Conference Coverage

A common adverse effect of the multiple sclerosis (MS) treatment alemtuzumab (Lemtrada) may be predicted by pretreatment levels of certain types of B cells, a new study suggests.

“Alemtuzumab has proven to be an effective treatment for patients with highly active remitting relapsing MS, but adverse events may limit the use of this drug, particularly autoimmune adverse events, which are the most prevalent, occurring in about 30% of patients. Reliable biomarkers to assess patient risk for developing this complication would be of great importance,” said lead author Paulette Walo, MD.

“Our results suggest that a higher percentage of total B cells, and in particular plasmablasts, could be a very predictive biomarker for autoimmunity after alemtuzumab treatment. This could help us in choosing the patients for this drug,” said Dr. Walo, an immunologist at Ramon y Cajal University Hospital, Madrid. She presented the findings at the Joint European Committee for Treatment and Research in Multiple Sclerosis–Americas Committee for Treatment and Research in Multiple Sclerosis (ECTRIMS-ACTRIMS) 2020, this year known as MSVirtual2020.

The objective of this study was to explore if patient blood lymphocyte profile before alemtuzumab treatment initiation can identify patients with an increased risk of developing later autoimmunity, Dr. Walo explained.

The study included 54 patients from five hospitals throughout Spain who had received treatment with alemtuzumab. Of these, the vast majority had received the normal two-dose cycle and two patients had received a third dose because of worsening MS activity.

Blood samples were collected before initiating treatment with alemtuzumab. Peripheral blood mononuclear cells were obtained and cryopreserved. Leukocyte populations were assessed by flow cytometry.

Autoimmune adverse events were defined as the development, at any point within 2 years of follow-up, of any autoimmune thyroid-associated event, immune thrombocytopenia, and/or autoimmune nephropathy.

Over the 2 years of follow-up, 14 patients (25.9%) experienced autoimmune adverse events, all of which were dysthyroidism. No immune thrombocytopenia or nephropathies were observed.

No statistical differences were found in clinical and demographic characteristics between patients who developed autoimmune adverse events and those who did not. Previous treatments did not influence B-cell percentages.

Analysis of blood lymphocyte profiles showed no difference in T-cell subsets between those who had an autoimmune event and those who did not.

Still, there were important differences in the B-cell profile, Dr. Walo said. “Total B cells were higher in patients who had an autoimmune event mainly due to naive B cells and plasmablasts.”

Patients who experienced autoimmune adverse events before treatment onset had a higher percentage of blood CD19+ B cells (P = .001), with a higher relative percentage of naive B cells and plasmablasts.

When individual types of cell numbers were explored, only plasmablast levels remained significant (P = .02).

The researchers calculated a CD19+ B-cell predictive value for autoimmunity of 7.6%. If patients had more than 7.6% B cells, they were at higher risk of an autoimmune adverse event after alemtuzumab treatment versus those with lower levels (odds ratio, 14.67; P ≤ .0001).

Similarly, the predictive value for plasmablasts was 0.13%. If patients had levels higher than 0.13% they had a higher risk of an autoimmune event after alemtuzumab treatment (P = .002). Plasmablasts are a category of B cells which are very differentiated and have the capacity to produce antibodies; they are a very active and aggressive subtype of B cells, Dr. Walo noted. 

She explained that, as was the case in this study, autoimmune events after alemtuzumab treatment normally manifests as the development of antibodies against the thyroid gland, with the development of either hyperthyroidism or hypothyroidism, necessitating long-term treatment to manage these conditions.

“Autoimmunity develops at variable timescales. It can appear in the first year after alemtuzumab treatment but it can also appear later on,” she said.

Dr. Walo’s group is hoping to validate their results in a larger study. “This is only a small study so we need to replicate these findings in a larger cohort. We are in the process of doing this, collaborating with other hospitals,” she commented. 

She said that, if the results are validated, then patients could undergo blood tests before alemtuzumab treatment to analyze their B-cell counts.

“For those with high levels of B cells – and particularly plasmablasts – alemtuzumab may not be the best treatment to choose,” Dr. Walo said.
 

Personalized strategy

During the postpresentation discussion, the suggestion was raised of giving an anti–B-cell drug before alemtuzumab to try and prevent autoimmunity. Dr. Walo responded that this is a possibility. “This is something that we are going to look into. If our larger study validates our initial results, then we would plan a study to give an anti–B-cell treatment such as rituximab before alemtuzumab and see whether this reduces the risk of autoimmunity.”

Commenting on the study, session comoderator Darin Okuda, MD, professor in the department of neurology and neurotherapeutics at the University of Texas Southwestern Medical Center, Dallas, said: “This is an intriguing approach and suggests a more personalized strategy for sure if we can identify patients who are at higher risk of developing autoimmunity.”

Also commenting, ACTRIMS president Jeffrey Cohen, MD, said: “One of the main drawbacks of alemtuzumab is the risk of antibody-mediated autoimmune conditions, so the ability to predict who is at risk for autoimmune adverse events prior to initiating alemtuzumab would be useful. Not surprisingly, factors related to B-cell number and profile were predictive.”

Dr. Cohen, who is a director of experimental neurotherapeutics at the Mellen Center for Multiple Sclerosis Treatment and Research at the Cleveland Clinic, added however that the suggestion of pretreating patients with an anti-CD20 monoclonal antibody “does not seem tenable to me,” because of the potential cost of such a strategy, and “no efficacy advantage for most patients over an anti-CD20 antibody alone.”

Commenting on this presentation, Alasdair J. Coles, MD, University of Cambridge (England), who was one of the co-inventors of alemtuzumab, said observations of an increased B-cell count before treatment as a risk predictor of thyroid autoimmunity after alemtuzumab had not been replicated in the clinical trial datasets of the drug. “So I fear we still do not have a reliable biomarker,” he added.

The study had no specific funding listed. Dr. Walo has disclosed no relevant financial relationships.

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

A common adverse effect of the multiple sclerosis (MS) treatment alemtuzumab (Lemtrada) may be predicted by pretreatment levels of certain types of B cells, a new study suggests.

“Alemtuzumab has proven to be an effective treatment for patients with highly active remitting relapsing MS, but adverse events may limit the use of this drug, particularly autoimmune adverse events, which are the most prevalent, occurring in about 30% of patients. Reliable biomarkers to assess patient risk for developing this complication would be of great importance,” said lead author Paulette Walo, MD.

“Our results suggest that a higher percentage of total B cells, and in particular plasmablasts, could be a very predictive biomarker for autoimmunity after alemtuzumab treatment. This could help us in choosing the patients for this drug,” said Dr. Walo, an immunologist at Ramon y Cajal University Hospital, Madrid. She presented the findings at the Joint European Committee for Treatment and Research in Multiple Sclerosis–Americas Committee for Treatment and Research in Multiple Sclerosis (ECTRIMS-ACTRIMS) 2020, this year known as MSVirtual2020.

The objective of this study was to explore if patient blood lymphocyte profile before alemtuzumab treatment initiation can identify patients with an increased risk of developing later autoimmunity, Dr. Walo explained.

The study included 54 patients from five hospitals throughout Spain who had received treatment with alemtuzumab. Of these, the vast majority had received the normal two-dose cycle and two patients had received a third dose because of worsening MS activity.

Blood samples were collected before initiating treatment with alemtuzumab. Peripheral blood mononuclear cells were obtained and cryopreserved. Leukocyte populations were assessed by flow cytometry.

Autoimmune adverse events were defined as the development, at any point within 2 years of follow-up, of any autoimmune thyroid-associated event, immune thrombocytopenia, and/or autoimmune nephropathy.

Over the 2 years of follow-up, 14 patients (25.9%) experienced autoimmune adverse events, all of which were dysthyroidism. No immune thrombocytopenia or nephropathies were observed.

No statistical differences were found in clinical and demographic characteristics between patients who developed autoimmune adverse events and those who did not. Previous treatments did not influence B-cell percentages.

Analysis of blood lymphocyte profiles showed no difference in T-cell subsets between those who had an autoimmune event and those who did not.

Still, there were important differences in the B-cell profile, Dr. Walo said. “Total B cells were higher in patients who had an autoimmune event mainly due to naive B cells and plasmablasts.”

Patients who experienced autoimmune adverse events before treatment onset had a higher percentage of blood CD19+ B cells (P = .001), with a higher relative percentage of naive B cells and plasmablasts.

When individual types of cell numbers were explored, only plasmablast levels remained significant (P = .02).

The researchers calculated a CD19+ B-cell predictive value for autoimmunity of 7.6%. If patients had more than 7.6% B cells, they were at higher risk of an autoimmune adverse event after alemtuzumab treatment versus those with lower levels (odds ratio, 14.67; P ≤ .0001).

Similarly, the predictive value for plasmablasts was 0.13%. If patients had levels higher than 0.13% they had a higher risk of an autoimmune event after alemtuzumab treatment (P = .002). Plasmablasts are a category of B cells which are very differentiated and have the capacity to produce antibodies; they are a very active and aggressive subtype of B cells, Dr. Walo noted. 

She explained that, as was the case in this study, autoimmune events after alemtuzumab treatment normally manifests as the development of antibodies against the thyroid gland, with the development of either hyperthyroidism or hypothyroidism, necessitating long-term treatment to manage these conditions.

“Autoimmunity develops at variable timescales. It can appear in the first year after alemtuzumab treatment but it can also appear later on,” she said.

Dr. Walo’s group is hoping to validate their results in a larger study. “This is only a small study so we need to replicate these findings in a larger cohort. We are in the process of doing this, collaborating with other hospitals,” she commented. 

She said that, if the results are validated, then patients could undergo blood tests before alemtuzumab treatment to analyze their B-cell counts.

“For those with high levels of B cells – and particularly plasmablasts – alemtuzumab may not be the best treatment to choose,” Dr. Walo said.
 

Personalized strategy

During the postpresentation discussion, the suggestion was raised of giving an anti–B-cell drug before alemtuzumab to try and prevent autoimmunity. Dr. Walo responded that this is a possibility. “This is something that we are going to look into. If our larger study validates our initial results, then we would plan a study to give an anti–B-cell treatment such as rituximab before alemtuzumab and see whether this reduces the risk of autoimmunity.”

Commenting on the study, session comoderator Darin Okuda, MD, professor in the department of neurology and neurotherapeutics at the University of Texas Southwestern Medical Center, Dallas, said: “This is an intriguing approach and suggests a more personalized strategy for sure if we can identify patients who are at higher risk of developing autoimmunity.”

Also commenting, ACTRIMS president Jeffrey Cohen, MD, said: “One of the main drawbacks of alemtuzumab is the risk of antibody-mediated autoimmune conditions, so the ability to predict who is at risk for autoimmune adverse events prior to initiating alemtuzumab would be useful. Not surprisingly, factors related to B-cell number and profile were predictive.”

Dr. Cohen, who is a director of experimental neurotherapeutics at the Mellen Center for Multiple Sclerosis Treatment and Research at the Cleveland Clinic, added however that the suggestion of pretreating patients with an anti-CD20 monoclonal antibody “does not seem tenable to me,” because of the potential cost of such a strategy, and “no efficacy advantage for most patients over an anti-CD20 antibody alone.”

Commenting on this presentation, Alasdair J. Coles, MD, University of Cambridge (England), who was one of the co-inventors of alemtuzumab, said observations of an increased B-cell count before treatment as a risk predictor of thyroid autoimmunity after alemtuzumab had not been replicated in the clinical trial datasets of the drug. “So I fear we still do not have a reliable biomarker,” he added.

The study had no specific funding listed. Dr. Walo has disclosed no relevant financial relationships.

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

A common adverse effect of the multiple sclerosis (MS) treatment alemtuzumab (Lemtrada) may be predicted by pretreatment levels of certain types of B cells, a new study suggests.

“Alemtuzumab has proven to be an effective treatment for patients with highly active remitting relapsing MS, but adverse events may limit the use of this drug, particularly autoimmune adverse events, which are the most prevalent, occurring in about 30% of patients. Reliable biomarkers to assess patient risk for developing this complication would be of great importance,” said lead author Paulette Walo, MD.

“Our results suggest that a higher percentage of total B cells, and in particular plasmablasts, could be a very predictive biomarker for autoimmunity after alemtuzumab treatment. This could help us in choosing the patients for this drug,” said Dr. Walo, an immunologist at Ramon y Cajal University Hospital, Madrid. She presented the findings at the Joint European Committee for Treatment and Research in Multiple Sclerosis–Americas Committee for Treatment and Research in Multiple Sclerosis (ECTRIMS-ACTRIMS) 2020, this year known as MSVirtual2020.

The objective of this study was to explore if patient blood lymphocyte profile before alemtuzumab treatment initiation can identify patients with an increased risk of developing later autoimmunity, Dr. Walo explained.

The study included 54 patients from five hospitals throughout Spain who had received treatment with alemtuzumab. Of these, the vast majority had received the normal two-dose cycle and two patients had received a third dose because of worsening MS activity.

Blood samples were collected before initiating treatment with alemtuzumab. Peripheral blood mononuclear cells were obtained and cryopreserved. Leukocyte populations were assessed by flow cytometry.

Autoimmune adverse events were defined as the development, at any point within 2 years of follow-up, of any autoimmune thyroid-associated event, immune thrombocytopenia, and/or autoimmune nephropathy.

Over the 2 years of follow-up, 14 patients (25.9%) experienced autoimmune adverse events, all of which were dysthyroidism. No immune thrombocytopenia or nephropathies were observed.

No statistical differences were found in clinical and demographic characteristics between patients who developed autoimmune adverse events and those who did not. Previous treatments did not influence B-cell percentages.

Analysis of blood lymphocyte profiles showed no difference in T-cell subsets between those who had an autoimmune event and those who did not.

Still, there were important differences in the B-cell profile, Dr. Walo said. “Total B cells were higher in patients who had an autoimmune event mainly due to naive B cells and plasmablasts.”

Patients who experienced autoimmune adverse events before treatment onset had a higher percentage of blood CD19+ B cells (P = .001), with a higher relative percentage of naive B cells and plasmablasts.

When individual types of cell numbers were explored, only plasmablast levels remained significant (P = .02).

The researchers calculated a CD19+ B-cell predictive value for autoimmunity of 7.6%. If patients had more than 7.6% B cells, they were at higher risk of an autoimmune adverse event after alemtuzumab treatment versus those with lower levels (odds ratio, 14.67; P ≤ .0001).

Similarly, the predictive value for plasmablasts was 0.13%. If patients had levels higher than 0.13% they had a higher risk of an autoimmune event after alemtuzumab treatment (P = .002). Plasmablasts are a category of B cells which are very differentiated and have the capacity to produce antibodies; they are a very active and aggressive subtype of B cells, Dr. Walo noted. 

She explained that, as was the case in this study, autoimmune events after alemtuzumab treatment normally manifests as the development of antibodies against the thyroid gland, with the development of either hyperthyroidism or hypothyroidism, necessitating long-term treatment to manage these conditions.

“Autoimmunity develops at variable timescales. It can appear in the first year after alemtuzumab treatment but it can also appear later on,” she said.

Dr. Walo’s group is hoping to validate their results in a larger study. “This is only a small study so we need to replicate these findings in a larger cohort. We are in the process of doing this, collaborating with other hospitals,” she commented. 

She said that, if the results are validated, then patients could undergo blood tests before alemtuzumab treatment to analyze their B-cell counts.

“For those with high levels of B cells – and particularly plasmablasts – alemtuzumab may not be the best treatment to choose,” Dr. Walo said.
 

Personalized strategy

During the postpresentation discussion, the suggestion was raised of giving an anti–B-cell drug before alemtuzumab to try and prevent autoimmunity. Dr. Walo responded that this is a possibility. “This is something that we are going to look into. If our larger study validates our initial results, then we would plan a study to give an anti–B-cell treatment such as rituximab before alemtuzumab and see whether this reduces the risk of autoimmunity.”

Commenting on the study, session comoderator Darin Okuda, MD, professor in the department of neurology and neurotherapeutics at the University of Texas Southwestern Medical Center, Dallas, said: “This is an intriguing approach and suggests a more personalized strategy for sure if we can identify patients who are at higher risk of developing autoimmunity.”

Also commenting, ACTRIMS president Jeffrey Cohen, MD, said: “One of the main drawbacks of alemtuzumab is the risk of antibody-mediated autoimmune conditions, so the ability to predict who is at risk for autoimmune adverse events prior to initiating alemtuzumab would be useful. Not surprisingly, factors related to B-cell number and profile were predictive.”

Dr. Cohen, who is a director of experimental neurotherapeutics at the Mellen Center for Multiple Sclerosis Treatment and Research at the Cleveland Clinic, added however that the suggestion of pretreating patients with an anti-CD20 monoclonal antibody “does not seem tenable to me,” because of the potential cost of such a strategy, and “no efficacy advantage for most patients over an anti-CD20 antibody alone.”

Commenting on this presentation, Alasdair J. Coles, MD, University of Cambridge (England), who was one of the co-inventors of alemtuzumab, said observations of an increased B-cell count before treatment as a risk predictor of thyroid autoimmunity after alemtuzumab had not been replicated in the clinical trial datasets of the drug. “So I fear we still do not have a reliable biomarker,” he added.

The study had no specific funding listed. Dr. Walo has disclosed no relevant financial relationships.

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

As approaches to airway management of patients with suspected or confirmed COVID-19 continue to evolve, practicing vigilant transmission-based infection control precautions remains essential.

This starts with observing droplet precautions to prevent exposure to droplets larger than 5 microns in size, Charles Griffis, PhD, CRNA, said at a Society for Critical Care Medicine virtual meeting: COVID-19: What’s Next. “These are particles exhaled from infected persons and which fall within around 6 feet and involve an exposure time of 15 or more minutes of contact,” said Dr. Griffis, of the department of anesthesiology at the University of Southern California, Los Angeles. “We will always observe standard precautions, which include hand hygiene, gloves, hair and eye cover, medical mask, and face shield. We will observe these at all times for all patients and layer our transmission-based precautions on top.”

