Conference Coverage

LAS VEGAS – Is the relationship between major depressive disorder and the development of cancer, cardiovascular disease, and other medical conditions a coincidence, or is there more at play?

According to Charles B. Nemeroff, MD, PhD, a host of circumstances potentially underlies this association, including treatment of the medical disorder itself.

Courtesy University of Texas, Austin

“The best example of that is probably the use of interferon-alpha for the treatment of malignant melanoma,” Dr. Nemeroff, professor and chair of the department of psychiatry and behavioral sciences at the University of Texas at Austin, said during an annual psychopharmacology update held by the Nevada Psychiatric Association. “Many patients treated with interferon-alpha ended up with very severe depression, including several documented suicides. Another possibility of the relationship between depression and medical disorders is that treating a patient for depression could result in a medical disorder. The best example of this is the use of 20 mg of olanzapine to augment the effects of an antidepressant, resulting in a 50-pound weight gain and the development of type 2 diabetes and metabolic syndrome. Both of those scenarios are well understood.”

Then there’s the behavioral aspects of the relationship, he continued, in which patients adopt the mindset that “I’m depressed. I don’t want to exercise. I’m a couch potato. I have been gaining a lot of weight. It’s bad for my heart.”

Converging biology is another possibility. “Is it possible that the biology of depression is linked to the biology of other disorders?” asked Dr. Nemeroff, who directs the university’s Institute for Early Life Adversity Research. “We can talk about this in relation to thyroid disease, a well known cause of depression, but we can also talk about the relationship to other disorders. There’s amazing epidemiologic evidence that patients with PTSD are much more likely to develop Alzheimer’s disease than patients without PTSD.”

Psychosocial issues also play a role. He recalled seeing patient in a clinic for the underserved who had underlying severe ulcerative colitis and anemia and couldn’t afford medical treatment. “The patient had a low hemoglobin, so it was impossible to distinguish between that and whether they had a primary depressive disorder or not,” he said.

In a study that explored the relationship between major depression and cancer, Dr. Nemeroff and colleagues found that the prevalence was highest in those with pancreatic cancer (50%), followed by oropharyngeal (40%), colon (13-25%), breast (18-25%), and gynecologic (23%), and Hodgkin’s lymphoma (17%) (Arch Gen Psychiatry 1995;52[2]:89-99). “Not all cancers have the same rate of depression,” he said. “One of the central questions is, not so much is the cancer patient depressed, but is depression a risk factor for developing cancer? The answer is a resounding yes. But what we don’t know is if you treat the depression aggressively, can you reduce that risk of either developing cancer or the progression of cancer?”

Dr. Nemeroff spotlighted several studies largely from the oncology literature, including a prospective survival analysis of 578 women with early-stage breast cancer (Lancet 1999;354:1331-6). After 5 years, 395 were alive and without relapse, 50 were alive with relapse, and 133 had died. The researchers found a significantly increased risk of death from all causes by 5 years in women with a high depression score (HR 3.59). There was a significantly increased risk of relapse or death at 5 years in women with high scores on helplessness and hopelessness measures.

In an analysis of the association between breast cancer and traumatic events, women who had severe stress or a traumatic event had lower rates of disease-free intervals (J Psychosomatic Res 2007;63:233-9). Another study by the same investigators found that a decrease in depression symptoms is associated with longer survival in patients with metastatic breast cancer (J Clin Oncol 2010;29:413-20). The median survival was 53.6 months for women with decreasing depression scores over 1 year and 25.1 months for women with increasing depression scores.

A more recent study of cervical cancer patients found that those exposed to psychological stress had an increased risk of cancer-specific mortality (HR 1.33) (Cancer Res 2019;79:3965-72). The association was mainly driven by distress experienced within 1 year before or after diagnosis (HR 1.30) but not afterward (HR 1.12). In addition, data from the large longitudinal Nurses’ Health Study II found that women with high PTSD symptoms had a twofold greater risk of ovarian cancer compared with women who had no trauma exposure (Cancer Res 2019;79:5113-20).

Authors of a separate study analyzed data from the Women’s Health Initiative to examine if depression precedes the development of a cancer diagnosis. They found that depression 3 years before a diagnosis of breast cancer was associated with all-cause mortality (HR 1.35) (Cancer 2017;123[16]:3107-15). Meanwhile, among women with late-stage breast cancer, newly developed depression at year 3 was significantly associated with all-cause mortality (HR 2.0) and breast cancer-specific mortality (HR 2.42). “That’s a pretty amazing finding,” Dr. Nemeroff said. “We have to think about depression as a systemic illness. What is depression doing that’s creating a fertile environment for cancer or worsening of cancer?”

