes viral infections, and injection site reactions, also suggested that there was no increased risk with active treatment.

Dupilumab is currently under review at the FDA and in Europe for the treatment of PN, according to dupilumab manufacturers Regeneron and Sanofi.

The study was sponsored by Sanofi in collaboration with Regeneron Pharmaceuticals. Dr. Yosipovitch has relationships with Arcutis Biotherapeutics, Bellus Health, Eli Lilly, Galderma, GSK, Kiniksa Pharmaceuticals, LEO Pharma, Novartis, Pfizer, Regeneron Pharmaceuticals, Sanofi, and Trevi Therapeutics.

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