During aerosol-producing procedures such as airway management maneuvers, tracheostomies, and bronchoscopies, very fine microscopic particles less than 5 microns in size are produced, which remain airborne for potentially many hours and travel long distances. “We will add an N95 mask or a powered air-purifying respirator (PAPR) device to filter out tiny particles in addition to our ever-present standard precautions,” he said. “Contact precautions are indicated for direct contact with patient saliva, blood, urine, and stool. In addition to standard precautions, we’re going to add an impermeable gown and we’ll continue with gloves, eye protection, and shoe covers. The message is to all of us. We have to observe all of the infection precautions that all of us have learned and trained in to avoid exposure.”

In terms of airway management for infected patients for elective procedures and surgery, recommendations based on current and previous coronavirus outbreaks suggest that all patients get polymerase chain reaction (PCR) tested within 24-48 hours of elective procedures or surgeries. If positive, they should be quarantined for 10-14 days and then, if asymptomatic, these patients may be retested or they can be regarded as negative. “Patients who are PCR positive with active infection and active symptoms receive only urgent or emergent care in most settings,” said Dr. Griffis, a member of the American Association of Nurse Anesthetists Infection Control Advisory Panel. “The care provided to our patients, whether they’re positive or not, is individualized per patient needs and institutional policy. Some folks have made the decision to treat all patients as infected and to use airborne precautions for all aerosol-producing procedures for all patients all the time.”

When a COVID-19 patient requires emergent or urgent airway management because of respiratory failure or some other surgical or procedural intervention necessitating airway management, preprocedural planning is key, he continued. This means establishing the steps in airway management scenarios for infected patients and rehearsing those steps in each ICU setting with key personnel such as nurses, respiratory therapists, and medical staff. “You want to make sure that the PPE is readily available and determine and limit the number of personnel that are going to enter the patient’s room or area for airway management,” Dr. Griffis said. “Have all the airway equipment and drugs immediately available. Perhaps you could organize them in a cart which is decontaminated after every use.”

He also recommends forming an intubation team for ICUs and perhaps even for ORs, where the most experienced clinicians perform airway management. “This helps to avoid unnecessary airway manipulation and minimizes personnel exposure and time to airway establishment,” he said.

Always attempt to house the infected patient in an airborne isolation, negative-pressure room, with a minimum of 12 exchanges per hour and which will take 35 minutes for 99.99% removal of airborne contaminants after airway management. “These numbers are important to remember for room turnover safety,” he said.

Patient factors to review during airway management include assessing the past medical history, inspecting the airway and considering the patient’s current physiological status as time permits. Previously in the pandemic, intubation was used earlier in the disease course, but now data suggest that patients do better without intubation if possible (Am J Trop Med Hyg. 2020;102[6]. doi: 10.4269/aitmh.20-0283). “This is because the pathophysiology of COVID-19 is such that the lung tissue is predisposed to iatrogenic barotrauma damage from positive-pressure ventilation,” Dr. Griffis said. “In addition, COVID patients appear to tolerate significant hypoxemia without distress in many cases. Therefore, many clinicians now hold off on intubation until the hypoxemic patient begins exhibiting signs and symptoms of respiratory distress.”

Options for delivering noninvasive airway support for COVID-19 patients include high-flow nasal cannula and noninvasive positive-pressure ventilation via CPAP or BiPAP. To mitigate the associated aerosol production, consider applying a surgical mask, helmet, or face mask over the airway device/patient’s face. “Another measure that has proven helpful in general respiratory support is to actually put the patient in a prone position to help redistribute ventilation throughout the lungs,” Dr. Griffis said (see Resp Care. 2015;60[11]:1660-87).

To prepare for the actual intubation procedure, gather two expert intubators who are going to be entering the patient’s room. The team should perform hand hygiene and don full PPE prior to entry. “It’s recommended that you consider wearing double gloves for the intubation,” he said. “Have the airway equipment easily accessible in a central location on a cart or in a kit, and use disposable, single-use equipment if possible. All of the usual intubation equipment to maintain a clear airway and give positive pressure ventilation should be arranged for easy access. A video laryngoscope should be used, if possible, for greater accuracy and reduced procedure time. Ready access to sedation and muscle relaxant drugs must be assured at all times.”

For the intubation procedure itself, Dr. Griffis recommends ensuring that an oxygen source, positive-pressure ventilation, and suction and resuscitation drugs and equipment are available per institutional protocol. Assign one person outside the room to coordinate supplies and assistance. “Preoxygenate the patient as permitted by clinical status,” he said. “A nonrebreathing oxygen mask can be used if sufficient spontaneous ventilation is present. Assess the airway, check and arrange equipment for easy access, and develop the safest airway management plan. Consider a rapid sequence induction and intubation as the first option.” Avoid positive-pressure ventilation or awake fiber optic intubation unless absolutely necessary, thus avoiding aerosol production. “Only ventilate the patient after the endotracheal tube cuff is inflated, to avoid aerosol release,” he said.

For intubation, administer airway procedural drugs and insert the laryngoscope – ideally a video laryngoscope if available. Intubate the trachea under direct vision, inflate the cuff, and remove outer gloves. Then attach the Ambu bag with a 99% filtration efficiency, heat-and-moisture exchange filter; and proceed to ventilate the patient, checking for chest rise, breath sounds, and CO₂ production. “Discard contaminated equipment in designated bins and secure the tube,” Dr. Griffis advised. “Attach the ventilator with an HMEF filter to protect the ventilator circuit and inner parts of the machine. Recheck your breath sounds, CO₂ production, and oxygen saturation, and adjust your vent settings as indicated.”

For post intubation, Dr. Griffis recommends securing contaminated discardable equipment in biohazard-labeled bins or bags, safely doffing your PPE, and retaining your N95 mask in the room. Remove your inner gloves, perform hand hygiene with soap and water if available, with alcohol-based hand rub if not, then don clean gloves. Exit the room, safely transporting any contaminated equipment that will be reused such as a cart or video laryngoscope to decontamination areas for processing. “Once clear of the room, order your chest x-ray to confirm your tube position per institutional protocol, understanding that radiology techs are all going to be following infection control procedures and wearing their PPE,” he said.

For extubation, Dr. Griffis recommends excusing all nonessential personnel from the patient room and assigning an assistant outside the room for necessary help. An experienced airway management expert should evaluate the patient wearing full PPE and be double-gloved. “If the extubation criteria are met, suction the pharynx and extubate,” he said. “Remove outer gloves and apply desired oxygen delivery equipment to the patient and assess respiratory status and vital signs for stability.” Next, discard all contaminated equipment in designated bins, doff contaminated PPE, and retain your N95 mask. Doff inner gloves, perform hand hygiene, and don clean gloves. “Exit the room, hand off contaminated equipment that is reusable, doff your gloves outside, do hand hygiene, then proceed to change your scrubs and complete your own personal hygiene measures,” he said.

Dr. Griffis reported having no financial disclosures.

“While the PPE used for intubation of a coronavirus patient is certainly more than the typical droplet precautions observed when intubating any other patient, the process and best practices aren’t terribly different from usual standard of care: Ensuring all necessary equipment is readily available with backup plans should the airway be difficult,” said Megan Conroy, MD, assistant professor of clinical medicine at The Ohio State University.

“We’ve been streamlining the team that’s present in the room for intubations of COVID patients, but I’m always amazed at the team members that stand at the ready to lend additional assistance just from the other side of the door. So while fewer personnel may be exposed, I wouldn’t consider the team needed for intubation to actually be much smaller, we’re just functioning differently.

In my practice the decision of when to intubate, clinically, doesn’t vary too much from any other form of severe ARDS. We may tolerate higher FiO₂ requirements on heated high-flow nasal cannula if the patient exhibits acceptable work of breathing, but I wouldn’t advise allowing a patient to remain hypoxemic with oxygen needs unmet by noninvasive methods out of fear of intubation or ventilator management. In my opinion, this simply delays a necessary therapy and only makes for a higher risk intubation. Certainly, the decision to intubate is never based on only one single data point, but takes an expert assessment of the whole clinical picture.

I’d assert that it’s true in every disease that patients do better if it’s possible to avoid intubation – but I would argue that the ability to avoid intubation is determined primarily by the disease course and clinical scenario, and not by whether the physician wishes to avoid intubation or not. If I can safely manage a patient off of a ventilator, I will always do so, COVID or otherwise. I think in this phase of the pandemic, patients ‘do better without intubation’ because those who didn’t require intubation were inherently doing better!”

dbrunk@mdedge.com

As approaches to airway management of patients with suspected or confirmed COVID-19 continue to evolve, practicing vigilant transmission-based infection control precautions remains essential.

This starts with observing droplet precautions to prevent exposure to droplets larger than 5 microns in size, Charles Griffis, PhD, CRNA, said at a Society for Critical Care Medicine virtual meeting: COVID-19: What’s Next. “These are particles exhaled from infected persons and which fall within around 6 feet and involve an exposure time of 15 or more minutes of contact,” said Dr. Griffis, of the department of anesthesiology at the University of Southern California, Los Angeles. “We will always observe standard precautions, which include hand hygiene, gloves, hair and eye cover, medical mask, and face shield. We will observe these at all times for all patients and layer our transmission-based precautions on top.”

During aerosol-producing procedures such as airway management maneuvers, tracheostomies, and bronchoscopies, very fine microscopic particles less than 5 microns in size are produced, which remain airborne for potentially many hours and travel long distances. “We will add an N95 mask or a powered air-purifying respirator (PAPR) device to filter out tiny particles in addition to our ever-present standard precautions,” he said. “Contact precautions are indicated for direct contact with patient saliva, blood, urine, and stool. In addition to standard precautions, we’re going to add an impermeable gown and we’ll continue with gloves, eye protection, and shoe covers. The message is to all of us. We have to observe all of the infection precautions that all of us have learned and trained in to avoid exposure.”

In terms of airway management for infected patients for elective procedures and surgery, recommendations based on current and previous coronavirus outbreaks suggest that all patients get polymerase chain reaction (PCR) tested within 24-48 hours of elective procedures or surgeries. If positive, they should be quarantined for 10-14 days and then, if asymptomatic, these patients may be retested or they can be regarded as negative. “Patients who are PCR positive with active infection and active symptoms receive only urgent or emergent care in most settings,” said Dr. Griffis, a member of the American Association of Nurse Anesthetists Infection Control Advisory Panel. “The care provided to our patients, whether they’re positive or not, is individualized per patient needs and institutional policy. Some folks have made the decision to treat all patients as infected and to use airborne precautions for all aerosol-producing procedures for all patients all the time.”

When a COVID-19 patient requires emergent or urgent airway management because of respiratory failure or some other surgical or procedural intervention necessitating airway management, preprocedural planning is key, he continued. This means establishing the steps in airway management scenarios for infected patients and rehearsing those steps in each ICU setting with key personnel such as nurses, respiratory therapists, and medical staff. “You want to make sure that the PPE is readily available and determine and limit the number of personnel that are going to enter the patient’s room or area for airway management,” Dr. Griffis said. “Have all the airway equipment and drugs immediately available. Perhaps you could organize them in a cart which is decontaminated after every use.”

He also recommends forming an intubation team for ICUs and perhaps even for ORs, where the most experienced clinicians perform airway management. “This helps to avoid unnecessary airway manipulation and minimizes personnel exposure and time to airway establishment,” he said.

Always attempt to house the infected patient in an airborne isolation, negative-pressure room, with a minimum of 12 exchanges per hour and which will take 35 minutes for 99.99% removal of airborne contaminants after airway management. “These numbers are important to remember for room turnover safety,” he said.

Patient factors to review during airway management include assessing the past medical history, inspecting the airway and considering the patient’s current physiological status as time permits. Previously in the pandemic, intubation was used earlier in the disease course, but now data suggest that patients do better without intubation if possible (Am J Trop Med Hyg. 2020;102[6]. doi: 10.4269/aitmh.20-0283). “This is because the pathophysiology of COVID-19 is such that the lung tissue is predisposed to iatrogenic barotrauma damage from positive-pressure ventilation,” Dr. Griffis said. “In addition, COVID patients appear to tolerate significant hypoxemia without distress in many cases. Therefore, many clinicians now hold off on intubation until the hypoxemic patient begins exhibiting signs and symptoms of respiratory distress.”

Options for delivering noninvasive airway support for COVID-19 patients include high-flow nasal cannula and noninvasive positive-pressure ventilation via CPAP or BiPAP. To mitigate the associated aerosol production, consider applying a surgical mask, helmet, or face mask over the airway device/patient’s face. “Another measure that has proven helpful in general respiratory support is to actually put the patient in a prone position to help redistribute ventilation throughout the lungs,” Dr. Griffis said (see Resp Care. 2015;60[11]:1660-87).

To prepare for the actual intubation procedure, gather two expert intubators who are going to be entering the patient’s room. The team should perform hand hygiene and don full PPE prior to entry. “It’s recommended that you consider wearing double gloves for the intubation,” he said. “Have the airway equipment easily accessible in a central location on a cart or in a kit, and use disposable, single-use equipment if possible. All of the usual intubation equipment to maintain a clear airway and give positive pressure ventilation should be arranged for easy access. A video laryngoscope should be used, if possible, for greater accuracy and reduced procedure time. Ready access to sedation and muscle relaxant drugs must be assured at all times.”

For the intubation procedure itself, Dr. Griffis recommends ensuring that an oxygen source, positive-pressure ventilation, and suction and resuscitation drugs and equipment are available per institutional protocol. Assign one person outside the room to coordinate supplies and assistance. “Preoxygenate the patient as permitted by clinical status,” he said. “A nonrebreathing oxygen mask can be used if sufficient spontaneous ventilation is present. Assess the airway, check and arrange equipment for easy access, and develop the safest airway management plan. Consider a rapid sequence induction and intubation as the first option.” Avoid positive-pressure ventilation or awake fiber optic intubation unless absolutely necessary, thus avoiding aerosol production. “Only ventilate the patient after the endotracheal tube cuff is inflated, to avoid aerosol release,” he said.

For intubation, administer airway procedural drugs and insert the laryngoscope – ideally a video laryngoscope if available. Intubate the trachea under direct vision, inflate the cuff, and remove outer gloves. Then attach the Ambu bag with a 99% filtration efficiency, heat-and-moisture exchange filter; and proceed to ventilate the patient, checking for chest rise, breath sounds, and CO₂ production. “Discard contaminated equipment in designated bins and secure the tube,” Dr. Griffis advised. “Attach the ventilator with an HMEF filter to protect the ventilator circuit and inner parts of the machine. Recheck your breath sounds, CO₂ production, and oxygen saturation, and adjust your vent settings as indicated.”

For post intubation, Dr. Griffis recommends securing contaminated discardable equipment in biohazard-labeled bins or bags, safely doffing your PPE, and retaining your N95 mask in the room. Remove your inner gloves, perform hand hygiene with soap and water if available, with alcohol-based hand rub if not, then don clean gloves. Exit the room, safely transporting any contaminated equipment that will be reused such as a cart or video laryngoscope to decontamination areas for processing. “Once clear of the room, order your chest x-ray to confirm your tube position per institutional protocol, understanding that radiology techs are all going to be following infection control procedures and wearing their PPE,” he said.

For extubation, Dr. Griffis recommends excusing all nonessential personnel from the patient room and assigning an assistant outside the room for necessary help. An experienced airway management expert should evaluate the patient wearing full PPE and be double-gloved. “If the extubation criteria are met, suction the pharynx and extubate,” he said. “Remove outer gloves and apply desired oxygen delivery equipment to the patient and assess respiratory status and vital signs for stability.” Next, discard all contaminated equipment in designated bins, doff contaminated PPE, and retain your N95 mask. Doff inner gloves, perform hand hygiene, and don clean gloves. “Exit the room, hand off contaminated equipment that is reusable, doff your gloves outside, do hand hygiene, then proceed to change your scrubs and complete your own personal hygiene measures,” he said.

Dr. Griffis reported having no financial disclosures.

“While the PPE used for intubation of a coronavirus patient is certainly more than the typical droplet precautions observed when intubating any other patient, the process and best practices aren’t terribly different from usual standard of care: Ensuring all necessary equipment is readily available with backup plans should the airway be difficult,” said Megan Conroy, MD, assistant professor of clinical medicine at The Ohio State University.

“We’ve been streamlining the team that’s present in the room for intubations of COVID patients, but I’m always amazed at the team members that stand at the ready to lend additional assistance just from the other side of the door. So while fewer personnel may be exposed, I wouldn’t consider the team needed for intubation to actually be much smaller, we’re just functioning differently.

In my practice the decision of when to intubate, clinically, doesn’t vary too much from any other form of severe ARDS. We may tolerate higher FiO₂ requirements on heated high-flow nasal cannula if the patient exhibits acceptable work of breathing, but I wouldn’t advise allowing a patient to remain hypoxemic with oxygen needs unmet by noninvasive methods out of fear of intubation or ventilator management. In my opinion, this simply delays a necessary therapy and only makes for a higher risk intubation. Certainly, the decision to intubate is never based on only one single data point, but takes an expert assessment of the whole clinical picture.

I’d assert that it’s true in every disease that patients do better if it’s possible to avoid intubation – but I would argue that the ability to avoid intubation is determined primarily by the disease course and clinical scenario, and not by whether the physician wishes to avoid intubation or not. If I can safely manage a patient off of a ventilator, I will always do so, COVID or otherwise. I think in this phase of the pandemic, patients ‘do better without intubation’ because those who didn’t require intubation were inherently doing better!”

dbrunk@mdedge.com

As approaches to airway management of patients with suspected or confirmed COVID-19 continue to evolve, practicing vigilant transmission-based infection control precautions remains essential.

This starts with observing droplet precautions to prevent exposure to droplets larger than 5 microns in size, Charles Griffis, PhD, CRNA, said at a Society for Critical Care Medicine virtual meeting: COVID-19: What’s Next. “These are particles exhaled from infected persons and which fall within around 6 feet and involve an exposure time of 15 or more minutes of contact,” said Dr. Griffis, of the department of anesthesiology at the University of Southern California, Los Angeles. “We will always observe standard precautions, which include hand hygiene, gloves, hair and eye cover, medical mask, and face shield. We will observe these at all times for all patients and layer our transmission-based precautions on top.”