He then discussed the risk of suicide in patients who are newly diagnosed with cancer. “No one ever talks about this, and I can’t get anybody to support research in this area,” he said. In one of the first studies on the topic, researchers conducted a case-control study of Medicare patients and determined risk of suicide among those with cancer was 2.3-fold higher compared with controls, even after adjustment for psychiatric illness and the risk of dying within a year (J Clin Oncol 2008;26[29]:4720-4). More recently, authors of a large population-based study in England found that the overall standardized mortality ratio for suicide was 1.20 (JAMA Psychiatry 2019;76[1]51-60). The risk was highest among patients with mesothelioma, with a 4.51-fold risk, followed by pancreatic (3.89-fold), esophageal (2.65-fold), lung (2.57-fold), and stomach cancer (2.20-fold). “They reported that the first 6 months after the diagnosis is associated with an increased risk of suicide – unrelated to prognosis,” Dr. Nemeroff said.

A separate analysis of SEER data from 1973-2014 and comprising more than 8.6 million cancer patients found that newly diagnosed cancer patients are 4.4 times more likely to die from suicide than patients in the same age group without cancer (Nat Commun 2019;10[1]:207). The highest risk was in lung cancer, followed by head and neck, testes, bladder, and Hodgkin’s lymphoma.

According to Dr. Nemeroff, the association between depression and the risk of certain forms of cancer or with a poor cancer prognosis “may have to do with immune function. Depression is associated with a change in inflammatory markers that very likely control the microenvironment of the tumor.” For example, he said, if the depressed environment is associated with a marked increase in tumor necrosis factor, interleukin 6, and other inflammatory markers, “that probably contributes to the body’s ability to fight disease. Ironically, depression is associated with an increase in inflammation but a decreased in T cell function. Remember, there are two fundamental types of immunity: the antibody response and the cellular response. What’s odd about depression is that there’s an increase in inflammatory markers but a decrease in the ability of T cells to function in terms of cellular immunity.”

Dr. Nemeroff disclosed that he has served as a consultant and/or scientific adviser for numerous pharmaceutical companies. He has received research and grant support from the National Institutes of Health.

LAS VEGAS – Is the relationship between major depressive disorder and the development of cancer, cardiovascular disease, and other medical conditions a coincidence, or is there more at play?

According to Charles B. Nemeroff, MD, PhD, a host of circumstances potentially underlies this association, including treatment of the medical disorder itself.

Courtesy University of Texas, Austin

“The best example of that is probably the use of interferon-alpha for the treatment of malignant melanoma,” Dr. Nemeroff, professor and chair of the department of psychiatry and behavioral sciences at the University of Texas at Austin, said during an annual psychopharmacology update held by the Nevada Psychiatric Association. “Many patients treated with interferon-alpha ended up with very severe depression, including several documented suicides. Another possibility of the relationship between depression and medical disorders is that treating a patient for depression could result in a medical disorder. The best example of this is the use of 20 mg of olanzapine to augment the effects of an antidepressant, resulting in a 50-pound weight gain and the development of type 2 diabetes and metabolic syndrome. Both of those scenarios are well understood.”

Then there’s the behavioral aspects of the relationship, he continued, in which patients adopt the mindset that “I’m depressed. I don’t want to exercise. I’m a couch potato. I have been gaining a lot of weight. It’s bad for my heart.”

Converging biology is another possibility. “Is it possible that the biology of depression is linked to the biology of other disorders?” asked Dr. Nemeroff, who directs the university’s Institute for Early Life Adversity Research. “We can talk about this in relation to thyroid disease, a well known cause of depression, but we can also talk about the relationship to other disorders. There’s amazing epidemiologic evidence that patients with PTSD are much more likely to develop Alzheimer’s disease than patients without PTSD.”

Psychosocial issues also play a role. He recalled seeing patient in a clinic for the underserved who had underlying severe ulcerative colitis and anemia and couldn’t afford medical treatment. “The patient had a low hemoglobin, so it was impossible to distinguish between that and whether they had a primary depressive disorder or not,” he said.

In a study that explored the relationship between major depression and cancer, Dr. Nemeroff and colleagues found that the prevalence was highest in those with pancreatic cancer (50%), followed by oropharyngeal (40%), colon (13-25%), breast (18-25%), and gynecologic (23%), and Hodgkin’s lymphoma (17%) (Arch Gen Psychiatry 1995;52[2]:89-99). “Not all cancers have the same rate of depression,” he said. “One of the central questions is, not so much is the cancer patient depressed, but is depression a risk factor for developing cancer? The answer is a resounding yes. But what we don’t know is if you treat the depression aggressively, can you reduce that risk of either developing cancer or the progression of cancer?”

Dr. Nemeroff spotlighted several studies largely from the oncology literature, including a prospective survival analysis of 578 women with early-stage breast cancer (Lancet 1999;354:1331-6). After 5 years, 395 were alive and without relapse, 50 were alive with relapse, and 133 had died. The researchers found a significantly increased risk of death from all causes by 5 years in women with a high depression score (HR 3.59). There was a significantly increased risk of relapse or death at 5 years in women with high scores on helplessness and hopelessness measures.

In an analysis of the association between breast cancer and traumatic events, women who had severe stress or a traumatic event had lower rates of disease-free intervals (J Psychosomatic Res 2007;63:233-9). Another study by the same investigators found that a decrease in depression symptoms is associated with longer survival in patients with metastatic breast cancer (J Clin Oncol 2010;29:413-20). The median survival was 53.6 months for women with decreasing depression scores over 1 year and 25.1 months for women with increasing depression scores.