During aerosol-producing procedures such as airway management maneuvers, tracheostomies, and bronchoscopies, very fine microscopic particles less than 5 microns in size are produced, which remain airborne for potentially many hours and travel long distances. “We will add an N95 mask or a powered air-purifying respirator (PAPR) device to filter out tiny particles in addition to our ever-present standard precautions,” he said. “Contact precautions are indicated for direct contact with patient saliva, blood, urine, and stool. In addition to standard precautions, we’re going to add an impermeable gown and we’ll continue with gloves, eye protection, and shoe covers. The message is to all of us. We have to observe all of the infection precautions that all of us have learned and trained in to avoid exposure.”

In terms of airway management for infected patients for elective procedures and surgery, recommendations based on current and previous coronavirus outbreaks suggest that all patients get polymerase chain reaction (PCR) tested within 24-48 hours of elective procedures or surgeries. If positive, they should be quarantined for 10-14 days and then, if asymptomatic, these patients may be retested or they can be regarded as negative. “Patients who are PCR positive with active infection and active symptoms receive only urgent or emergent care in most settings,” said Dr. Griffis, a member of the American Association of Nurse Anesthetists Infection Control Advisory Panel. “The care provided to our patients, whether they’re positive or not, is individualized per patient needs and institutional policy. Some folks have made the decision to treat all patients as infected and to use airborne precautions for all aerosol-producing procedures for all patients all the time.”

When a COVID-19 patient requires emergent or urgent airway management because of respiratory failure or some other surgical or procedural intervention necessitating airway management, preprocedural planning is key, he continued. This means establishing the steps in airway management scenarios for infected patients and rehearsing those steps in each ICU setting with key personnel such as nurses, respiratory therapists, and medical staff. “You want to make sure that the PPE is readily available and determine and limit the number of personnel that are going to enter the patient’s room or area for airway management,” Dr. Griffis said. “Have all the airway equipment and drugs immediately available. Perhaps you could organize them in a cart which is decontaminated after every use.”

He also recommends forming an intubation team for ICUs and perhaps even for ORs, where the most experienced clinicians perform airway management. “This helps to avoid unnecessary airway manipulation and minimizes personnel exposure and time to airway establishment,” he said.

Always attempt to house the infected patient in an airborne isolation, negative-pressure room, with a minimum of 12 exchanges per hour and which will take 35 minutes for 99.99% removal of airborne contaminants after airway management. “These numbers are important to remember for room turnover safety,” he said.

Patient factors to review during airway management include assessing the past medical history, inspecting the airway and considering the patient’s current physiological status as time permits. Previously in the pandemic, intubation was used earlier in the disease course, but now data suggest that patients do better without intubation if possible (Am J Trop Med Hyg. 2020;102[6]. doi: 10.4269/aitmh.20-0283). “This is because the pathophysiology of COVID-19 is such that the lung tissue is predisposed to iatrogenic barotrauma damage from positive-pressure ventilation,” Dr. Griffis said. “In addition, COVID patients appear to tolerate significant hypoxemia without distress in many cases. Therefore, many clinicians now hold off on intubation until the hypoxemic patient begins exhibiting signs and symptoms of respiratory distress.”

Options for delivering noninvasive airway support for COVID-19 patients include high-flow nasal cannula and noninvasive positive-pressure ventilation via CPAP or BiPAP. To mitigate the associated aerosol production, consider applying a surgical mask, helmet, or face mask over the airway device/patient’s face. “Another measure that has proven helpful in general respiratory support is to actually put the patient in a prone position to help redistribute ventilation throughout the lungs,” Dr. Griffis said (see Resp Care. 2015;60[11]:1660-87).

To prepare for the actual intubation procedure, gather two expert intubators who are going to be entering the patient’s room. The team should perform hand hygiene and don full PPE prior to entry. “It’s recommended that you consider wearing double gloves for the intubation,” he said. “Have the airway equipment easily accessible in a central location on a cart or in a kit, and use disposable, single-use equipment if possible. All of the usual intubation equipment to maintain a clear airway and give positive pressure ventilation should be arranged for easy access. A video laryngoscope should be used, if possible, for greater accuracy and reduced procedure time. Ready access to sedation and muscle relaxant drugs must be assured at all times.”

For the intubation procedure itself, Dr. Griffis recommends ensuring that an oxygen source, positive-pressure ventilation, and suction and resuscitation drugs and equipment are available per institutional protocol. Assign one person outside the room to coordinate supplies and assistance. “Preoxygenate the patient as permitted by clinical status,” he said. “A nonrebreathing oxygen mask can be used if sufficient spontaneous ventilation is present. Assess the airway, check and arrange equipment for easy access, and develop the safest airway management plan. Consider a rapid sequence induction and intubation as the first option.” Avoid positive-pressure ventilation or awake fiber optic intubation unless absolutely necessary, thus avoiding aerosol production. “Only ventilate the patient after the endotracheal tube cuff is inflated, to avoid aerosol release,” he said.

For intubation, administer airway procedural drugs and insert the laryngoscope – ideally a video laryngoscope if available. Intubate the trachea under direct vision, inflate the cuff, and remove outer gloves. Then attach the Ambu bag with a 99% filtration efficiency, heat-and-moisture exchange filter; and proceed to ventilate the patient, checking for chest rise, breath sounds, and CO₂ production. “Discard contaminated equipment in designated bins and secure the tube,” Dr. Griffis advised. “Attach the ventilator with an HMEF filter to protect the ventilator circuit and inner parts of the machine. Recheck your breath sounds, CO₂ production, and oxygen saturation, and adjust your vent settings as indicated.”

For post intubation, Dr. Griffis recommends securing contaminated discardable equipment in biohazard-labeled bins or bags, safely doffing your PPE, and retaining your N95 mask in the room. Remove your inner gloves, perform hand hygiene with soap and water if available, with alcohol-based hand rub if not, then don clean gloves. Exit the room, safely transporting any contaminated equipment that will be reused such as a cart or video laryngoscope to decontamination areas for processing. “Once clear of the room, order your chest x-ray to confirm your tube position per institutional protocol, understanding that radiology techs are all going to be following infection control procedures and wearing their PPE,” he said.

For extubation, Dr. Griffis recommends excusing all nonessential personnel from the patient room and assigning an assistant outside the room for necessary help. An experienced airway management expert should evaluate the patient wearing full PPE and be double-gloved. “If the extubation criteria are met, suction the pharynx and extubate,” he said. “Remove outer gloves and apply desired oxygen delivery equipment to the patient and assess respiratory status and vital signs for stability.” Next, discard all contaminated equipment in designated bins, doff contaminated PPE, and retain your N95 mask. Doff inner gloves, perform hand hygiene, and don clean gloves. “Exit the room, hand off contaminated equipment that is reusable, doff your gloves outside, do hand hygiene, then proceed to change your scrubs and complete your own personal hygiene measures,” he said.

Dr. Griffis reported having no financial disclosures.

“While the PPE used for intubation of a coronavirus patient is certainly more than the typical droplet precautions observed when intubating any other patient, the process and best practices aren’t terribly different from usual standard of care: Ensuring all necessary equipment is readily available with backup plans should the airway be difficult,” said Megan Conroy, MD, assistant professor of clinical medicine at The Ohio State University.

“We’ve been streamlining the team that’s present in the room for intubations of COVID patients, but I’m always amazed at the team members that stand at the ready to lend additional assistance just from the other side of the door. So while fewer personnel may be exposed, I wouldn’t consider the team needed for intubation to actually be much smaller, we’re just functioning differently.

In my practice the decision of when to intubate, clinically, doesn’t vary too much from any other form of severe ARDS. We may tolerate higher FiO₂ requirements on heated high-flow nasal cannula if the patient exhibits acceptable work of breathing, but I wouldn’t advise allowing a patient to remain hypoxemic with oxygen needs unmet by noninvasive methods out of fear of intubation or ventilator management. In my opinion, this simply delays a necessary therapy and only makes for a higher risk intubation. Certainly, the decision to intubate is never based on only one single data point, but takes an expert assessment of the whole clinical picture.

I’d assert that it’s true in every disease that patients do better if it’s possible to avoid intubation – but I would argue that the ability to avoid intubation is determined primarily by the disease course and clinical scenario, and not by whether the physician wishes to avoid intubation or not. If I can safely manage a patient off of a ventilator, I will always do so, COVID or otherwise. I think in this phase of the pandemic, patients ‘do better without intubation’ because those who didn’t require intubation were inherently doing better!”

dbrunk@mdedge.com

Patients with gastric cancer or gastroesophageal junction cancer (GEJ) could experience significantly improved progression-free survival (PFS), and maybe overall survival (OS), with nivolumab (Opdivo) in the first-line and neoadjuvant settings, suggest data from three phase 3 trials.

However, contrasting results between the trials and question marks over the effect of the drug in all-comers leave some questions yet to be answered, despite the “practice-changing” findings, said experts discussing the new data.

The research was presented Sept. 21 at the European Society for Medical Oncology Virtual Congress 2020.

Gastric cancer and GEJ have been an area of interest for immunotherapy in recent years, as standard first-line chemotherapy is associated with poor OS at a median of less than 1 year.

Previous smaller studies have suggested that nivolumab has promising activity in the first-line setting, improving survival particularly in individuals with a combined positive score (CPS) for programmed death–ligand 1 (PD-L1) expression ≥5.

The new results come from the largest phase 3 trial of its kind to date, CheckMate 649, which involved 1,581 previously untreated patients with unresectable HER2-negative gastric cancer, GEJ, or esophageal adenocarcinoma.

Among these patients, 60% had a PD-L1 CPS ≥5.

Patients were randomly assigned to one of three treatment groups: Nivolumab plus ipilimumab (Yervoy), nivolumab plus oxaliplatin-based chemotherapy, or chemotherapy alone.

Results, after a minimum follow-up of 12 months, show that nivolumab plus chemotherapy was associated with significantly better OS than chemotherapy alone, reported Markus Moehler, MD, PhD, Johannes-Gutenberg University Clinic, Mainz, Germany.

In patients with PD-L1 CPS ≥5, median OS was 14.4 months with nivolumab-chemotherapy versus 11.1 months for chemotherapy alone (hazard ratio 0.71, P < .0001).

The figures were similar for patients with a PD-L1 CPS ≥1, at 14.0 months and 11.3 months (HR, 0.77; P = .0001), and also across the whole study population (13.8 months vs. 11.6 months; HR, 0.80, P = .0002).

PFS, however, was significantly improved with the nivolumab-chemotherapy combination only in patients with a PD-L1 CPS ≥5, at a median of 7.7 months vs 6.0 months (HR, 0.68, P < .0001).

The proportion of patients with treatment-related adverse events leading to discontinuation were 36% with nivolumab plus chemotherapy and 24% for chemotherapy alone.

At a press conference, Dr. Moehler said the benefits seen with nivolumab plus chemotherapy are “highly clinically meaningful,” and the combination “represents a new potential standard first-line treatment” for these patients.

These results are “practice changing” and are “clearly significant,” commented Salah-Eddin Al-Batran, MD, Krankenhaus Nordwest-University Cancer Center, Frankfurt, Germany, who was not involved with the study.

“However, as a physician,” he continued, “I am treating an individual patient and, for me, it’s important to know the efficacy in the patients with a CPS of 1-4, or of 0.”

“We have to be sure that we do not inflate the results for the all-comers by the very responsive group of high-expressers,” he said, adding that other factors to consider will be microsatellite instability and tumor mutational burden. “I think these questions have to be addressed to give us a clear picture of how to treat the patient sitting in front of us.”

Surprisingly, the results from ATTRACTION-4, a very similar phase 3 trial conducted in Japan, Korea, and Taiwan, did not follow the same pattern.

This trial involved 724 previously untreated patients with HER2-negative gastric cancer or GEJ randomly assigned to receive nivolumab plus chemotherapy or chemotherapy alone.

Lead author Narikazu Boku, MD, PhD, National Cancer Center Hospital, Tokyo, Japan, said that, after a median follow-up of 11.6 months, the combination treatment was associated with a significant improvement in PFS, at a median 10.5 months versus 8.3 months with chemotherapy alone (HR, 0.68, P = .0007).

In contrast, there was no significant difference in OS between the nivolumab and placebo arms, at a median of 17.5 months and 17.2 months, respectively (HR, 0.90; P = .257).

Invited discussant Elizabeth Smyth, MD, from Addenbrooke’s Hospital in Cambridge, England, suggested the lack of OS benefit seen in ATTRACTION-4 could be the result of a number of factors, including that PD-L1 status was assessed on tumor cells only and there were no key endpoints based around PD-L1 status.

Moreover, the posttrial therapy could have affected the overall results, as Asian patients typically receive more subsequent therapies than those elsewhere.

Dr. Smyth also commented that both CheckMate 649 and ATTRACTION-4 represent a “paradigm shift” in the first-line treatment of gastroesophageal adenocarcinoma.
 

Nivolumab in adjuvant setting

The results of a third trial presented at the ESMO meeting suggest a role for nivolumab in the adjuvant setting, following neoadjuvant chemoradiation therapy in patients with resected esophageal or GEJ cancer.

This was the CheckMate 577 trial, which compared adjuvant nivolumab with placebo in 794 patients from across the globe.

Nivolumab significantly increased median disease-free survival to 22.4 months versus 11.0 months with placebo (HR, 0.69, P = .0003).

Treatment-related adverse events leading to discontinuation were reported in 9% of nivolumab patients versus 3% on placebo, reported Ronan J. Kelly, MD, chief of oncology at Baylor Scott & White Health in Dallas.

Interestingly, patient-reported health status on the EQ-5D-3L visual analogue scale (VAS) and utility index were similar between nivolumab- and placebo-treated patients, with both groups experiencing clinically meaningful improvements.

Dr. Kelly said this is “the first adjuvant therapy to provide a statistically significant and clinically meaningful improvement” in patients with esophageal cancer or GEJ cancer following neoadjuvant chemoradiation.

Consequently, the results “represent the first advance in years for this group of patients, potentially establishing adjuvant nivolumab as a new standard of care.”

However, the invited discussant raised several issues with the trial design. Preoperative chemoradiation is not “universally accepted” as the standard of care in this setting, disease-free survival is not currently validated as a major endpoint in gastroesophageal cancers, and the median follow-up was short, commented Andrés Cervantes, MD, PhD, University of Valencia (Spain), and president-elect of ESMO.

In addition, there was no differentiation between esophageal squamous cell and adenocarcinoma histologies.

Nevertheless, CheckMate 577 is the first positive adjuvant study for checkpoint inhibitors in gastrointestinal tumors and, crucially, the results “are independent of PD-L1 status,” Dr. Cervantes said.

CheckMate 649 was funded by Bristol-Myers Squibb. ATTRACTION-4 was funded by Ono Pharmaceutical and Bristol-Myers Squibb. CheckMate 577 was funded by Bristol-Myers Squibb. Many of the presenters reported relationships with pharmaceutical companies.

This article first appeared on Medscape.com.

Patients with gastric cancer or gastroesophageal junction cancer (GEJ) could experience significantly improved progression-free survival (PFS), and maybe overall survival (OS), with nivolumab (Opdivo) in the first-line and neoadjuvant settings, suggest data from three phase 3 trials.

However, contrasting results between the trials and question marks over the effect of the drug in all-comers leave some questions yet to be answered, despite the “practice-changing” findings, said experts discussing the new data.

The research was presented Sept. 21 at the European Society for Medical Oncology Virtual Congress 2020.

Gastric cancer and GEJ have been an area of interest for immunotherapy in recent years, as standard first-line chemotherapy is associated with poor OS at a median of less than 1 year.

Previous smaller studies have suggested that nivolumab has promising activity in the first-line setting, improving survival particularly in individuals with a combined positive score (CPS) for programmed death–ligand 1 (PD-L1) expression ≥5.

The new results come from the largest phase 3 trial of its kind to date, CheckMate 649, which involved 1,581 previously untreated patients with unresectable HER2-negative gastric cancer, GEJ, or esophageal adenocarcinoma.

Among these patients, 60% had a PD-L1 CPS ≥5.

Patients were randomly assigned to one of three treatment groups: Nivolumab plus ipilimumab (Yervoy), nivolumab plus oxaliplatin-based chemotherapy, or chemotherapy alone.

Results, after a minimum follow-up of 12 months, show that nivolumab plus chemotherapy was associated with significantly better OS than chemotherapy alone, reported Markus Moehler, MD, PhD, Johannes-Gutenberg University Clinic, Mainz, Germany.

In patients with PD-L1 CPS ≥5, median OS was 14.4 months with nivolumab-chemotherapy versus 11.1 months for chemotherapy alone (hazard ratio 0.71, P < .0001).

The figures were similar for patients with a PD-L1 CPS ≥1, at 14.0 months and 11.3 months (HR, 0.77; P = .0001), and also across the whole study population (13.8 months vs. 11.6 months; HR, 0.80, P = .0002).

PFS, however, was significantly improved with the nivolumab-chemotherapy combination only in patients with a PD-L1 CPS ≥5, at a median of 7.7 months vs 6.0 months (HR, 0.68, P < .0001).

The proportion of patients with treatment-related adverse events leading to discontinuation were 36% with nivolumab plus chemotherapy and 24% for chemotherapy alone.

At a press conference, Dr. Moehler said the benefits seen with nivolumab plus chemotherapy are “highly clinically meaningful,” and the combination “represents a new potential standard first-line treatment” for these patients.

These results are “practice changing” and are “clearly significant,” commented Salah-Eddin Al-Batran, MD, Krankenhaus Nordwest-University Cancer Center, Frankfurt, Germany, who was not involved with the study.

“However, as a physician,” he continued, “I am treating an individual patient and, for me, it’s important to know the efficacy in the patients with a CPS of 1-4, or of 0.”

“We have to be sure that we do not inflate the results for the all-comers by the very responsive group of high-expressers,” he said, adding that other factors to consider will be microsatellite instability and tumor mutational burden. “I think these questions have to be addressed to give us a clear picture of how to treat the patient sitting in front of us.”

Surprisingly, the results from ATTRACTION-4, a very similar phase 3 trial conducted in Japan, Korea, and Taiwan, did not follow the same pattern.

This trial involved 724 previously untreated patients with HER2-negative gastric cancer or GEJ randomly assigned to receive nivolumab plus chemotherapy or chemotherapy alone.

Lead author Narikazu Boku, MD, PhD, National Cancer Center Hospital, Tokyo, Japan, said that, after a median follow-up of 11.6 months, the combination treatment was associated with a significant improvement in PFS, at a median 10.5 months versus 8.3 months with chemotherapy alone (HR, 0.68, P = .0007).

In contrast, there was no significant difference in OS between the nivolumab and placebo arms, at a median of 17.5 months and 17.2 months, respectively (HR, 0.90; P = .257).

Invited discussant Elizabeth Smyth, MD, from Addenbrooke’s Hospital in Cambridge, England, suggested the lack of OS benefit seen in ATTRACTION-4 could be the result of a number of factors, including that PD-L1 status was assessed on tumor cells only and there were no key endpoints based around PD-L1 status.

Moreover, the posttrial therapy could have affected the overall results, as Asian patients typically receive more subsequent therapies than those elsewhere.

Dr. Smyth also commented that both CheckMate 649 and ATTRACTION-4 represent a “paradigm shift” in the first-line treatment of gastroesophageal adenocarcinoma.
 

Nivolumab in adjuvant setting

The results of a third trial presented at the ESMO meeting suggest a role for nivolumab in the adjuvant setting, following neoadjuvant chemoradiation therapy in patients with resected esophageal or GEJ cancer.

This was the CheckMate 577 trial, which compared adjuvant nivolumab with placebo in 794 patients from across the globe.

Nivolumab significantly increased median disease-free survival to 22.4 months versus 11.0 months with placebo (HR, 0.69, P = .0003).

Treatment-related adverse events leading to discontinuation were reported in 9% of nivolumab patients versus 3% on placebo, reported Ronan J. Kelly, MD, chief of oncology at Baylor Scott & White Health in Dallas.

Interestingly, patient-reported health status on the EQ-5D-3L visual analogue scale (VAS) and utility index were similar between nivolumab- and placebo-treated patients, with both groups experiencing clinically meaningful improvements.

Dr. Kelly said this is “the first adjuvant therapy to provide a statistically significant and clinically meaningful improvement” in patients with esophageal cancer or GEJ cancer following neoadjuvant chemoradiation.

Consequently, the results “represent the first advance in years for this group of patients, potentially establishing adjuvant nivolumab as a new standard of care.”

However, the invited discussant raised several issues with the trial design. Preoperative chemoradiation is not “universally accepted” as the standard of care in this setting, disease-free survival is not currently validated as a major endpoint in gastroesophageal cancers, and the median follow-up was short, commented Andrés Cervantes, MD, PhD, University of Valencia (Spain), and president-elect of ESMO.

In addition, there was no differentiation between esophageal squamous cell and adenocarcinoma histologies.

Nevertheless, CheckMate 577 is the first positive adjuvant study for checkpoint inhibitors in gastrointestinal tumors and, crucially, the results “are independent of PD-L1 status,” Dr. Cervantes said.

CheckMate 649 was funded by Bristol-Myers Squibb. ATTRACTION-4 was funded by Ono Pharmaceutical and Bristol-Myers Squibb. CheckMate 577 was funded by Bristol-Myers Squibb. Many of the presenters reported relationships with pharmaceutical companies.

This article first appeared on Medscape.com.

Patients with gastric cancer or gastroesophageal junction cancer (GEJ) could experience significantly improved progression-free survival (PFS), and maybe overall survival (OS), with nivolumab (Opdivo) in the first-line and neoadjuvant settings, suggest data from three phase 3 trials.

However, contrasting results between the trials and question marks over the effect of the drug in all-comers leave some questions yet to be answered, despite the “practice-changing” findings, said experts discussing the new data.

The research was presented Sept. 21 at the European Society for Medical Oncology Virtual Congress 2020.

Gastric cancer and GEJ have been an area of interest for immunotherapy in recent years, as standard first-line chemotherapy is associated with poor OS at a median of less than 1 year.

Previous smaller studies have suggested that nivolumab has promising activity in the first-line setting, improving survival particularly in individuals with a combined positive score (CPS) for programmed death–ligand 1 (PD-L1) expression ≥5.

The new results come from the largest phase 3 trial of its kind to date, CheckMate 649, which involved 1,581 previously untreated patients with unresectable HER2-negative gastric cancer, GEJ, or esophageal adenocarcinoma.

Among these patients, 60% had a PD-L1 CPS ≥5.

Patients were randomly assigned to one of three treatment groups: Nivolumab plus ipilimumab (Yervoy), nivolumab plus oxaliplatin-based chemotherapy, or chemotherapy alone.

Results, after a minimum follow-up of 12 months, show that nivolumab plus chemotherapy was associated with significantly better OS than chemotherapy alone, reported Markus Moehler, MD, PhD, Johannes-Gutenberg University Clinic, Mainz, Germany.

In patients with PD-L1 CPS ≥5, median OS was 14.4 months with nivolumab-chemotherapy versus 11.1 months for chemotherapy alone (hazard ratio 0.71, P < .0001).

The figures were similar for patients with a PD-L1 CPS ≥1, at 14.0 months and 11.3 months (HR, 0.77; P = .0001), and also across the whole study population (13.8 months vs. 11.6 months; HR, 0.80, P = .0002).

PFS, however, was significantly improved with the nivolumab-chemotherapy combination only in patients with a PD-L1 CPS ≥5, at a median of 7.7 months vs 6.0 months (HR, 0.68, P < .0001).

The proportion of patients with treatment-related adverse events leading to discontinuation were 36% with nivolumab plus chemotherapy and 24% for chemotherapy alone.

At a press conference, Dr. Moehler said the benefits seen with nivolumab plus chemotherapy are “highly clinically meaningful,” and the combination “represents a new potential standard first-line treatment” for these patients.

These results are “practice changing” and are “clearly significant,” commented Salah-Eddin Al-Batran, MD, Krankenhaus Nordwest-University Cancer Center, Frankfurt, Germany, who was not involved with the study.

“However, as a physician,” he continued, “I am treating an individual patient and, for me, it’s important to know the efficacy in the patients with a CPS of 1-4, or of 0.”

“We have to be sure that we do not inflate the results for the all-comers by the very responsive group of high-expressers,” he said, adding that other factors to consider will be microsatellite instability and tumor mutational burden. “I think these questions have to be addressed to give us a clear picture of how to treat the patient sitting in front of us.”

Surprisingly, the results from ATTRACTION-4, a very similar phase 3 trial conducted in Japan, Korea, and Taiwan, did not follow the same pattern.

This trial involved 724 previously untreated patients with HER2-negative gastric cancer or GEJ randomly assigned to receive nivolumab plus chemotherapy or chemotherapy alone.

Lead author Narikazu Boku, MD, PhD, National Cancer Center Hospital, Tokyo, Japan, said that, after a median follow-up of 11.6 months, the combination treatment was associated with a significant improvement in PFS, at a median 10.5 months versus 8.3 months with chemotherapy alone (HR, 0.68, P = .0007).

In contrast, there was no significant difference in OS between the nivolumab and placebo arms, at a median of 17.5 months and 17.2 months, respectively (HR, 0.90; P = .257).

Invited discussant Elizabeth Smyth, MD, from Addenbrooke’s Hospital in Cambridge, England, suggested the lack of OS benefit seen in ATTRACTION-4 could be the result of a number of factors, including that PD-L1 status was assessed on tumor cells only and there were no key endpoints based around PD-L1 status.

Moreover, the posttrial therapy could have affected the overall results, as Asian patients typically receive more subsequent therapies than those elsewhere.

Dr. Smyth also commented that both CheckMate 649 and ATTRACTION-4 represent a “paradigm shift” in the first-line treatment of gastroesophageal adenocarcinoma.
 

Nivolumab in adjuvant setting

The results of a third trial presented at the ESMO meeting suggest a role for nivolumab in the adjuvant setting, following neoadjuvant chemoradiation therapy in patients with resected esophageal or GEJ cancer.

This was the CheckMate 577 trial, which compared adjuvant nivolumab with placebo in 794 patients from across the globe.

Nivolumab significantly increased median disease-free survival to 22.4 months versus 11.0 months with placebo (HR, 0.69, P = .0003).

Treatment-related adverse events leading to discontinuation were reported in 9% of nivolumab patients versus 3% on placebo, reported Ronan J. Kelly, MD, chief of oncology at Baylor Scott & White Health in Dallas.

Interestingly, patient-reported health status on the EQ-5D-3L visual analogue scale (VAS) and utility index were similar between nivolumab- and placebo-treated patients, with both groups experiencing clinically meaningful improvements.

Dr. Kelly said this is “the first adjuvant therapy to provide a statistically significant and clinically meaningful improvement” in patients with esophageal cancer or GEJ cancer following neoadjuvant chemoradiation.

Consequently, the results “represent the first advance in years for this group of patients, potentially establishing adjuvant nivolumab as a new standard of care.”

However, the invited discussant raised several issues with the trial design. Preoperative chemoradiation is not “universally accepted” as the standard of care in this setting, disease-free survival is not currently validated as a major endpoint in gastroesophageal cancers, and the median follow-up was short, commented Andrés Cervantes, MD, PhD, University of Valencia (Spain), and president-elect of ESMO.

In addition, there was no differentiation between esophageal squamous cell and adenocarcinoma histologies.

Nevertheless, CheckMate 577 is the first positive adjuvant study for checkpoint inhibitors in gastrointestinal tumors and, crucially, the results “are independent of PD-L1 status,” Dr. Cervantes said.

CheckMate 649 was funded by Bristol-Myers Squibb. ATTRACTION-4 was funded by Ono Pharmaceutical and Bristol-Myers Squibb. CheckMate 577 was funded by Bristol-Myers Squibb. Many of the presenters reported relationships with pharmaceutical companies.

This article first appeared on Medscape.com.

Further analyses from the cardiovascular outcome trial of the sodium-glucose transporter 2 inhibitor ertugliflozin in patients with type 2 diabetes helped better define positive effects the drug had on preserving renal function, and also gave a tantalizing hint that this drug, and hence possibly the entire SGLT2 inhibitor drug class, may benefit patients with heart failure with reduced ejection fraction.

But the underlying problem for ertugliflozin (Steglatro) – first seen when results from the VERTIS CV trial initially came out in June 2020 at the annual meeting of the American Diabetes Association – was that, while the trial met its primary endpoint of proving noninferiority to placebo for the combined endpoint of cardiovascular death, nonfatal MI, or nonfatal stroke, treatment with ertugliflozin showed no suggestion of benefit, compared with placebo for reducing this endpoint, producing a nonsignificant 3% relative cut in the combined rate of these adverse events, compared with placebo treatment.
 

‘Somewhat disappointing’ trial performance

Overall, results from VERTIS CV with ertugliflozin were “somewhat disappointing,” commented Melanie J. Davies, MD, who was not involved with the study and chaired a session at the virtual annual meeting of the European Association for the Study of Diabetes that reviewed the main results, put them into perspective, and added a few new exploratory analyses.

Although the results from 8,246-patient VERTIS CV (Evaluation of Ertugliflozin Efficacy and Safety Cardiovascular Outcomes Trial) put ertugliflozin in the same league as other drugs from its class for safety, “we do not see the significant benefits observed in many of the previous cardiovascular outcomes trials” for other drugs in the SGLT2 inhibitor class, specifically canagliflozin (Invokana), dapagliflozin (Farxiga), and empagliflozin (Jardiance), Dr. Davies said in an interview. The upshot, for at least the time being, is that ertugliflozin “is unlikely to receive a label for any new indications,” she predicted. In contrast, the other drugs in the class have, for example, received a U.S. labeled indication to reduce cardiovascular death (empagliflozin) or major cardiovascular disease events (canagliflozin) in adults with type 2 diabetes (T2D) and cardiovascular disease, or to reduce heart failure hospitalizations (dapagliflozin).

The main results from VERTIS CV, posted online in the New England Journal of Medicine after the EASD session, showed a single significant outcome difference between treatment with ertugliflozin and placebo over a median of 3.0 years of follow-up from among 10 reported secondary outcomes: a 30% relative reduction (a 1.1% absolute reduction) in the rate of hospitalization for heart failure, the sole criterion in the report by which ertugliflozin matched the benefits of the other SGLT2 inhibitors.

But the prespecified design of VERTIS CV called for a hierarchical sequence of secondary analyses. The statistically significant noninferiority of the primary endpoint allowed calculation of the initial secondary endpoint, a reduction in the combined rate of cardiovascular death or hospitalization for heart failure. Ertugliflozin treatment cut this outcome by a relative 12%, compared with placebo, a difference that was not significant.

This neutral finding brought to a stop further statistical testing of any of the other secondary endpoints, including impact on hospitalization for heart failure by itself. It also guaranteed that no beneficial effect inferred from the trial’s data would qualify for statistical validity, making it unlikely that ertugliflozin would gain any new label indications from these results. The drug carries a U.S. label that is limited to providing glycemic control.

Choosing among the SGLT2 inhibitors

“What we can say for sure is that there is a glycemic benefit and a heart failure hospitalization benefit” across all four of the SGLT2 inhibitors. “Beyond that, the best we can say today [about using these drugs in practice] is to follow regulatory indications and guidelines recommendations,” commented Javed Butler, MD, a cardiologist and professor and chair of medicine at the University of Mississippi Medical Center, Jackson.

“These results are going to lead to some serious discussions among the research, clinical, and regulatory communities about class effects versus drug effects, and specific trial data versus the totality of evidence,” he said in an interview.

“I think it will influence prescribing ertugliflozin, particularly in patients with established cardiovascular disease, or when the goal is to improve heart failure outcomes of reduce chronic kidney disease,” added Dr. Davies, a professor of diabetes medicine at the University of Leicester (England). “We already have positive benefits [proven for these outcomes] using other agents in the class.”

Perhaps one feature potentially in ertugliflozin’s favor is its price, and whatever impact that might have for payers or patients with inadequate coverage for their drug costs. U.S. websites show a typical retail price for ertugliflozin that is roughly 40% below the three other agents in the class, a difference that can add up to an annual cost savings of about $2,500.

A major consideration for clinicians deciding which SGLT2 inhibitor to prescribe should be “what can the patient afford,” noted Darren K. McGuire, MD, a coinvestigator for VERTIS CV, during discussion of the trial at the EASD virtual meeting.
 

New analyses show more renal-effect consistency

One surprise in the initial VERTIS CV report was in the study’s key renal outcome, a composite of renal death, need for dialysis, or a doubling of the serum creatinine level, which reflects a cut of at least a 50% in estimated glomerular filtration rate (eGFR). This composite outcome trended toward a significant benefit but fell short, producing a nominal 19% relative reduction. This combined endpoint probably “set the bar too high,” said David Z.I. Cherney, MD, a nephrologist who led the renal assessments run in the trial. He presented several exploratory analyses during the virtual EASD session that provided reassuring evidence that ertugliflozin was not an outlier among the SGLT2 inhibitors when it came to kidney benefits.

Perhaps the most compelling analysis he reported was a slight tweak to the main renal composite endpoint that substituted prevention of a 40% or greater reduction in eGFR for prevention of a 50% or greater reduction. By this somewhat lower bar for efficacy, treatment with ertugliflozin in VERTIS CV linked with a 34% relative risk reduction, compared with placebo (a roughly 1% absolute reduction) that was statistically significant, and importantly came out very close to the effect for this revised endpoint that had been seen for the other three SGLT2 inhibitor drugs.

Focusing on prevention of a 40% or greater drop in eGFR “gives a much more robust measure of renal protection,” Dr. Cherney, a clinician and researcher at the University of Toronto, said in an interview. “The key message is that renal protection is much more uniform” with the rest of the drugs in the class when looked at this way or by some of the other alternative parameters he reported. But the new renal analyses do not address disparities seen among the drugs in the class for several cardiovascular disease effects.

“The overall impression from VERTIS CV is that there was less cardiovascular disease benefit,” except for prevention of heart failure hospitalization, he said.

A teaser for HFpEF

One additional notable new finding discussed during the EASD session stemmed from the investigators ability to mine the medical records of enrolled patients for information about their heart failure history and left ventricular ejection fractions, a data set that was “unique,” compared with the other cardiovascular outcome trials for the drugs in the class, noted Francesco Cosentino, MD, another VERTIS CV coinvestigator and professor of cardiology at the Karolinska Institute in Stockholm.

Roughly a quarter of the enrolled patients had a history of heart failure, and about half of these patients had heart failure with preserved ejection fraction, about 1,000 total patients. In this subgroup treatment with ertugliflozin linked with a 30% relative reduction in hospitalization for heart failure, compared with placebo, a roughly 0.5% absolute reduction. The numbers were small and underpowered for producing convincing evidence, but it provided an intriguing hint of benefit for an unmet need that is currently undergoing further testing in studies designed to specifically explore benefit in this type of heart failure patient, said Dr. Cosentino.

VERTIS CV was sponsored by Merck and Pfizer, the companies that market ertugliflozin. Dr. Davies has been a speaker on behalf of Merck and has had relationships with several other companies. Dr. Butler is a consultant to Merck and several other companies. Dr. McGuire has received honoraria from Merck, nonfinancial support from Pfizer, and has had relationships with several other companies. Dr. Cherney has received honoraria from Merck, nonfinancial research support from Pfizer, and has also had relationships with several other companies. Dr. Cosentino has received fees from Merck and Pfizer, and also from Abbott, AstraZeneca, Bayer, Bristol-Myers Squibb, and Novo Nordisk

mzoler@mdedge.com

Further analyses from the cardiovascular outcome trial of the sodium-glucose transporter 2 inhibitor ertugliflozin in patients with type 2 diabetes helped better define positive effects the drug had on preserving renal function, and also gave a tantalizing hint that this drug, and hence possibly the entire SGLT2 inhibitor drug class, may benefit patients with heart failure with reduced ejection fraction.