A more recent study of cervical cancer patients found that those exposed to psychological stress had an increased risk of cancer-specific mortality (HR 1.33) (Cancer Res 2019;79:3965-72). The association was mainly driven by distress experienced within 1 year before or after diagnosis (HR 1.30) but not afterward (HR 1.12). In addition, data from the large longitudinal Nurses’ Health Study II found that women with high PTSD symptoms had a twofold greater risk of ovarian cancer compared with women who had no trauma exposure (Cancer Res 2019;79:5113-20).

Authors of a separate study analyzed data from the Women’s Health Initiative to examine if depression precedes the development of a cancer diagnosis. They found that depression 3 years before a diagnosis of breast cancer was associated with all-cause mortality (HR 1.35) (Cancer 2017;123[16]:3107-15). Meanwhile, among women with late-stage breast cancer, newly developed depression at year 3 was significantly associated with all-cause mortality (HR 2.0) and breast cancer-specific mortality (HR 2.42). “That’s a pretty amazing finding,” Dr. Nemeroff said. “We have to think about depression as a systemic illness. What is depression doing that’s creating a fertile environment for cancer or worsening of cancer?”

He then discussed the risk of suicide in patients who are newly diagnosed with cancer. “No one ever talks about this, and I can’t get anybody to support research in this area,” he said. In one of the first studies on the topic, researchers conducted a case-control study of Medicare patients and determined risk of suicide among those with cancer was 2.3-fold higher compared with controls, even after adjustment for psychiatric illness and the risk of dying within a year (J Clin Oncol 2008;26[29]:4720-4). More recently, authors of a large population-based study in England found that the overall standardized mortality ratio for suicide was 1.20 (JAMA Psychiatry 2019;76[1]51-60). The risk was highest among patients with mesothelioma, with a 4.51-fold risk, followed by pancreatic (3.89-fold), esophageal (2.65-fold), lung (2.57-fold), and stomach cancer (2.20-fold). “They reported that the first 6 months after the diagnosis is associated with an increased risk of suicide – unrelated to prognosis,” Dr. Nemeroff said.

A separate analysis of SEER data from 1973-2014 and comprising more than 8.6 million cancer patients found that newly diagnosed cancer patients are 4.4 times more likely to die from suicide than patients in the same age group without cancer (Nat Commun 2019;10[1]:207). The highest risk was in lung cancer, followed by head and neck, testes, bladder, and Hodgkin’s lymphoma.

According to Dr. Nemeroff, the association between depression and the risk of certain forms of cancer or with a poor cancer prognosis “may have to do with immune function. Depression is associated with a change in inflammatory markers that very likely control the microenvironment of the tumor.” For example, he said, if the depressed environment is associated with a marked increase in tumor necrosis factor, interleukin 6, and other inflammatory markers, “that probably contributes to the body’s ability to fight disease. Ironically, depression is associated with an increase in inflammation but a decreased in T cell function. Remember, there are two fundamental types of immunity: the antibody response and the cellular response. What’s odd about depression is that there’s an increase in inflammatory markers but a decrease in the ability of T cells to function in terms of cellular immunity.”

Dr. Nemeroff disclosed that he has served as a consultant and/or scientific adviser for numerous pharmaceutical companies. He has received research and grant support from the National Institutes of Health.

LAS VEGAS – Is the relationship between major depressive disorder and the development of cancer, cardiovascular disease, and other medical conditions a coincidence, or is there more at play?

According to Charles B. Nemeroff, MD, PhD, a host of circumstances potentially underlies this association, including treatment of the medical disorder itself.

Courtesy University of Texas, Austin

“The best example of that is probably the use of interferon-alpha for the treatment of malignant melanoma,” Dr. Nemeroff, professor and chair of the department of psychiatry and behavioral sciences at the University of Texas at Austin, said during an annual psychopharmacology update held by the Nevada Psychiatric Association. “Many patients treated with interferon-alpha ended up with very severe depression, including several documented suicides. Another possibility of the relationship between depression and medical disorders is that treating a patient for depression could result in a medical disorder. The best example of this is the use of 20 mg of olanzapine to augment the effects of an antidepressant, resulting in a 50-pound weight gain and the development of type 2 diabetes and metabolic syndrome. Both of those scenarios are well understood.”

Then there’s the behavioral aspects of the relationship, he continued, in which patients adopt the mindset that “I’m depressed. I don’t want to exercise. I’m a couch potato. I have been gaining a lot of weight. It’s bad for my heart.”

Converging biology is another possibility. “Is it possible that the biology of depression is linked to the biology of other disorders?” asked Dr. Nemeroff, who directs the university’s Institute for Early Life Adversity Research. “We can talk about this in relation to thyroid disease, a well known cause of depression, but we can also talk about the relationship to other disorders. There’s amazing epidemiologic evidence that patients with PTSD are much more likely to develop Alzheimer’s disease than patients without PTSD.”

Psychosocial issues also play a role. He recalled seeing patient in a clinic for the underserved who had underlying severe ulcerative colitis and anemia and couldn’t afford medical treatment. “The patient had a low hemoglobin, so it was impossible to distinguish between that and whether they had a primary depressive disorder or not,” he said.

In a study that explored the relationship between major depression and cancer, Dr. Nemeroff and colleagues found that the prevalence was highest in those with pancreatic cancer (50%), followed by oropharyngeal (40%), colon (13-25%), breast (18-25%), and gynecologic (23%), and Hodgkin’s lymphoma (17%) (Arch Gen Psychiatry 1995;52[2]:89-99). “Not all cancers have the same rate of depression,” he said. “One of the central questions is, not so much is the cancer patient depressed, but is depression a risk factor for developing cancer? The answer is a resounding yes. But what we don’t know is if you treat the depression aggressively, can you reduce that risk of either developing cancer or the progression of cancer?”

Dr. Nemeroff spotlighted several studies largely from the oncology literature, including a prospective survival analysis of 578 women with early-stage breast cancer (Lancet 1999;354:1331-6). After 5 years, 395 were alive and without relapse, 50 were alive with relapse, and 133 had died. The researchers found a significantly increased risk of death from all causes by 5 years in women with a high depression score (HR 3.59). There was a significantly increased risk of relapse or death at 5 years in women with high scores on helplessness and hopelessness measures.

In an analysis of the association between breast cancer and traumatic events, women who had severe stress or a traumatic event had lower rates of disease-free intervals (J Psychosomatic Res 2007;63:233-9). Another study by the same investigators found that a decrease in depression symptoms is associated with longer survival in patients with metastatic breast cancer (J Clin Oncol 2010;29:413-20). The median survival was 53.6 months for women with decreasing depression scores over 1 year and 25.1 months for women with increasing depression scores.

A more recent study of cervical cancer patients found that those exposed to psychological stress had an increased risk of cancer-specific mortality (HR 1.33) (Cancer Res 2019;79:3965-72). The association was mainly driven by distress experienced within 1 year before or after diagnosis (HR 1.30) but not afterward (HR 1.12). In addition, data from the large longitudinal Nurses’ Health Study II found that women with high PTSD symptoms had a twofold greater risk of ovarian cancer compared with women who had no trauma exposure (Cancer Res 2019;79:5113-20).

Authors of a separate study analyzed data from the Women’s Health Initiative to examine if depression precedes the development of a cancer diagnosis. They found that depression 3 years before a diagnosis of breast cancer was associated with all-cause mortality (HR 1.35) (Cancer 2017;123[16]:3107-15). Meanwhile, among women with late-stage breast cancer, newly developed depression at year 3 was significantly associated with all-cause mortality (HR 2.0) and breast cancer-specific mortality (HR 2.42). “That’s a pretty amazing finding,” Dr. Nemeroff said. “We have to think about depression as a systemic illness. What is depression doing that’s creating a fertile environment for cancer or worsening of cancer?”

He then discussed the risk of suicide in patients who are newly diagnosed with cancer. “No one ever talks about this, and I can’t get anybody to support research in this area,” he said. In one of the first studies on the topic, researchers conducted a case-control study of Medicare patients and determined risk of suicide among those with cancer was 2.3-fold higher compared with controls, even after adjustment for psychiatric illness and the risk of dying within a year (J Clin Oncol 2008;26[29]:4720-4). More recently, authors of a large population-based study in England found that the overall standardized mortality ratio for suicide was 1.20 (JAMA Psychiatry 2019;76[1]51-60). The risk was highest among patients with mesothelioma, with a 4.51-fold risk, followed by pancreatic (3.89-fold), esophageal (2.65-fold), lung (2.57-fold), and stomach cancer (2.20-fold). “They reported that the first 6 months after the diagnosis is associated with an increased risk of suicide – unrelated to prognosis,” Dr. Nemeroff said.

A separate analysis of SEER data from 1973-2014 and comprising more than 8.6 million cancer patients found that newly diagnosed cancer patients are 4.4 times more likely to die from suicide than patients in the same age group without cancer (Nat Commun 2019;10[1]:207). The highest risk was in lung cancer, followed by head and neck, testes, bladder, and Hodgkin’s lymphoma.

According to Dr. Nemeroff, the association between depression and the risk of certain forms of cancer or with a poor cancer prognosis “may have to do with immune function. Depression is associated with a change in inflammatory markers that very likely control the microenvironment of the tumor.” For example, he said, if the depressed environment is associated with a marked increase in tumor necrosis factor, interleukin 6, and other inflammatory markers, “that probably contributes to the body’s ability to fight disease. Ironically, depression is associated with an increase in inflammation but a decreased in T cell function. Remember, there are two fundamental types of immunity: the antibody response and the cellular response. What’s odd about depression is that there’s an increase in inflammatory markers but a decrease in the ability of T cells to function in terms of cellular immunity.”