But the underlying problem for ertugliflozin (Steglatro) – first seen when results from the VERTIS CV trial initially came out in June 2020 at the annual meeting of the American Diabetes Association – was that, while the trial met its primary endpoint of proving noninferiority to placebo for the combined endpoint of cardiovascular death, nonfatal MI, or nonfatal stroke, treatment with ertugliflozin showed no suggestion of benefit, compared with placebo for reducing this endpoint, producing a nonsignificant 3% relative cut in the combined rate of these adverse events, compared with placebo treatment.
 

‘Somewhat disappointing’ trial performance

Overall, results from VERTIS CV with ertugliflozin were “somewhat disappointing,” commented Melanie J. Davies, MD, who was not involved with the study and chaired a session at the virtual annual meeting of the European Association for the Study of Diabetes that reviewed the main results, put them into perspective, and added a few new exploratory analyses.

Although the results from 8,246-patient VERTIS CV (Evaluation of Ertugliflozin Efficacy and Safety Cardiovascular Outcomes Trial) put ertugliflozin in the same league as other drugs from its class for safety, “we do not see the significant benefits observed in many of the previous cardiovascular outcomes trials” for other drugs in the SGLT2 inhibitor class, specifically canagliflozin (Invokana), dapagliflozin (Farxiga), and empagliflozin (Jardiance), Dr. Davies said in an interview. The upshot, for at least the time being, is that ertugliflozin “is unlikely to receive a label for any new indications,” she predicted. In contrast, the other drugs in the class have, for example, received a U.S. labeled indication to reduce cardiovascular death (empagliflozin) or major cardiovascular disease events (canagliflozin) in adults with type 2 diabetes (T2D) and cardiovascular disease, or to reduce heart failure hospitalizations (dapagliflozin).

The main results from VERTIS CV, posted online in the New England Journal of Medicine after the EASD session, showed a single significant outcome difference between treatment with ertugliflozin and placebo over a median of 3.0 years of follow-up from among 10 reported secondary outcomes: a 30% relative reduction (a 1.1% absolute reduction) in the rate of hospitalization for heart failure, the sole criterion in the report by which ertugliflozin matched the benefits of the other SGLT2 inhibitors.

But the prespecified design of VERTIS CV called for a hierarchical sequence of secondary analyses. The statistically significant noninferiority of the primary endpoint allowed calculation of the initial secondary endpoint, a reduction in the combined rate of cardiovascular death or hospitalization for heart failure. Ertugliflozin treatment cut this outcome by a relative 12%, compared with placebo, a difference that was not significant.

This neutral finding brought to a stop further statistical testing of any of the other secondary endpoints, including impact on hospitalization for heart failure by itself. It also guaranteed that no beneficial effect inferred from the trial’s data would qualify for statistical validity, making it unlikely that ertugliflozin would gain any new label indications from these results. The drug carries a U.S. label that is limited to providing glycemic control.

Choosing among the SGLT2 inhibitors

“What we can say for sure is that there is a glycemic benefit and a heart failure hospitalization benefit” across all four of the SGLT2 inhibitors. “Beyond that, the best we can say today [about using these drugs in practice] is to follow regulatory indications and guidelines recommendations,” commented Javed Butler, MD, a cardiologist and professor and chair of medicine at the University of Mississippi Medical Center, Jackson.

“These results are going to lead to some serious discussions among the research, clinical, and regulatory communities about class effects versus drug effects, and specific trial data versus the totality of evidence,” he said in an interview.

“I think it will influence prescribing ertugliflozin, particularly in patients with established cardiovascular disease, or when the goal is to improve heart failure outcomes of reduce chronic kidney disease,” added Dr. Davies, a professor of diabetes medicine at the University of Leicester (England). “We already have positive benefits [proven for these outcomes] using other agents in the class.”

Perhaps one feature potentially in ertugliflozin’s favor is its price, and whatever impact that might have for payers or patients with inadequate coverage for their drug costs. U.S. websites show a typical retail price for ertugliflozin that is roughly 40% below the three other agents in the class, a difference that can add up to an annual cost savings of about $2,500.

A major consideration for clinicians deciding which SGLT2 inhibitor to prescribe should be “what can the patient afford,” noted Darren K. McGuire, MD, a coinvestigator for VERTIS CV, during discussion of the trial at the EASD virtual meeting.
 

New analyses show more renal-effect consistency

One surprise in the initial VERTIS CV report was in the study’s key renal outcome, a composite of renal death, need for dialysis, or a doubling of the serum creatinine level, which reflects a cut of at least a 50% in estimated glomerular filtration rate (eGFR). This composite outcome trended toward a significant benefit but fell short, producing a nominal 19% relative reduction. This combined endpoint probably “set the bar too high,” said David Z.I. Cherney, MD, a nephrologist who led the renal assessments run in the trial. He presented several exploratory analyses during the virtual EASD session that provided reassuring evidence that ertugliflozin was not an outlier among the SGLT2 inhibitors when it came to kidney benefits.

Perhaps the most compelling analysis he reported was a slight tweak to the main renal composite endpoint that substituted prevention of a 40% or greater reduction in eGFR for prevention of a 50% or greater reduction. By this somewhat lower bar for efficacy, treatment with ertugliflozin in VERTIS CV linked with a 34% relative risk reduction, compared with placebo (a roughly 1% absolute reduction) that was statistically significant, and importantly came out very close to the effect for this revised endpoint that had been seen for the other three SGLT2 inhibitor drugs.

Focusing on prevention of a 40% or greater drop in eGFR “gives a much more robust measure of renal protection,” Dr. Cherney, a clinician and researcher at the University of Toronto, said in an interview. “The key message is that renal protection is much more uniform” with the rest of the drugs in the class when looked at this way or by some of the other alternative parameters he reported. But the new renal analyses do not address disparities seen among the drugs in the class for several cardiovascular disease effects.

“The overall impression from VERTIS CV is that there was less cardiovascular disease benefit,” except for prevention of heart failure hospitalization, he said.

A teaser for HFpEF

One additional notable new finding discussed during the EASD session stemmed from the investigators ability to mine the medical records of enrolled patients for information about their heart failure history and left ventricular ejection fractions, a data set that was “unique,” compared with the other cardiovascular outcome trials for the drugs in the class, noted Francesco Cosentino, MD, another VERTIS CV coinvestigator and professor of cardiology at the Karolinska Institute in Stockholm.

Roughly a quarter of the enrolled patients had a history of heart failure, and about half of these patients had heart failure with preserved ejection fraction, about 1,000 total patients. In this subgroup treatment with ertugliflozin linked with a 30% relative reduction in hospitalization for heart failure, compared with placebo, a roughly 0.5% absolute reduction. The numbers were small and underpowered for producing convincing evidence, but it provided an intriguing hint of benefit for an unmet need that is currently undergoing further testing in studies designed to specifically explore benefit in this type of heart failure patient, said Dr. Cosentino.

VERTIS CV was sponsored by Merck and Pfizer, the companies that market ertugliflozin. Dr. Davies has been a speaker on behalf of Merck and has had relationships with several other companies. Dr. Butler is a consultant to Merck and several other companies. Dr. McGuire has received honoraria from Merck, nonfinancial support from Pfizer, and has had relationships with several other companies. Dr. Cherney has received honoraria from Merck, nonfinancial research support from Pfizer, and has also had relationships with several other companies. Dr. Cosentino has received fees from Merck and Pfizer, and also from Abbott, AstraZeneca, Bayer, Bristol-Myers Squibb, and Novo Nordisk

mzoler@mdedge.com

Further analyses from the cardiovascular outcome trial of the sodium-glucose transporter 2 inhibitor ertugliflozin in patients with type 2 diabetes helped better define positive effects the drug had on preserving renal function, and also gave a tantalizing hint that this drug, and hence possibly the entire SGLT2 inhibitor drug class, may benefit patients with heart failure with reduced ejection fraction.

But the underlying problem for ertugliflozin (Steglatro) – first seen when results from the VERTIS CV trial initially came out in June 2020 at the annual meeting of the American Diabetes Association – was that, while the trial met its primary endpoint of proving noninferiority to placebo for the combined endpoint of cardiovascular death, nonfatal MI, or nonfatal stroke, treatment with ertugliflozin showed no suggestion of benefit, compared with placebo for reducing this endpoint, producing a nonsignificant 3% relative cut in the combined rate of these adverse events, compared with placebo treatment.
 

‘Somewhat disappointing’ trial performance

Overall, results from VERTIS CV with ertugliflozin were “somewhat disappointing,” commented Melanie J. Davies, MD, who was not involved with the study and chaired a session at the virtual annual meeting of the European Association for the Study of Diabetes that reviewed the main results, put them into perspective, and added a few new exploratory analyses.

Although the results from 8,246-patient VERTIS CV (Evaluation of Ertugliflozin Efficacy and Safety Cardiovascular Outcomes Trial) put ertugliflozin in the same league as other drugs from its class for safety, “we do not see the significant benefits observed in many of the previous cardiovascular outcomes trials” for other drugs in the SGLT2 inhibitor class, specifically canagliflozin (Invokana), dapagliflozin (Farxiga), and empagliflozin (Jardiance), Dr. Davies said in an interview. The upshot, for at least the time being, is that ertugliflozin “is unlikely to receive a label for any new indications,” she predicted. In contrast, the other drugs in the class have, for example, received a U.S. labeled indication to reduce cardiovascular death (empagliflozin) or major cardiovascular disease events (canagliflozin) in adults with type 2 diabetes (T2D) and cardiovascular disease, or to reduce heart failure hospitalizations (dapagliflozin).

The main results from VERTIS CV, posted online in the New England Journal of Medicine after the EASD session, showed a single significant outcome difference between treatment with ertugliflozin and placebo over a median of 3.0 years of follow-up from among 10 reported secondary outcomes: a 30% relative reduction (a 1.1% absolute reduction) in the rate of hospitalization for heart failure, the sole criterion in the report by which ertugliflozin matched the benefits of the other SGLT2 inhibitors.

But the prespecified design of VERTIS CV called for a hierarchical sequence of secondary analyses. The statistically significant noninferiority of the primary endpoint allowed calculation of the initial secondary endpoint, a reduction in the combined rate of cardiovascular death or hospitalization for heart failure. Ertugliflozin treatment cut this outcome by a relative 12%, compared with placebo, a difference that was not significant.

This neutral finding brought to a stop further statistical testing of any of the other secondary endpoints, including impact on hospitalization for heart failure by itself. It also guaranteed that no beneficial effect inferred from the trial’s data would qualify for statistical validity, making it unlikely that ertugliflozin would gain any new label indications from these results. The drug carries a U.S. label that is limited to providing glycemic control.

Choosing among the SGLT2 inhibitors

“What we can say for sure is that there is a glycemic benefit and a heart failure hospitalization benefit” across all four of the SGLT2 inhibitors. “Beyond that, the best we can say today [about using these drugs in practice] is to follow regulatory indications and guidelines recommendations,” commented Javed Butler, MD, a cardiologist and professor and chair of medicine at the University of Mississippi Medical Center, Jackson.

“These results are going to lead to some serious discussions among the research, clinical, and regulatory communities about class effects versus drug effects, and specific trial data versus the totality of evidence,” he said in an interview.

“I think it will influence prescribing ertugliflozin, particularly in patients with established cardiovascular disease, or when the goal is to improve heart failure outcomes of reduce chronic kidney disease,” added Dr. Davies, a professor of diabetes medicine at the University of Leicester (England). “We already have positive benefits [proven for these outcomes] using other agents in the class.”

Perhaps one feature potentially in ertugliflozin’s favor is its price, and whatever impact that might have for payers or patients with inadequate coverage for their drug costs. U.S. websites show a typical retail price for ertugliflozin that is roughly 40% below the three other agents in the class, a difference that can add up to an annual cost savings of about $2,500.

A major consideration for clinicians deciding which SGLT2 inhibitor to prescribe should be “what can the patient afford,” noted Darren K. McGuire, MD, a coinvestigator for VERTIS CV, during discussion of the trial at the EASD virtual meeting.
 

New analyses show more renal-effect consistency

One surprise in the initial VERTIS CV report was in the study’s key renal outcome, a composite of renal death, need for dialysis, or a doubling of the serum creatinine level, which reflects a cut of at least a 50% in estimated glomerular filtration rate (eGFR). This composite outcome trended toward a significant benefit but fell short, producing a nominal 19% relative reduction. This combined endpoint probably “set the bar too high,” said David Z.I. Cherney, MD, a nephrologist who led the renal assessments run in the trial. He presented several exploratory analyses during the virtual EASD session that provided reassuring evidence that ertugliflozin was not an outlier among the SGLT2 inhibitors when it came to kidney benefits.

Perhaps the most compelling analysis he reported was a slight tweak to the main renal composite endpoint that substituted prevention of a 40% or greater reduction in eGFR for prevention of a 50% or greater reduction. By this somewhat lower bar for efficacy, treatment with ertugliflozin in VERTIS CV linked with a 34% relative risk reduction, compared with placebo (a roughly 1% absolute reduction) that was statistically significant, and importantly came out very close to the effect for this revised endpoint that had been seen for the other three SGLT2 inhibitor drugs.

Focusing on prevention of a 40% or greater drop in eGFR “gives a much more robust measure of renal protection,” Dr. Cherney, a clinician and researcher at the University of Toronto, said in an interview. “The key message is that renal protection is much more uniform” with the rest of the drugs in the class when looked at this way or by some of the other alternative parameters he reported. But the new renal analyses do not address disparities seen among the drugs in the class for several cardiovascular disease effects.

“The overall impression from VERTIS CV is that there was less cardiovascular disease benefit,” except for prevention of heart failure hospitalization, he said.

A teaser for HFpEF

One additional notable new finding discussed during the EASD session stemmed from the investigators ability to mine the medical records of enrolled patients for information about their heart failure history and left ventricular ejection fractions, a data set that was “unique,” compared with the other cardiovascular outcome trials for the drugs in the class, noted Francesco Cosentino, MD, another VERTIS CV coinvestigator and professor of cardiology at the Karolinska Institute in Stockholm.

Roughly a quarter of the enrolled patients had a history of heart failure, and about half of these patients had heart failure with preserved ejection fraction, about 1,000 total patients. In this subgroup treatment with ertugliflozin linked with a 30% relative reduction in hospitalization for heart failure, compared with placebo, a roughly 0.5% absolute reduction. The numbers were small and underpowered for producing convincing evidence, but it provided an intriguing hint of benefit for an unmet need that is currently undergoing further testing in studies designed to specifically explore benefit in this type of heart failure patient, said Dr. Cosentino.

VERTIS CV was sponsored by Merck and Pfizer, the companies that market ertugliflozin. Dr. Davies has been a speaker on behalf of Merck and has had relationships with several other companies. Dr. Butler is a consultant to Merck and several other companies. Dr. McGuire has received honoraria from Merck, nonfinancial support from Pfizer, and has had relationships with several other companies. Dr. Cherney has received honoraria from Merck, nonfinancial research support from Pfizer, and has also had relationships with several other companies. Dr. Cosentino has received fees from Merck and Pfizer, and also from Abbott, AstraZeneca, Bayer, Bristol-Myers Squibb, and Novo Nordisk

mzoler@mdedge.com

Rates of hepatocellular carcinoma (HCC) continue to rise in the United States, but unevenly so given how the incidence has become highest in the Hispanic population, which is reflected in increased rates in the southern and western states, Hashem B. El-Serag, MD, of Baylor College of Medicine, Houston, said in a virtual presentation at the annual Digestive Diseases: New Advances, which is jointly provided by Rutgers and Global Academy for Medical Education.

In addition to this demographic shift, the risk factors for HCC are shifting, he said. Hepatitis C virus (HCV) has been the dominant risk factor for HCC; for patients with active HCV, the factors historically associated with increased HCC risk have included alcohol consumption, obesity, diabetes, coinfection, and genetics, he said.

This pattern is starting to change. In fact, for patients with active HCV, antiviral treatment with a sustained virologic response has surfaced as the most significant risk factor in the development of HCC, said Dr. El-Serag: Among these patients, sustained virologic response from direct-acting antivirals is associated with a significant reduction in HCC risk. However, it is important to recognize that a residual risk of HCC remains that doesn’t go away for several years, he noted.

“Who are those people who got treated, got cured, and still developed HCC? Those with cirrhosis at the time of treatment,” he said. Those with cirrhosis have cumulative incidence of 1.8% per year, but those without cirrhosis had very low risk, he said.

Some good news in HCC is that rates appear to be declining among young men, and this is thought to be one of the groups who are achieving a cure of HCV, he said.

“One would hope, if goals for HCV elimination are met, that will translate into massive reduction of HCC,” he said.

“The issue now for hepatitis is finding infected patients and curing them,” he noted.

Dr. El-Serag touched on hepatitis B (HBV), which continues to be the driving force of hepatitis infections globally. However, in patients who receive and respond to antiviral treatment “there is a significant and considerable reduction in HCC in the context of hepatitis B” similar to that seen with hepatitis C. Vaccination programs for HBV have started to make the desired impact of reducing HCC in HBV-endemic areas, he noted.

However, current risk factors for HCC are related less to HCV and HBV and more to metabolic syndrome because more people are treated for HCV and HBV, Dr. El-Serag said. He went on to address the new dominant global risk factor for HCC: obesity. Based on data from multiple studies, those who are obese, defined as a body mass index greater than 30 kg/m², carry a twofold increased risk of developing HCC, he said.

To reduce this risk, treatment targets might address intermediate factors such as abdominal obesity, said Dr. El-Serag. He cited a study published in Hepatology in which individuals in the highest tertile for waist-hip ratio had a threefold higher risk of HCC, compared with those in the lowest tertile.

In addition, consideration of obesity must include type 2 diabetes, which is often linked to obesity and occurs in approximately one-third of adults in the United States, Dr. El-Serag said.

Treatment of type 2 diabetes may make a difference in HCC risk reduction, Dr. El-Serag noted. “The impact of treatment of diabetes on HCC risk is an area of intense interest,” he said. Based on the latest research, “the bottom line is that those treated with metformin experience a 50% reduction in the risk of HCC,” he said

Dr. El-Serag also acknowledged the impact of other risk factors for HCC: the use of statins and the presence of nonalcoholic fatty liver disease (NAFLD).

Dr. El-Serag noted that, among NAFLD patients, subgroups at even greater risk for HCC include those with diabetes, those older than 65 years, Hispanic race, and those with cirrhosis. These patients should be candidates for surveillance. Metabolic dysfunction traits such as obesity and diabetes are very common conditions, so it’s important to look at other, more specific factors, he added. “I hope that there will be tools to help clinicians classify or risk-stratify patients into different buckets,” he said.

Areas for further research on HCC continue to include risk stratification, mechanisms of action, and HCC prevention related to treatment of metabolic syndrome, he emphasized.

Dr. El-Serag had no financial conflicts to disclose. Global Academy for Medical Education and this news organization are owned by the same parent company.

*This story was updated on Oct. 28, 2020. 

SOURCE: El-Serag HB. Digestive Diseases: New Advances 2020.

Rates of hepatocellular carcinoma (HCC) continue to rise in the United States, but unevenly so given how the incidence has become highest in the Hispanic population, which is reflected in increased rates in the southern and western states, Hashem B. El-Serag, MD, of Baylor College of Medicine, Houston, said in a virtual presentation at the annual Digestive Diseases: New Advances, which is jointly provided by Rutgers and Global Academy for Medical Education.

In addition to this demographic shift, the risk factors for HCC are shifting, he said. Hepatitis C virus (HCV) has been the dominant risk factor for HCC; for patients with active HCV, the factors historically associated with increased HCC risk have included alcohol consumption, obesity, diabetes, coinfection, and genetics, he said.

This pattern is starting to change. In fact, for patients with active HCV, antiviral treatment with a sustained virologic response has surfaced as the most significant risk factor in the development of HCC, said Dr. El-Serag: Among these patients, sustained virologic response from direct-acting antivirals is associated with a significant reduction in HCC risk. However, it is important to recognize that a residual risk of HCC remains that doesn’t go away for several years, he noted.

“Who are those people who got treated, got cured, and still developed HCC? Those with cirrhosis at the time of treatment,” he said. Those with cirrhosis have cumulative incidence of 1.8% per year, but those without cirrhosis had very low risk, he said.

Some good news in HCC is that rates appear to be declining among young men, and this is thought to be one of the groups who are achieving a cure of HCV, he said.

“One would hope, if goals for HCV elimination are met, that will translate into massive reduction of HCC,” he said.

“The issue now for hepatitis is finding infected patients and curing them,” he noted.

Dr. El-Serag touched on hepatitis B (HBV), which continues to be the driving force of hepatitis infections globally. However, in patients who receive and respond to antiviral treatment “there is a significant and considerable reduction in HCC in the context of hepatitis B” similar to that seen with hepatitis C. Vaccination programs for HBV have started to make the desired impact of reducing HCC in HBV-endemic areas, he noted.

However, current risk factors for HCC are related less to HCV and HBV and more to metabolic syndrome because more people are treated for HCV and HBV, Dr. El-Serag said. He went on to address the new dominant global risk factor for HCC: obesity. Based on data from multiple studies, those who are obese, defined as a body mass index greater than 30 kg/m², carry a twofold increased risk of developing HCC, he said.

To reduce this risk, treatment targets might address intermediate factors such as abdominal obesity, said Dr. El-Serag. He cited a study published in Hepatology in which individuals in the highest tertile for waist-hip ratio had a threefold higher risk of HCC, compared with those in the lowest tertile.

In addition, consideration of obesity must include type 2 diabetes, which is often linked to obesity and occurs in approximately one-third of adults in the United States, Dr. El-Serag said.

Treatment of type 2 diabetes may make a difference in HCC risk reduction, Dr. El-Serag noted. “The impact of treatment of diabetes on HCC risk is an area of intense interest,” he said. Based on the latest research, “the bottom line is that those treated with metformin experience a 50% reduction in the risk of HCC,” he said

Dr. El-Serag also acknowledged the impact of other risk factors for HCC: the use of statins and the presence of nonalcoholic fatty liver disease (NAFLD).

Dr. El-Serag noted that, among NAFLD patients, subgroups at even greater risk for HCC include those with diabetes, those older than 65 years, Hispanic race, and those with cirrhosis. These patients should be candidates for surveillance. Metabolic dysfunction traits such as obesity and diabetes are very common conditions, so it’s important to look at other, more specific factors, he added. “I hope that there will be tools to help clinicians classify or risk-stratify patients into different buckets,” he said.

Areas for further research on HCC continue to include risk stratification, mechanisms of action, and HCC prevention related to treatment of metabolic syndrome, he emphasized.

Dr. El-Serag had no financial conflicts to disclose. Global Academy for Medical Education and this news organization are owned by the same parent company.

*This story was updated on Oct. 28, 2020. 

SOURCE: El-Serag HB. Digestive Diseases: New Advances 2020.

Rates of hepatocellular carcinoma (HCC) continue to rise in the United States, but unevenly so given how the incidence has become highest in the Hispanic population, which is reflected in increased rates in the southern and western states, Hashem B. El-Serag, MD, of Baylor College of Medicine, Houston, said in a virtual presentation at the annual Digestive Diseases: New Advances, which is jointly provided by Rutgers and Global Academy for Medical Education.

In addition to this demographic shift, the risk factors for HCC are shifting, he said. Hepatitis C virus (HCV) has been the dominant risk factor for HCC; for patients with active HCV, the factors historically associated with increased HCC risk have included alcohol consumption, obesity, diabetes, coinfection, and genetics, he said.

This pattern is starting to change. In fact, for patients with active HCV, antiviral treatment with a sustained virologic response has surfaced as the most significant risk factor in the development of HCC, said Dr. El-Serag: Among these patients, sustained virologic response from direct-acting antivirals is associated with a significant reduction in HCC risk. However, it is important to recognize that a residual risk of HCC remains that doesn’t go away for several years, he noted.

“Who are those people who got treated, got cured, and still developed HCC? Those with cirrhosis at the time of treatment,” he said. Those with cirrhosis have cumulative incidence of 1.8% per year, but those without cirrhosis had very low risk, he said.

Some good news in HCC is that rates appear to be declining among young men, and this is thought to be one of the groups who are achieving a cure of HCV, he said.

“One would hope, if goals for HCV elimination are met, that will translate into massive reduction of HCC,” he said.

“The issue now for hepatitis is finding infected patients and curing them,” he noted.

Dr. El-Serag touched on hepatitis B (HBV), which continues to be the driving force of hepatitis infections globally. However, in patients who receive and respond to antiviral treatment “there is a significant and considerable reduction in HCC in the context of hepatitis B” similar to that seen with hepatitis C. Vaccination programs for HBV have started to make the desired impact of reducing HCC in HBV-endemic areas, he noted.

However, current risk factors for HCC are related less to HCV and HBV and more to metabolic syndrome because more people are treated for HCV and HBV, Dr. El-Serag said. He went on to address the new dominant global risk factor for HCC: obesity. Based on data from multiple studies, those who are obese, defined as a body mass index greater than 30 kg/m², carry a twofold increased risk of developing HCC, he said.

To reduce this risk, treatment targets might address intermediate factors such as abdominal obesity, said Dr. El-Serag. He cited a study published in Hepatology in which individuals in the highest tertile for waist-hip ratio had a threefold higher risk of HCC, compared with those in the lowest tertile.

In addition, consideration of obesity must include type 2 diabetes, which is often linked to obesity and occurs in approximately one-third of adults in the United States, Dr. El-Serag said.

Treatment of type 2 diabetes may make a difference in HCC risk reduction, Dr. El-Serag noted. “The impact of treatment of diabetes on HCC risk is an area of intense interest,” he said. Based on the latest research, “the bottom line is that those treated with metformin experience a 50% reduction in the risk of HCC,” he said

Dr. El-Serag also acknowledged the impact of other risk factors for HCC: the use of statins and the presence of nonalcoholic fatty liver disease (NAFLD).

Dr. El-Serag noted that, among NAFLD patients, subgroups at even greater risk for HCC include those with diabetes, those older than 65 years, Hispanic race, and those with cirrhosis. These patients should be candidates for surveillance. Metabolic dysfunction traits such as obesity and diabetes are very common conditions, so it’s important to look at other, more specific factors, he added. “I hope that there will be tools to help clinicians classify or risk-stratify patients into different buckets,” he said.

Areas for further research on HCC continue to include risk stratification, mechanisms of action, and HCC prevention related to treatment of metabolic syndrome, he emphasized.

Dr. El-Serag had no financial conflicts to disclose. Global Academy for Medical Education and this news organization are owned by the same parent company.

*This story was updated on Oct. 28, 2020. 

SOURCE: El-Serag HB. Digestive Diseases: New Advances 2020.

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

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

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

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

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

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

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

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

Little change in treatment

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

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

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

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

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

Study details

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

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

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

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

Mixed histologies muddy results

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

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

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

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

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

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

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

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

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

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

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

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

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

This story first appeared on Medscape.com.

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

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

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

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

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

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

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

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

Little change in treatment

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

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

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

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

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

Study details

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

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

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

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

Mixed histologies muddy results

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

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

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

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

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

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

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

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

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

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

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

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

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

This story first appeared on Medscape.com.

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

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

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

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

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

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

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

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

Little change in treatment

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

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

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

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

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

Study details

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

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

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

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

Mixed histologies muddy results

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

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

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

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

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

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

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

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

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

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

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

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

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

This story first appeared on Medscape.com.

Type 2 diabetes patients who had never used insulin showed sustained remission 10 years after bariatric surgery in a prospective study of 85 patients.

Having diabetes for less than 5 years was also predictive of achieving long-term diabetes remission, Diego Moriconi, MD, of the University of Pisa (Italy) and presenting study investigator, reported at the virtual annual meeting of the European Association for the Study of Diabetes.

“Weight loss was associated with type 2 diabetes remission 1 year after surgery, but it had no impact on the long-term relapse of diabetes,” Dr. Moriconi said.

The findings are important, commented Tina Vilsbøll, MD, DMSc, chief consultant at the Steno Diabetes Centre Copenhagen, who chaired the session. They’re important because they would help “to set the expectations for patients before they have surgery, what to expect in respect to resolution or remission of diabetes.”

If patients were taking insulin, for instance, the take home would seem to be not to expect too much in terms of remission of their diabetes, Dr. Vilsbøll said. She added: “Usually I am not a big fan of [relying on] diabetes duration, because often we know that patients with type 2 diabetes have had diabetes for a long time before they’re actually diagnosed.” However, “it seems to be very important here.”

Dr. Moriconi reported the findings of an observational study that had started in 2006 and recruited individuals about to undergo bariatric surgery for type 2 diabetes. Participants were evaluated before surgery and every 6-12 months after, undergoing various clinical and laboratory investigations, for a period of 10 years.

The majority of the recruited patients (76%) were women. Most (also 76%) had undergone gastric bypass (Roux-en-Y) surgery, and the remainder had undergone sleeve gastrectomy. Both types of surgery were equally as good at getting people into remission, as defined by the American Diabetes Association Standards of Medical Care in Diabetes, Dr. Moriconi said. As such, remission was achieved if the fasting blood glucose fell below 100 mg/dL and the hemoglobin A1c below 5.7%.

In the first year following surgery, 75% of patients had met diabetes remission criteria. This fell to 61% of patients after 5 years, and to 55% at 10 years. At each of these time points, 25% of patients had type 2 diabetes, with 14% relapsing back at 5 years and 20% at 10 years.

Dr. Moriconi pointed out some of the different characteristics of the 47 patients who had achieved diabetes remission at 10 years, compared with the 17 who had “relapsed” back to having type 2 diabetes and the 21 who had remained with type 2 diabetes.

The decrease in body mass index achieved at 10 years was no different between the three groups. However, 1 year after surgery, there had been a significantly greater drop in body in those who achieved remission, compared with those who did not (P = .04).

“Glycemic control improved with time in all the three groups after bariatric surgery, although more markedly so in the remission group,” Dr. Moriconi said.

He highlighted how none of the patients who had achieved remission had used insulin, whereas 12% of those who had relapsed and half (52%) of those who remained with type 2 diabetes had used insulin (P < .0001).

Patients who achieved remission at 1, 5, and 10 years were more likely to have had diabetes for less than 5 years than those who remained with type 2 diabetes. The average duration of diabetes was 2 years in those achieving remission versus 8 years in those who had relapsed and 13 years in those who had remained diabetic (P < .0001).

Logistic regression analysis, which adjusted for all major confounding factors such as age, sex, and type of surgery, showed that only the duration of diabetes and insulin therapy before surgery were the only predictors of long-term diabetes remission.

The study had no commercial funding. Dr. Moriconi and Dr. Vilsbøll had no conflicts of interest to disclose.

SOURCE: Moriconi D. EASD 2020, Oral presentation 120.

Type 2 diabetes patients who had never used insulin showed sustained remission 10 years after bariatric surgery in a prospective study of 85 patients.

Having diabetes for less than 5 years was also predictive of achieving long-term diabetes remission, Diego Moriconi, MD, of the University of Pisa (Italy) and presenting study investigator, reported at the virtual annual meeting of the European Association for the Study of Diabetes.

“Weight loss was associated with type 2 diabetes remission 1 year after surgery, but it had no impact on the long-term relapse of diabetes,” Dr. Moriconi said.

The findings are important, commented Tina Vilsbøll, MD, DMSc, chief consultant at the Steno Diabetes Centre Copenhagen, who chaired the session. They’re important because they would help “to set the expectations for patients before they have surgery, what to expect in respect to resolution or remission of diabetes.”

If patients were taking insulin, for instance, the take home would seem to be not to expect too much in terms of remission of their diabetes, Dr. Vilsbøll said. She added: “Usually I am not a big fan of [relying on] diabetes duration, because often we know that patients with type 2 diabetes have had diabetes for a long time before they’re actually diagnosed.” However, “it seems to be very important here.”

Dr. Moriconi reported the findings of an observational study that had started in 2006 and recruited individuals about to undergo bariatric surgery for type 2 diabetes. Participants were evaluated before surgery and every 6-12 months after, undergoing various clinical and laboratory investigations, for a period of 10 years.

The majority of the recruited patients (76%) were women. Most (also 76%) had undergone gastric bypass (Roux-en-Y) surgery, and the remainder had undergone sleeve gastrectomy. Both types of surgery were equally as good at getting people into remission, as defined by the American Diabetes Association Standards of Medical Care in Diabetes, Dr. Moriconi said. As such, remission was achieved if the fasting blood glucose fell below 100 mg/dL and the hemoglobin A1c below 5.7%.

In the first year following surgery, 75% of patients had met diabetes remission criteria. This fell to 61% of patients after 5 years, and to 55% at 10 years. At each of these time points, 25% of patients had type 2 diabetes, with 14% relapsing back at 5 years and 20% at 10 years.

Dr. Moriconi pointed out some of the different characteristics of the 47 patients who had achieved diabetes remission at 10 years, compared with the 17 who had “relapsed” back to having type 2 diabetes and the 21 who had remained with type 2 diabetes.

The decrease in body mass index achieved at 10 years was no different between the three groups. However, 1 year after surgery, there had been a significantly greater drop in body in those who achieved remission, compared with those who did not (P = .04).

“Glycemic control improved with time in all the three groups after bariatric surgery, although more markedly so in the remission group,” Dr. Moriconi said.

He highlighted how none of the patients who had achieved remission had used insulin, whereas 12% of those who had relapsed and half (52%) of those who remained with type 2 diabetes had used insulin (P < .0001).

Patients who achieved remission at 1, 5, and 10 years were more likely to have had diabetes for less than 5 years than those who remained with type 2 diabetes. The average duration of diabetes was 2 years in those achieving remission versus 8 years in those who had relapsed and 13 years in those who had remained diabetic (P < .0001).

Logistic regression analysis, which adjusted for all major confounding factors such as age, sex, and type of surgery, showed that only the duration of diabetes and insulin therapy before surgery were the only predictors of long-term diabetes remission.

The study had no commercial funding. Dr. Moriconi and Dr. Vilsbøll had no conflicts of interest to disclose.

SOURCE: Moriconi D. EASD 2020, Oral presentation 120.

Type 2 diabetes patients who had never used insulin showed sustained remission 10 years after bariatric surgery in a prospective study of 85 patients.

Having diabetes for less than 5 years was also predictive of achieving long-term diabetes remission, Diego Moriconi, MD, of the University of Pisa (Italy) and presenting study investigator, reported at the virtual annual meeting of the European Association for the Study of Diabetes.

“Weight loss was associated with type 2 diabetes remission 1 year after surgery, but it had no impact on the long-term relapse of diabetes,” Dr. Moriconi said.

The findings are important, commented Tina Vilsbøll, MD, DMSc, chief consultant at the Steno Diabetes Centre Copenhagen, who chaired the session. They’re important because they would help “to set the expectations for patients before they have surgery, what to expect in respect to resolution or remission of diabetes.”

If patients were taking insulin, for instance, the take home would seem to be not to expect too much in terms of remission of their diabetes, Dr. Vilsbøll said. She added: “Usually I am not a big fan of [relying on] diabetes duration, because often we know that patients with type 2 diabetes have had diabetes for a long time before they’re actually diagnosed.” However, “it seems to be very important here.”

Dr. Moriconi reported the findings of an observational study that had started in 2006 and recruited individuals about to undergo bariatric surgery for type 2 diabetes. Participants were evaluated before surgery and every 6-12 months after, undergoing various clinical and laboratory investigations, for a period of 10 years.

The majority of the recruited patients (76%) were women. Most (also 76%) had undergone gastric bypass (Roux-en-Y) surgery, and the remainder had undergone sleeve gastrectomy. Both types of surgery were equally as good at getting people into remission, as defined by the American Diabetes Association Standards of Medical Care in Diabetes, Dr. Moriconi said. As such, remission was achieved if the fasting blood glucose fell below 100 mg/dL and the hemoglobin A1c below 5.7%.