Dr. Nemeroff disclosed that he has served as a consultant and/or scientific adviser for numerous pharmaceutical companies. He has received research and grant support from the National Institutes of Health.

A new analysis of KEYNOTE-564 demonstrates that pembrolizumab continues to show consistent and clinically meaningful improvement in disease-free survival for patients at high risk of a renal cell carcinoma recurrence.

The updated analysis was presented at the American Society of Clinical Oncology Genitourinary Cancers Symposium.

The study, which was led by Toni K. Choueiri, MD, director of the Lank Center for Genitourinary Oncology at Dana-Farber Cancer Institute, Boston, found no increase in high-grade, or other, adverse events with 30 months of follow-up.

Pembrolizumab (Keytruda, Merck) is approved by the Food and Drug Administration in combination with axitinib, as a first-line treatment for patients with advanced renal cell carcinoma (RCC). The combination is also recommended by the European Society for Medical Oncology for advanced RCC.

KEYNOTE-564 is a phase 3, double-blind, multicenter trial of pembrolizumab versus placebo after surgery in participants with renal cell carcinoma. In previously presented interim KEYNOTE-564 results, the primary endpoint of disease-free survival for adjuvant pembrolizumab versus placebo was met in the intent-to-treat population (hazard ratio, 0.68; 95% confidence interval, 0.53-0.87; P = .001).

KEYNOTE-564 includes 994 patients (mean age, 60 years; 71% male) with confirmed clear cell RCC who were either intermediate to high risk, high risk, or M1 with no evidence of disease after surgery. All patients had surgery 12 or fewer weeks prior to randomization.

At 30.1 months, the disease-free survival difference in the intent-to-treat population between pembrolizumab and placebo at 78.3% versus 67.3% had a HR of 0.63 (95% CI, 0.50-0.80; nominal P < .0001), greater than the 77.3% versus 68.1% difference at 24.1 months (hazard ratio, 0.68, 95% CI, 0.53-0.87; P = .001).

Analysis of disease-free survival by recurrence risk subgroups showed an increasing benefit with increasing risk. In the intermediate- to high-risk group, the 24-month rates were 81.1% and 72.0% for pembrolizumab and placebo, respectively (HR, 0.68; 95% CI, 0.52-0.89). In the high-risk group, the 24-month rates were 48.7% and 35.4%, respectively (HR, 0.60; 95% CI, 0.33-1.10). In the M1 NED group, the rates were 78.4% and 37.9% for pembrolizumab and placebo, respectively (HR, 0.28; 95% CI, 0.12-0.66).

During a discussion about the presentation, Daniel M Geynisman, MD, of Fox Chase Cancer Center, Philadelphia, pointed to the respective absolute differences between pembrolizumab and placebo of 9% in the intermediate- to high-risk group, 13% in the high-risk group, and a “whopping difference of 41% in the M1 NED group,” but underscored that the M1 NED population represents only a small part of the trial population (5.8%). The same relationship was evident among sarcomatoid status subgroups, with 24-month absolute differences of 10.1% favoring pembrolizumab (HR, 0.63) with sarcomatoid features absent and 19.8% (HR, 0.54) when they were present.

Overall survival estimates showed an increasing benefit for pembrolizumab versus placebo (96.6% vs. 93.5%; HR, 0.54) at 24.1 months (96.2% vs. 93.8%, HR, 0.52), but this wasn’t statistically significance because the data collection was incomplete.

Between 24.1 months and 30.1 months, rates of treatment-related adverse events remained the same at 79.1% for pembrolizumab and 53.4% for placebo, with a treatment-related discontinuations in the pembrolizumab group at 17.6% and 18.6% at 24.1 and 30.1 months, respectively.

The study was funded by Merck Sharp & Dohme.

A new analysis of KEYNOTE-564 demonstrates that pembrolizumab continues to show consistent and clinically meaningful improvement in disease-free survival for patients at high risk of a renal cell carcinoma recurrence.

The updated analysis was presented at the American Society of Clinical Oncology Genitourinary Cancers Symposium.

The study, which was led by Toni K. Choueiri, MD, director of the Lank Center for Genitourinary Oncology at Dana-Farber Cancer Institute, Boston, found no increase in high-grade, or other, adverse events with 30 months of follow-up.

Pembrolizumab (Keytruda, Merck) is approved by the Food and Drug Administration in combination with axitinib, as a first-line treatment for patients with advanced renal cell carcinoma (RCC). The combination is also recommended by the European Society for Medical Oncology for advanced RCC.

KEYNOTE-564 is a phase 3, double-blind, multicenter trial of pembrolizumab versus placebo after surgery in participants with renal cell carcinoma. In previously presented interim KEYNOTE-564 results, the primary endpoint of disease-free survival for adjuvant pembrolizumab versus placebo was met in the intent-to-treat population (hazard ratio, 0.68; 95% confidence interval, 0.53-0.87; P = .001).