In the first year following surgery, 75% of patients had met diabetes remission criteria. This fell to 61% of patients after 5 years, and to 55% at 10 years. At each of these time points, 25% of patients had type 2 diabetes, with 14% relapsing back at 5 years and 20% at 10 years.

Dr. Moriconi pointed out some of the different characteristics of the 47 patients who had achieved diabetes remission at 10 years, compared with the 17 who had “relapsed” back to having type 2 diabetes and the 21 who had remained with type 2 diabetes.

The decrease in body mass index achieved at 10 years was no different between the three groups. However, 1 year after surgery, there had been a significantly greater drop in body in those who achieved remission, compared with those who did not (P = .04).

“Glycemic control improved with time in all the three groups after bariatric surgery, although more markedly so in the remission group,” Dr. Moriconi said.

He highlighted how none of the patients who had achieved remission had used insulin, whereas 12% of those who had relapsed and half (52%) of those who remained with type 2 diabetes had used insulin (P < .0001).

Patients who achieved remission at 1, 5, and 10 years were more likely to have had diabetes for less than 5 years than those who remained with type 2 diabetes. The average duration of diabetes was 2 years in those achieving remission versus 8 years in those who had relapsed and 13 years in those who had remained diabetic (P < .0001).

Logistic regression analysis, which adjusted for all major confounding factors such as age, sex, and type of surgery, showed that only the duration of diabetes and insulin therapy before surgery were the only predictors of long-term diabetes remission.

The study had no commercial funding. Dr. Moriconi and Dr. Vilsbøll had no conflicts of interest to disclose.

SOURCE: Moriconi D. EASD 2020, Oral presentation 120.

Not only the prevalence, but the impact of nonalcoholic fatty liver disease (NAFLD) is increasing in much of the world, Arun J. Sanyal, MD, said in a virtual presentation at the meeting jointly provided by Rutgers and Global Academy for Medical Education. “It is currently estimated that the number of people living with cirrhosis or with decompensated cirrhosis will increase two- to threefold from 2015 to 2030,” which underlines the public health impact and the need for improved treatment paradigms, he emphasized.

“The thing to remember about NAFLD is that it does not exist in a vacuum,” Dr. Sanyal said. NAFLD is a multisystem disorder. Most patients have concomitant cardiovascular disease, but others may have type 2 diabetes, hypertension, and dyslipidemia, all of which are now accepted as risk factors for nonalcoholic steatohepatitis (NASH), he said.

“What ties these conditions together is metabolic stress leading to systemic inflammation and fibrosis. This is primarily due to diet-induced obesity. If you think about treating all of these competing risks to the patient’s life, the optimal way is to treat the root cause,” he said.

Various options exist to manage the conditions that can lead to NASH, but several of these also appear promising as a treatment of NASH, Dr. Sanyal said. Glucagonlike peptide–1 agonists and sodium-glucose transporter 2 inhibitors have been shown to improve multiple outcomes of interest in type 2 diabetes. However, insulin can cause weight gain at the expense of controlling HbA1C levels, he said.

Bariatric surgery can improve histology, but many patients with advanced fibrosis do not demonstrate improvement in fibrosis. Also, bariatric surgery has its own associated morbidity, including an increased suicide rate across multiple studies, Dr. Sanyal noted.

A new and interesting option is duodenal mucosal resurfacing (DMR) “a novel, minimally invasive outpatient upper-endoscopic procedure,” said Dr. Sanyal. DMR involves use of a catheter to perform a submucosal lift and hydrothermal mucosal ablation, prompting healthy epithelial regrowth, he explained. “The mucosa sloughs off, fresh epithelium grows in, and the hormonal signal from the gut to the rest of the body is restored to a more normal pattern,” he noted.

In the REVITA-2 study of patients with diabetes and NAFLD, the average fat loss was 5.4% in those randomized to DMR vs. 2.4% in sham-procedure patients and represented “quite significant defatting of the liver,” Dr. Sanyal said.

Dr. Sanyal then focused on fatty liver disease. “The first step when you see a patient with fatty liver disease is to see how scarred is the liver, and whether the patient has silent cirrhosis. The more scarred the liver, the greater risk of liver-related outcomes,” he said. The goal of therapy for these patients is to reduce the risk of progression to cirrhosis, he added. Dr. Sanyal recommended evaluating fibrosis using the Fibrosis 4 score (Fib4). “If the Fib4 is less than 1.3, the likelihood of significant scarring in the liver is less than 10%,” he said. On the other hand, a Fib4 greater than 2.67 suggests advanced fibrosis, he noted.

Overall, the goals of treatment for NASH patients are to prevent cirrhosis, reduce decompensation, and prevent hepatocellular carcinoma, said Dr. Sanyal.

“The ideal drug for NASH should also help other end organs, or at least be neutral,” said Dr. Sanyal.

Current frontline therapies for precirrhotic NASH include thiazolidinediones (TZD), farnesoid X receptor (FXR)/fibroblast growth factor 19 (FGF-19), FGF21, thyroxine B-R, and glucagonlike peptide-1. Clinical evidence varies based on different populations, endpoints, assessment methods, and treatment duration, he said.

Looking ahead to the next decade, a NASH management paradigm will likely play out that can be applied in the clinic today, Dr. Sanyal said. First, make an initial assessment of the status of the end organs. Start with a weight-loss regimen; use statins and GLP-1 and SGLT2 inhibitors as needed. Follow and reassess, and if the patient still has disease, progress to targeted therapy for active NASH while continuing to encourage weight loss and healthy living, he said.

“The ultimate proof that what we are doing is working is that we are improving mortality, reducing health care costs, and improving patients’ function and quality of life,” he concluded.

Dr. Sanyal is president of Sanyal Biotechnologies. He also disclosed stock options for Durect, Exhalenz, Galmed, Genfit, Immuton, Indalo, and Tiziana, as well as various relationships with Allergan, AMRA, Astra Zeneca-Medimmune, Birdrock, Boehringer Ingelheim, Bristol Myers, Echosense, GE, Genentech, Gilead, Hemoshear, IFMO, Innovate, Intercept, Lilly, Lipocine, Merck, Novartis, Novo Nordisk, OWL, Pfizer, RedX, Sundise, Tern, and Zydus.

Global Academy for Medical Education and this news organization are owned by the same parent company.

Not only the prevalence, but the impact of nonalcoholic fatty liver disease (NAFLD) is increasing in much of the world, Arun J. Sanyal, MD, said in a virtual presentation at the meeting jointly provided by Rutgers and Global Academy for Medical Education. “It is currently estimated that the number of people living with cirrhosis or with decompensated cirrhosis will increase two- to threefold from 2015 to 2030,” which underlines the public health impact and the need for improved treatment paradigms, he emphasized.

“The thing to remember about NAFLD is that it does not exist in a vacuum,” Dr. Sanyal said. NAFLD is a multisystem disorder. Most patients have concomitant cardiovascular disease, but others may have type 2 diabetes, hypertension, and dyslipidemia, all of which are now accepted as risk factors for nonalcoholic steatohepatitis (NASH), he said.

“What ties these conditions together is metabolic stress leading to systemic inflammation and fibrosis. This is primarily due to diet-induced obesity. If you think about treating all of these competing risks to the patient’s life, the optimal way is to treat the root cause,” he said.

Various options exist to manage the conditions that can lead to NASH, but several of these also appear promising as a treatment of NASH, Dr. Sanyal said. Glucagonlike peptide–1 agonists and sodium-glucose transporter 2 inhibitors have been shown to improve multiple outcomes of interest in type 2 diabetes. However, insulin can cause weight gain at the expense of controlling HbA1C levels, he said.

Bariatric surgery can improve histology, but many patients with advanced fibrosis do not demonstrate improvement in fibrosis. Also, bariatric surgery has its own associated morbidity, including an increased suicide rate across multiple studies, Dr. Sanyal noted.

A new and interesting option is duodenal mucosal resurfacing (DMR) “a novel, minimally invasive outpatient upper-endoscopic procedure,” said Dr. Sanyal. DMR involves use of a catheter to perform a submucosal lift and hydrothermal mucosal ablation, prompting healthy epithelial regrowth, he explained. “The mucosa sloughs off, fresh epithelium grows in, and the hormonal signal from the gut to the rest of the body is restored to a more normal pattern,” he noted.

In the REVITA-2 study of patients with diabetes and NAFLD, the average fat loss was 5.4% in those randomized to DMR vs. 2.4% in sham-procedure patients and represented “quite significant defatting of the liver,” Dr. Sanyal said.

Dr. Sanyal then focused on fatty liver disease. “The first step when you see a patient with fatty liver disease is to see how scarred is the liver, and whether the patient has silent cirrhosis. The more scarred the liver, the greater risk of liver-related outcomes,” he said. The goal of therapy for these patients is to reduce the risk of progression to cirrhosis, he added. Dr. Sanyal recommended evaluating fibrosis using the Fibrosis 4 score (Fib4). “If the Fib4 is less than 1.3, the likelihood of significant scarring in the liver is less than 10%,” he said. On the other hand, a Fib4 greater than 2.67 suggests advanced fibrosis, he noted.

Overall, the goals of treatment for NASH patients are to prevent cirrhosis, reduce decompensation, and prevent hepatocellular carcinoma, said Dr. Sanyal.

“The ideal drug for NASH should also help other end organs, or at least be neutral,” said Dr. Sanyal.

Current frontline therapies for precirrhotic NASH include thiazolidinediones (TZD), farnesoid X receptor (FXR)/fibroblast growth factor 19 (FGF-19), FGF21, thyroxine B-R, and glucagonlike peptide-1. Clinical evidence varies based on different populations, endpoints, assessment methods, and treatment duration, he said.

Looking ahead to the next decade, a NASH management paradigm will likely play out that can be applied in the clinic today, Dr. Sanyal said. First, make an initial assessment of the status of the end organs. Start with a weight-loss regimen; use statins and GLP-1 and SGLT2 inhibitors as needed. Follow and reassess, and if the patient still has disease, progress to targeted therapy for active NASH while continuing to encourage weight loss and healthy living, he said.

“The ultimate proof that what we are doing is working is that we are improving mortality, reducing health care costs, and improving patients’ function and quality of life,” he concluded.

Dr. Sanyal is president of Sanyal Biotechnologies. He also disclosed stock options for Durect, Exhalenz, Galmed, Genfit, Immuton, Indalo, and Tiziana, as well as various relationships with Allergan, AMRA, Astra Zeneca-Medimmune, Birdrock, Boehringer Ingelheim, Bristol Myers, Echosense, GE, Genentech, Gilead, Hemoshear, IFMO, Innovate, Intercept, Lilly, Lipocine, Merck, Novartis, Novo Nordisk, OWL, Pfizer, RedX, Sundise, Tern, and Zydus.

Global Academy for Medical Education and this news organization are owned by the same parent company.

Not only the prevalence, but the impact of nonalcoholic fatty liver disease (NAFLD) is increasing in much of the world, Arun J. Sanyal, MD, said in a virtual presentation at the meeting jointly provided by Rutgers and Global Academy for Medical Education. “It is currently estimated that the number of people living with cirrhosis or with decompensated cirrhosis will increase two- to threefold from 2015 to 2030,” which underlines the public health impact and the need for improved treatment paradigms, he emphasized.

“The thing to remember about NAFLD is that it does not exist in a vacuum,” Dr. Sanyal said. NAFLD is a multisystem disorder. Most patients have concomitant cardiovascular disease, but others may have type 2 diabetes, hypertension, and dyslipidemia, all of which are now accepted as risk factors for nonalcoholic steatohepatitis (NASH), he said.

“What ties these conditions together is metabolic stress leading to systemic inflammation and fibrosis. This is primarily due to diet-induced obesity. If you think about treating all of these competing risks to the patient’s life, the optimal way is to treat the root cause,” he said.

Various options exist to manage the conditions that can lead to NASH, but several of these also appear promising as a treatment of NASH, Dr. Sanyal said. Glucagonlike peptide–1 agonists and sodium-glucose transporter 2 inhibitors have been shown to improve multiple outcomes of interest in type 2 diabetes. However, insulin can cause weight gain at the expense of controlling HbA1C levels, he said.

Bariatric surgery can improve histology, but many patients with advanced fibrosis do not demonstrate improvement in fibrosis. Also, bariatric surgery has its own associated morbidity, including an increased suicide rate across multiple studies, Dr. Sanyal noted.

A new and interesting option is duodenal mucosal resurfacing (DMR) “a novel, minimally invasive outpatient upper-endoscopic procedure,” said Dr. Sanyal. DMR involves use of a catheter to perform a submucosal lift and hydrothermal mucosal ablation, prompting healthy epithelial regrowth, he explained. “The mucosa sloughs off, fresh epithelium grows in, and the hormonal signal from the gut to the rest of the body is restored to a more normal pattern,” he noted.

In the REVITA-2 study of patients with diabetes and NAFLD, the average fat loss was 5.4% in those randomized to DMR vs. 2.4% in sham-procedure patients and represented “quite significant defatting of the liver,” Dr. Sanyal said.

Dr. Sanyal then focused on fatty liver disease. “The first step when you see a patient with fatty liver disease is to see how scarred is the liver, and whether the patient has silent cirrhosis. The more scarred the liver, the greater risk of liver-related outcomes,” he said. The goal of therapy for these patients is to reduce the risk of progression to cirrhosis, he added. Dr. Sanyal recommended evaluating fibrosis using the Fibrosis 4 score (Fib4). “If the Fib4 is less than 1.3, the likelihood of significant scarring in the liver is less than 10%,” he said. On the other hand, a Fib4 greater than 2.67 suggests advanced fibrosis, he noted.

Overall, the goals of treatment for NASH patients are to prevent cirrhosis, reduce decompensation, and prevent hepatocellular carcinoma, said Dr. Sanyal.

“The ideal drug for NASH should also help other end organs, or at least be neutral,” said Dr. Sanyal.

Current frontline therapies for precirrhotic NASH include thiazolidinediones (TZD), farnesoid X receptor (FXR)/fibroblast growth factor 19 (FGF-19), FGF21, thyroxine B-R, and glucagonlike peptide-1. Clinical evidence varies based on different populations, endpoints, assessment methods, and treatment duration, he said.

Looking ahead to the next decade, a NASH management paradigm will likely play out that can be applied in the clinic today, Dr. Sanyal said. First, make an initial assessment of the status of the end organs. Start with a weight-loss regimen; use statins and GLP-1 and SGLT2 inhibitors as needed. Follow and reassess, and if the patient still has disease, progress to targeted therapy for active NASH while continuing to encourage weight loss and healthy living, he said.

“The ultimate proof that what we are doing is working is that we are improving mortality, reducing health care costs, and improving patients’ function and quality of life,” he concluded.

Dr. Sanyal is president of Sanyal Biotechnologies. He also disclosed stock options for Durect, Exhalenz, Galmed, Genfit, Immuton, Indalo, and Tiziana, as well as various relationships with Allergan, AMRA, Astra Zeneca-Medimmune, Birdrock, Boehringer Ingelheim, Bristol Myers, Echosense, GE, Genentech, Gilead, Hemoshear, IFMO, Innovate, Intercept, Lilly, Lipocine, Merck, Novartis, Novo Nordisk, OWL, Pfizer, RedX, Sundise, Tern, and Zydus.

Global Academy for Medical Education and this news organization are owned by the same parent company.

States have begun preparing to distribute a COVID-19 vaccine if one is approved, a CDC official said today.

The CDC released guidance for states on Sept. 16 titled COVID-19 Vaccination Program Interim Playbook for Jurisdiction Operations. The document discusses vaccine ordering, storage, and handling and says that states should submit their plans for vaccine distribution to the agency by Oct. 16.

“Every jurisdiction is heavily involved right now in their plan development,” CDC official Janell Routh, MD, told the Advisory Committee on Immunization Practices during its Sept. 22 meeting. “It was really impressive to me that, even though the playbook only went out last week, states and jurisdictions have been thinking about this for quite some time.”

However, one committee member suggested that setting a deadline before more safety, efficacy, and storage information is known may be premature.

“I cannot imagine that we will actually know the final storage requirements for this vaccine by Oct. 16, which makes me a little concerned about finalizing state plans,” said Helen “Keipp” Talbot, MD, MPH, associate professor of medicine at Vanderbilt University Medical Center in Nashville, Tenn. “We also don’t know the best populations yet when it comes to efficacy and safety.”

Dr. Routh said the CDC is asking states to plan on the basis of assumptions. “We know those plans will constantly be improving, changing, as we learn more information,” Dr. Routh said. States agreed to return a plan 30 days after the playbook was released, which is how the Oct. 16 deadline was established, she said.

States are encouraged to think broadly. Plans may include contingencies for a product that requires ultracold storage or for distributing more than one vaccine product, Dr. Routh said.

“One goal is to be ready on the first day that we can actually distribute vaccine,” Nancy Messonnier, MD, director of the National Center for Immunization and Respiratory Diseases, said during the meeting. “Our colleagues in Operation Warp Speed say that they expect there will be vaccine as early as November, and therefore we need to be ready so there is no delay in distributing that vaccine. And that phase, that early phase, is really close upon us.”

Many states have already developed plans, and the CDC is providing technical assistance as needed to monitor the plans regularly, Dr. Routh said.
 

Key issues identified

From holding pilot meetings with five jurisdictions, officials learned that public confidence in the vaccine is among states’ greatest concerns, Dr. Routh said. In addition, distribution is resource intensive, and social distancing adds logistical complexity.

Specific guidance on whom to vaccinate in the early stages will smooth the process, officials suggested during the pilot meetings. For the first several weeks, vaccine doses may be limited to priority populations, such as health care workers.

“This interim playbook is a living document,” Dr. Routh emphasized. “We definitely plan to update the content regularly as we learn more information about what vaccines and when they will be released.”

During the early stages of COVID-19 vaccination, officials plan to implement an enhanced monitoring program in which vaccine recipients would complete surveys about adverse events, in addition to the traditional vaccine safety monitoring programs that already exist, officials said.
 