KEYNOTE-564 includes 994 patients (mean age, 60 years; 71% male) with confirmed clear cell RCC who were either intermediate to high risk, high risk, or M1 with no evidence of disease after surgery. All patients had surgery 12 or fewer weeks prior to randomization.

At 30.1 months, the disease-free survival difference in the intent-to-treat population between pembrolizumab and placebo at 78.3% versus 67.3% had a HR of 0.63 (95% CI, 0.50-0.80; nominal P < .0001), greater than the 77.3% versus 68.1% difference at 24.1 months (hazard ratio, 0.68, 95% CI, 0.53-0.87; P = .001).

Analysis of disease-free survival by recurrence risk subgroups showed an increasing benefit with increasing risk. In the intermediate- to high-risk group, the 24-month rates were 81.1% and 72.0% for pembrolizumab and placebo, respectively (HR, 0.68; 95% CI, 0.52-0.89). In the high-risk group, the 24-month rates were 48.7% and 35.4%, respectively (HR, 0.60; 95% CI, 0.33-1.10). In the M1 NED group, the rates were 78.4% and 37.9% for pembrolizumab and placebo, respectively (HR, 0.28; 95% CI, 0.12-0.66).

During a discussion about the presentation, Daniel M Geynisman, MD, of Fox Chase Cancer Center, Philadelphia, pointed to the respective absolute differences between pembrolizumab and placebo of 9% in the intermediate- to high-risk group, 13% in the high-risk group, and a “whopping difference of 41% in the M1 NED group,” but underscored that the M1 NED population represents only a small part of the trial population (5.8%). The same relationship was evident among sarcomatoid status subgroups, with 24-month absolute differences of 10.1% favoring pembrolizumab (HR, 0.63) with sarcomatoid features absent and 19.8% (HR, 0.54) when they were present.

Overall survival estimates showed an increasing benefit for pembrolizumab versus placebo (96.6% vs. 93.5%; HR, 0.54) at 24.1 months (96.2% vs. 93.8%, HR, 0.52), but this wasn’t statistically significance because the data collection was incomplete.

Between 24.1 months and 30.1 months, rates of treatment-related adverse events remained the same at 79.1% for pembrolizumab and 53.4% for placebo, with a treatment-related discontinuations in the pembrolizumab group at 17.6% and 18.6% at 24.1 and 30.1 months, respectively.

The study was funded by Merck Sharp & Dohme.

A new analysis of KEYNOTE-564 demonstrates that pembrolizumab continues to show consistent and clinically meaningful improvement in disease-free survival for patients at high risk of a renal cell carcinoma recurrence.

The updated analysis was presented at the American Society of Clinical Oncology Genitourinary Cancers Symposium.

The study, which was led by Toni K. Choueiri, MD, director of the Lank Center for Genitourinary Oncology at Dana-Farber Cancer Institute, Boston, found no increase in high-grade, or other, adverse events with 30 months of follow-up.

Pembrolizumab (Keytruda, Merck) is approved by the Food and Drug Administration in combination with axitinib, as a first-line treatment for patients with advanced renal cell carcinoma (RCC). The combination is also recommended by the European Society for Medical Oncology for advanced RCC.

KEYNOTE-564 is a phase 3, double-blind, multicenter trial of pembrolizumab versus placebo after surgery in participants with renal cell carcinoma. In previously presented interim KEYNOTE-564 results, the primary endpoint of disease-free survival for adjuvant pembrolizumab versus placebo was met in the intent-to-treat population (hazard ratio, 0.68; 95% confidence interval, 0.53-0.87; P = .001).

KEYNOTE-564 includes 994 patients (mean age, 60 years; 71% male) with confirmed clear cell RCC who were either intermediate to high risk, high risk, or M1 with no evidence of disease after surgery. All patients had surgery 12 or fewer weeks prior to randomization.

At 30.1 months, the disease-free survival difference in the intent-to-treat population between pembrolizumab and placebo at 78.3% versus 67.3% had a HR of 0.63 (95% CI, 0.50-0.80; nominal P < .0001), greater than the 77.3% versus 68.1% difference at 24.1 months (hazard ratio, 0.68, 95% CI, 0.53-0.87; P = .001).

Analysis of disease-free survival by recurrence risk subgroups showed an increasing benefit with increasing risk. In the intermediate- to high-risk group, the 24-month rates were 81.1% and 72.0% for pembrolizumab and placebo, respectively (HR, 0.68; 95% CI, 0.52-0.89). In the high-risk group, the 24-month rates were 48.7% and 35.4%, respectively (HR, 0.60; 95% CI, 0.33-1.10). In the M1 NED group, the rates were 78.4% and 37.9% for pembrolizumab and placebo, respectively (HR, 0.28; 95% CI, 0.12-0.66).

During a discussion about the presentation, Daniel M Geynisman, MD, of Fox Chase Cancer Center, Philadelphia, pointed to the respective absolute differences between pembrolizumab and placebo of 9% in the intermediate- to high-risk group, 13% in the high-risk group, and a “whopping difference of 41% in the M1 NED group,” but underscored that the M1 NED population represents only a small part of the trial population (5.8%). The same relationship was evident among sarcomatoid status subgroups, with 24-month absolute differences of 10.1% favoring pembrolizumab (HR, 0.63) with sarcomatoid features absent and 19.8% (HR, 0.54) when they were present.

Overall survival estimates showed an increasing benefit for pembrolizumab versus placebo (96.6% vs. 93.5%; HR, 0.54) at 24.1 months (96.2% vs. 93.8%, HR, 0.52), but this wasn’t statistically significance because the data collection was incomplete.

Between 24.1 months and 30.1 months, rates of treatment-related adverse events remained the same at 79.1% for pembrolizumab and 53.4% for placebo, with a treatment-related discontinuations in the pembrolizumab group at 17.6% and 18.6% at 24.1 and 30.1 months, respectively.

The study was funded by Merck Sharp & Dohme.

Multiple sclerosis (MS) remains a challenging disease to diagnose, but recent advances in magnetic resonance imaging (MRI) have the potential to improve both the sensitivity and specificity of diagnosis. One method involves use of MRI to detect central vein sign (CVS) in MRI images. The CVS is a hypointense vessel at the center of a hyperintense focal lesion, and various retrospective analyses have revealed an association between a greater percentage of lesions being CVS and a diagnosis of MS.

“This is a very frequent finding in MS patients, but it’s a very infrequent finding in non-MS patients, specifically radiological mimics or clinical mimics that are typically confused with MS at the time of clinical diagnosis, and could lead to misdiagnosis. The idea here of a central vein sign is to use it diagnostically as early as possible in the evaluation of the MS, and use it as complementary to the existing McDonald criteria to improve sensitivity and specificity,” Pascal Sati, PhD, said in an interview. Dr. Sati presented an overview of the topic at the annual meeting held by the Americas Committee for Treatment and Research in Multiple Sclerosis (ACTRIMS). He is associate professor of neurology at Cedars Sinai Medical Center in Los Angeles and the director of the neuroimaging program in the department of neurology at Cedars Sinai.

The findings could address an important issue in MS. “Misdiagnosis is a big problem in multiple sclerosis, and it has been for a long time. There are recent surveys of physicians that show that something like 95% of MS physicians have seen a case of misdiagnosis in the last year,” Kevin Patel, MD, said in an interview. Dr. Patel is assistant professor of neurology at the University of California, Los Angeles, and moderated the session where Dr. Sati presented.
 

What is the diagnostic threshold of CVS positivity?

A key question is what percentage of lesions should be CVS positive (CVS+) to predict a diagnosis of MS. One meta-analysis found that an average of 73% CVS positivity in MS patients, but levels below 40% in conditions that can mimic MS, such as migraine (22%), cerebral small vessel disease (28.5%), and neuromyelitis optica spectrum disorder (33.5%). However, both biological and technical effects can influence that percentage. The percentage is lower among older patients with MS, and those with vascular comorbidities, likely due to noninflammatory or ischemic plaques, or other lesion types, said Dr. Sati.

On the technical side, lower field strengths tend to reveal a lower proportion of CVS than higher field strengths, which are more sensitive. However, the choice of MRI technique can influence sensitivity, and the optimized T2* EPI and FLAIR* techniques have been shown to reveal higher percentages of CVS, even at lower field strengths like the commonly available 3-T.

Forty percent CVS positivity has been suggested as a diagnostic for MS, but this can be time consuming to determine in patients with large numbers of lesions. An alternative is to analyze a subset of lesions and make a diagnosis if these lesions display the CVS. For example, ‘Select 3*’ would establish an MS diagnosis if at least 3 brain lesions have the CVS, or the ‘6-lesion rule’ would establish an MS diagnosis if at least 6 out 10 brain lesions have the CVS. Recent retrospective studies have supported these simplified diagnostic criteria, suggesting that these approaches perform similarly to the 40% rule.
 

What will change clinical practice?

However, retrospective studies aren’t enough to change international diagnostic guidelines and clinical practice. Dr. Sati is part of a group of investigators from the North American Imaging in MS (NAIMS) Cooperative that is conducting a large prospective diagnostic study (CAVS-MS) with a $7.2 million grant from the National Institutes of Health, which is currently recruiting 400 patients being evaluated for MS. The MRI protocol will use the optimized T2* EPI/FLAIR* techniques developed by Dr. Sati on 3-T scanners. “It’s a twofold goal: First the evaluation of the diagnostic power of the central vein sign in a real-world cohort, and then the validation of the advanced MRI technology that we’re developing to image the central vein sign clinically,” said Dr. Sati.

Neurologists generally are becoming more aware of these techniques, according to Dr. Patel, but they aren’t yet widely used outside of research settings.

“We haven’t collected enough evidence to really warrant wide implementation. I suspect that that’s one of the major reasons why it is that we don’t see this deployed more widely. I think there’ll be a bit of time before this is integrated to the standard sequences that are done for evaluation of multiple sclerosis,” said Dr. Patel.