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

States have begun preparing to distribute a COVID-19 vaccine if one is approved, a CDC official said today.

The CDC released guidance for states on Sept. 16 titled COVID-19 Vaccination Program Interim Playbook for Jurisdiction Operations. The document discusses vaccine ordering, storage, and handling and says that states should submit their plans for vaccine distribution to the agency by Oct. 16.

“Every jurisdiction is heavily involved right now in their plan development,” CDC official Janell Routh, MD, told the Advisory Committee on Immunization Practices during its Sept. 22 meeting. “It was really impressive to me that, even though the playbook only went out last week, states and jurisdictions have been thinking about this for quite some time.”

However, one committee member suggested that setting a deadline before more safety, efficacy, and storage information is known may be premature.

“I cannot imagine that we will actually know the final storage requirements for this vaccine by Oct. 16, which makes me a little concerned about finalizing state plans,” said Helen “Keipp” Talbot, MD, MPH, associate professor of medicine at Vanderbilt University Medical Center in Nashville, Tenn. “We also don’t know the best populations yet when it comes to efficacy and safety.”

Dr. Routh said the CDC is asking states to plan on the basis of assumptions. “We know those plans will constantly be improving, changing, as we learn more information,” Dr. Routh said. States agreed to return a plan 30 days after the playbook was released, which is how the Oct. 16 deadline was established, she said.

States are encouraged to think broadly. Plans may include contingencies for a product that requires ultracold storage or for distributing more than one vaccine product, Dr. Routh said.

“One goal is to be ready on the first day that we can actually distribute vaccine,” Nancy Messonnier, MD, director of the National Center for Immunization and Respiratory Diseases, said during the meeting. “Our colleagues in Operation Warp Speed say that they expect there will be vaccine as early as November, and therefore we need to be ready so there is no delay in distributing that vaccine. And that phase, that early phase, is really close upon us.”

Many states have already developed plans, and the CDC is providing technical assistance as needed to monitor the plans regularly, Dr. Routh said.
 

Key issues identified

From holding pilot meetings with five jurisdictions, officials learned that public confidence in the vaccine is among states’ greatest concerns, Dr. Routh said. In addition, distribution is resource intensive, and social distancing adds logistical complexity.

Specific guidance on whom to vaccinate in the early stages will smooth the process, officials suggested during the pilot meetings. For the first several weeks, vaccine doses may be limited to priority populations, such as health care workers.

“This interim playbook is a living document,” Dr. Routh emphasized. “We definitely plan to update the content regularly as we learn more information about what vaccines and when they will be released.”

During the early stages of COVID-19 vaccination, officials plan to implement an enhanced monitoring program in which vaccine recipients would complete surveys about adverse events, in addition to the traditional vaccine safety monitoring programs that already exist, officials said.
 

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

States have begun preparing to distribute a COVID-19 vaccine if one is approved, a CDC official said today.

The CDC released guidance for states on Sept. 16 titled COVID-19 Vaccination Program Interim Playbook for Jurisdiction Operations. The document discusses vaccine ordering, storage, and handling and says that states should submit their plans for vaccine distribution to the agency by Oct. 16.

“Every jurisdiction is heavily involved right now in their plan development,” CDC official Janell Routh, MD, told the Advisory Committee on Immunization Practices during its Sept. 22 meeting. “It was really impressive to me that, even though the playbook only went out last week, states and jurisdictions have been thinking about this for quite some time.”

However, one committee member suggested that setting a deadline before more safety, efficacy, and storage information is known may be premature.

“I cannot imagine that we will actually know the final storage requirements for this vaccine by Oct. 16, which makes me a little concerned about finalizing state plans,” said Helen “Keipp” Talbot, MD, MPH, associate professor of medicine at Vanderbilt University Medical Center in Nashville, Tenn. “We also don’t know the best populations yet when it comes to efficacy and safety.”

Dr. Routh said the CDC is asking states to plan on the basis of assumptions. “We know those plans will constantly be improving, changing, as we learn more information,” Dr. Routh said. States agreed to return a plan 30 days after the playbook was released, which is how the Oct. 16 deadline was established, she said.

States are encouraged to think broadly. Plans may include contingencies for a product that requires ultracold storage or for distributing more than one vaccine product, Dr. Routh said.

“One goal is to be ready on the first day that we can actually distribute vaccine,” Nancy Messonnier, MD, director of the National Center for Immunization and Respiratory Diseases, said during the meeting. “Our colleagues in Operation Warp Speed say that they expect there will be vaccine as early as November, and therefore we need to be ready so there is no delay in distributing that vaccine. And that phase, that early phase, is really close upon us.”

Many states have already developed plans, and the CDC is providing technical assistance as needed to monitor the plans regularly, Dr. Routh said.
 

Key issues identified

From holding pilot meetings with five jurisdictions, officials learned that public confidence in the vaccine is among states’ greatest concerns, Dr. Routh said. In addition, distribution is resource intensive, and social distancing adds logistical complexity.

Specific guidance on whom to vaccinate in the early stages will smooth the process, officials suggested during the pilot meetings. For the first several weeks, vaccine doses may be limited to priority populations, such as health care workers.

“This interim playbook is a living document,” Dr. Routh emphasized. “We definitely plan to update the content regularly as we learn more information about what vaccines and when they will be released.”

During the early stages of COVID-19 vaccination, officials plan to implement an enhanced monitoring program in which vaccine recipients would complete surveys about adverse events, in addition to the traditional vaccine safety monitoring programs that already exist, officials said.
 

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

Monitor antidrug antibodies for their impact on drug clearance to maximize treatment outcomes in rheumatology patients treated with biologics, Niels Vande Casteele, PharmD, PhD, said in a virtual presentation at the annual Perspectives in Rheumatic Diseases held by Global Academy for Medical Education.

Antidrug antibodies (ADAb) are associated with impaired drug efficacy and safety, he noted. Furthermore, he indicated that when ADAb bind to the drug, they can either block the activity of the drug directly and/or may cause the formation of complexes, leading to accelerated drug clearance and reduced drug exposure.

Dr. Vande Casteele, assistant professor in the department of medicine at the University of California, San Diego, outlined factors that contribute to immunogenicity, which occurs when the body reacts to neoantigens, or when there is a breakdown in immune tolerance, he said.

Genetics can play a key role in the risk for immunogenicity, as can the route of administration, dose, treatment duration, and concomitant diseases or medications, he explained.

In addition, product-related factors including sequence variation, glycosylation, host cells, contaminants and processing impurities, formulation, and handling and storage issues can impact immunogenicity, he noted.

For example, Dr. Vande Casteele cited a study in which the proportion of infliximab-treated patients with positive ADAbs was substantially higher among those receiving the drug intravenously, compared with those receiving it subcutaneously. As for treatment dosing, data on patients treated with infliximab have shown that maintenance therapy is associated with lower rates of immunogenicity, compared to episodic therapy, he said.

In terms of genetics, Dr. Vande Casteele cited a study published in January in Gastroenterology showing the presence of the HLA-DQA1*05 allele, carried by approximately 40% of the European population, significantly increased the rate of immunogenicity to infliximab and adalimumab in patients with Crohn’s disease (hazard ratio, 1.90).
 

Therapeutic drug monitoring and overcoming immunogenicity

Dr. Vande Casteele also reviewed how to measure ADAbs. “Antidrug antibody units and concentrations can differ across assays,” he said.

In clinical practice, “the majority of patients at the time of secondary loss of response will present with low drug exposure, and that is when you measure antidrug antibodies,” he said.

In rheumatology patients, the presence of ADAbs against anti–tumor necrosis factor monoclonal antibodies conveys a risk for treatment discontinuation, as well as “a risk of development of hypersensitivity reactions in all immune-mediated inflammatory diseases,” Dr. Vande Casteele said.

However, “the combined use of anti–tumor necrosis factor monoclonal antibodies and disease-modifying antirheumatic drugs reduces the development of antibodies and subsequent risks,” he noted.

For therapeutic drug monitoring in patients with a secondary loss of response, “first, look at the trough concentration,” Dr. Vande Casteele said. “If it is optimal, then ADAbs are probably inconsequential.” If the trough is low or undetectable, examine ADAbs, he added. To manage ADAbs, data support the use of drug dose escalation in some cases. However, “you may be able to overcome the antidrug antibodies in some patients with dose escalation, but this is not always a cost-effective strategy in the long term,” and some patients fail a drug despite adequate drug concentration, which may mean they are failing the mechanism, and not because of pharmacokinetic-related issues, he said.

Dr. Vande Casteele cited a post hoc analysis of the TAXIT trial, published in Gastroenterology. It was the first prospective study to look at proactive therapeutic drug monitoring in patients with inflammatory bowel diseases treated with maintenance infliximab. This post hoc analysis showed that ADAbs were overcome with dose escalation in nearly 50% of patients in the lowest two ADAb quartiles at the start of the trial, and although ADAb were masked by dose escalation in the highest two quartiles, measurement with a drug-sensitive assay showed that ADAb never disappeared, he said.

Another strategy to try to overcome immunogenicity is to add an immunomodulator, Dr. Vande Casteele said. He cited a recent study published in Rheumatology showing that the effect of methotrexate was mediated through immunogenicity for immunogenic compounds such as adalimumab.

Importantly, there is a risk for immunogenicity across agents, he noted. “Patients who are antibody positive to the prior anti-TNF are at a higher risk of developing antibodies to subsequent anti-TNFs.”

Dr. Vande Casteele reported receiving research grants from R-Biopharm; grants and personal fees from Takeda and UCB; and personal fees from Alimentiv (formerly Robarts Clinical Trials), Celltrion, and Prometheus. Global Academy for Medical Education and this news organization are owned by the same parent company.

Monitor antidrug antibodies for their impact on drug clearance to maximize treatment outcomes in rheumatology patients treated with biologics, Niels Vande Casteele, PharmD, PhD, said in a virtual presentation at the annual Perspectives in Rheumatic Diseases held by Global Academy for Medical Education.

Antidrug antibodies (ADAb) are associated with impaired drug efficacy and safety, he noted. Furthermore, he indicated that when ADAb bind to the drug, they can either block the activity of the drug directly and/or may cause the formation of complexes, leading to accelerated drug clearance and reduced drug exposure.

Dr. Vande Casteele, assistant professor in the department of medicine at the University of California, San Diego, outlined factors that contribute to immunogenicity, which occurs when the body reacts to neoantigens, or when there is a breakdown in immune tolerance, he said.

Genetics can play a key role in the risk for immunogenicity, as can the route of administration, dose, treatment duration, and concomitant diseases or medications, he explained.

In addition, product-related factors including sequence variation, glycosylation, host cells, contaminants and processing impurities, formulation, and handling and storage issues can impact immunogenicity, he noted.

For example, Dr. Vande Casteele cited a study in which the proportion of infliximab-treated patients with positive ADAbs was substantially higher among those receiving the drug intravenously, compared with those receiving it subcutaneously. As for treatment dosing, data on patients treated with infliximab have shown that maintenance therapy is associated with lower rates of immunogenicity, compared to episodic therapy, he said.

In terms of genetics, Dr. Vande Casteele cited a study published in January in Gastroenterology showing the presence of the HLA-DQA1*05 allele, carried by approximately 40% of the European population, significantly increased the rate of immunogenicity to infliximab and adalimumab in patients with Crohn’s disease (hazard ratio, 1.90).
 

Therapeutic drug monitoring and overcoming immunogenicity

Dr. Vande Casteele also reviewed how to measure ADAbs. “Antidrug antibody units and concentrations can differ across assays,” he said.

In clinical practice, “the majority of patients at the time of secondary loss of response will present with low drug exposure, and that is when you measure antidrug antibodies,” he said.

In rheumatology patients, the presence of ADAbs against anti–tumor necrosis factor monoclonal antibodies conveys a risk for treatment discontinuation, as well as “a risk of development of hypersensitivity reactions in all immune-mediated inflammatory diseases,” Dr. Vande Casteele said.

However, “the combined use of anti–tumor necrosis factor monoclonal antibodies and disease-modifying antirheumatic drugs reduces the development of antibodies and subsequent risks,” he noted.

For therapeutic drug monitoring in patients with a secondary loss of response, “first, look at the trough concentration,” Dr. Vande Casteele said. “If it is optimal, then ADAbs are probably inconsequential.” If the trough is low or undetectable, examine ADAbs, he added. To manage ADAbs, data support the use of drug dose escalation in some cases. However, “you may be able to overcome the antidrug antibodies in some patients with dose escalation, but this is not always a cost-effective strategy in the long term,” and some patients fail a drug despite adequate drug concentration, which may mean they are failing the mechanism, and not because of pharmacokinetic-related issues, he said.

Dr. Vande Casteele cited a post hoc analysis of the TAXIT trial, published in Gastroenterology. It was the first prospective study to look at proactive therapeutic drug monitoring in patients with inflammatory bowel diseases treated with maintenance infliximab. This post hoc analysis showed that ADAbs were overcome with dose escalation in nearly 50% of patients in the lowest two ADAb quartiles at the start of the trial, and although ADAb were masked by dose escalation in the highest two quartiles, measurement with a drug-sensitive assay showed that ADAb never disappeared, he said.

Another strategy to try to overcome immunogenicity is to add an immunomodulator, Dr. Vande Casteele said. He cited a recent study published in Rheumatology showing that the effect of methotrexate was mediated through immunogenicity for immunogenic compounds such as adalimumab.

Importantly, there is a risk for immunogenicity across agents, he noted. “Patients who are antibody positive to the prior anti-TNF are at a higher risk of developing antibodies to subsequent anti-TNFs.”

Dr. Vande Casteele reported receiving research grants from R-Biopharm; grants and personal fees from Takeda and UCB; and personal fees from Alimentiv (formerly Robarts Clinical Trials), Celltrion, and Prometheus. Global Academy for Medical Education and this news organization are owned by the same parent company.

Monitor antidrug antibodies for their impact on drug clearance to maximize treatment outcomes in rheumatology patients treated with biologics, Niels Vande Casteele, PharmD, PhD, said in a virtual presentation at the annual Perspectives in Rheumatic Diseases held by Global Academy for Medical Education.

Antidrug antibodies (ADAb) are associated with impaired drug efficacy and safety, he noted. Furthermore, he indicated that when ADAb bind to the drug, they can either block the activity of the drug directly and/or may cause the formation of complexes, leading to accelerated drug clearance and reduced drug exposure.

Dr. Vande Casteele, assistant professor in the department of medicine at the University of California, San Diego, outlined factors that contribute to immunogenicity, which occurs when the body reacts to neoantigens, or when there is a breakdown in immune tolerance, he said.

Genetics can play a key role in the risk for immunogenicity, as can the route of administration, dose, treatment duration, and concomitant diseases or medications, he explained.

In addition, product-related factors including sequence variation, glycosylation, host cells, contaminants and processing impurities, formulation, and handling and storage issues can impact immunogenicity, he noted.

For example, Dr. Vande Casteele cited a study in which the proportion of infliximab-treated patients with positive ADAbs was substantially higher among those receiving the drug intravenously, compared with those receiving it subcutaneously. As for treatment dosing, data on patients treated with infliximab have shown that maintenance therapy is associated with lower rates of immunogenicity, compared to episodic therapy, he said.

In terms of genetics, Dr. Vande Casteele cited a study published in January in Gastroenterology showing the presence of the HLA-DQA1*05 allele, carried by approximately 40% of the European population, significantly increased the rate of immunogenicity to infliximab and adalimumab in patients with Crohn’s disease (hazard ratio, 1.90).
 

Therapeutic drug monitoring and overcoming immunogenicity

Dr. Vande Casteele also reviewed how to measure ADAbs. “Antidrug antibody units and concentrations can differ across assays,” he said.

In clinical practice, “the majority of patients at the time of secondary loss of response will present with low drug exposure, and that is when you measure antidrug antibodies,” he said.

In rheumatology patients, the presence of ADAbs against anti–tumor necrosis factor monoclonal antibodies conveys a risk for treatment discontinuation, as well as “a risk of development of hypersensitivity reactions in all immune-mediated inflammatory diseases,” Dr. Vande Casteele said.

However, “the combined use of anti–tumor necrosis factor monoclonal antibodies and disease-modifying antirheumatic drugs reduces the development of antibodies and subsequent risks,” he noted.

For therapeutic drug monitoring in patients with a secondary loss of response, “first, look at the trough concentration,” Dr. Vande Casteele said. “If it is optimal, then ADAbs are probably inconsequential.” If the trough is low or undetectable, examine ADAbs, he added. To manage ADAbs, data support the use of drug dose escalation in some cases. However, “you may be able to overcome the antidrug antibodies in some patients with dose escalation, but this is not always a cost-effective strategy in the long term,” and some patients fail a drug despite adequate drug concentration, which may mean they are failing the mechanism, and not because of pharmacokinetic-related issues, he said.

Dr. Vande Casteele cited a post hoc analysis of the TAXIT trial, published in Gastroenterology. It was the first prospective study to look at proactive therapeutic drug monitoring in patients with inflammatory bowel diseases treated with maintenance infliximab. This post hoc analysis showed that ADAbs were overcome with dose escalation in nearly 50% of patients in the lowest two ADAb quartiles at the start of the trial, and although ADAb were masked by dose escalation in the highest two quartiles, measurement with a drug-sensitive assay showed that ADAb never disappeared, he said.

Another strategy to try to overcome immunogenicity is to add an immunomodulator, Dr. Vande Casteele said. He cited a recent study published in Rheumatology showing that the effect of methotrexate was mediated through immunogenicity for immunogenic compounds such as adalimumab.

Importantly, there is a risk for immunogenicity across agents, he noted. “Patients who are antibody positive to the prior anti-TNF are at a higher risk of developing antibodies to subsequent anti-TNFs.”

Dr. Vande Casteele reported receiving research grants from R-Biopharm; grants and personal fees from Takeda and UCB; and personal fees from Alimentiv (formerly Robarts Clinical Trials), Celltrion, and Prometheus. Global Academy for Medical Education and this news organization are owned by the same parent company.