The technique must contend with comorbid factors, especially vascular comorbidities such as hypertension, diabetes, or high cholesterol, that can cause white matter hyperintensities as individuals age. “This can create difficulties with using this procedure, because if you have small vessel disease at the same time you have MS, you have much more T2 lesion volume. It becomes a little bit more difficult to suss out whether the person has MS. So there’s a little bit of work that needs to be done along those lines as well,” said Dr. Patel.

With more research, the technology has the potential to improve MS diagnosis, both among community neurologists and even among specialists, according to Dr. Patel. “There are definitely cases that are rather ambiguous that even though they present at a major academic center, it’s sometimes very difficult for us to determine as to whether the person has multiple sclerosis or not. And this sort of technique can potentially help us in distinguishing those cases. Sometimes even after they see folks at tertiary centers, folks still don’t have a definitive diagnosis,” said Dr. Patel.

Dr. Sati and Dr. Patel have no relevant financial disclosures.

Multiple sclerosis (MS) remains a challenging disease to diagnose, but recent advances in magnetic resonance imaging (MRI) have the potential to improve both the sensitivity and specificity of diagnosis. One method involves use of MRI to detect central vein sign (CVS) in MRI images. The CVS is a hypointense vessel at the center of a hyperintense focal lesion, and various retrospective analyses have revealed an association between a greater percentage of lesions being CVS and a diagnosis of MS.

“This is a very frequent finding in MS patients, but it’s a very infrequent finding in non-MS patients, specifically radiological mimics or clinical mimics that are typically confused with MS at the time of clinical diagnosis, and could lead to misdiagnosis. The idea here of a central vein sign is to use it diagnostically as early as possible in the evaluation of the MS, and use it as complementary to the existing McDonald criteria to improve sensitivity and specificity,” Pascal Sati, PhD, said in an interview. Dr. Sati presented an overview of the topic at the annual meeting held by the Americas Committee for Treatment and Research in Multiple Sclerosis (ACTRIMS). He is associate professor of neurology at Cedars Sinai Medical Center in Los Angeles and the director of the neuroimaging program in the department of neurology at Cedars Sinai.

The findings could address an important issue in MS. “Misdiagnosis is a big problem in multiple sclerosis, and it has been for a long time. There are recent surveys of physicians that show that something like 95% of MS physicians have seen a case of misdiagnosis in the last year,” Kevin Patel, MD, said in an interview. Dr. Patel is assistant professor of neurology at the University of California, Los Angeles, and moderated the session where Dr. Sati presented.
 

What is the diagnostic threshold of CVS positivity?

A key question is what percentage of lesions should be CVS positive (CVS+) to predict a diagnosis of MS. One meta-analysis found that an average of 73% CVS positivity in MS patients, but levels below 40% in conditions that can mimic MS, such as migraine (22%), cerebral small vessel disease (28.5%), and neuromyelitis optica spectrum disorder (33.5%). However, both biological and technical effects can influence that percentage. The percentage is lower among older patients with MS, and those with vascular comorbidities, likely due to noninflammatory or ischemic plaques, or other lesion types, said Dr. Sati.

On the technical side, lower field strengths tend to reveal a lower proportion of CVS than higher field strengths, which are more sensitive. However, the choice of MRI technique can influence sensitivity, and the optimized T2* EPI and FLAIR* techniques have been shown to reveal higher percentages of CVS, even at lower field strengths like the commonly available 3-T.

Forty percent CVS positivity has been suggested as a diagnostic for MS, but this can be time consuming to determine in patients with large numbers of lesions. An alternative is to analyze a subset of lesions and make a diagnosis if these lesions display the CVS. For example, ‘Select 3*’ would establish an MS diagnosis if at least 3 brain lesions have the CVS, or the ‘6-lesion rule’ would establish an MS diagnosis if at least 6 out 10 brain lesions have the CVS. Recent retrospective studies have supported these simplified diagnostic criteria, suggesting that these approaches perform similarly to the 40% rule.
 

What will change clinical practice?

However, retrospective studies aren’t enough to change international diagnostic guidelines and clinical practice. Dr. Sati is part of a group of investigators from the North American Imaging in MS (NAIMS) Cooperative that is conducting a large prospective diagnostic study (CAVS-MS) with a $7.2 million grant from the National Institutes of Health, which is currently recruiting 400 patients being evaluated for MS. The MRI protocol will use the optimized T2* EPI/FLAIR* techniques developed by Dr. Sati on 3-T scanners. “It’s a twofold goal: First the evaluation of the diagnostic power of the central vein sign in a real-world cohort, and then the validation of the advanced MRI technology that we’re developing to image the central vein sign clinically,” said Dr. Sati.

Neurologists generally are becoming more aware of these techniques, according to Dr. Patel, but they aren’t yet widely used outside of research settings.

“We haven’t collected enough evidence to really warrant wide implementation. I suspect that that’s one of the major reasons why it is that we don’t see this deployed more widely. I think there’ll be a bit of time before this is integrated to the standard sequences that are done for evaluation of multiple sclerosis,” said Dr. Patel.

The technique must contend with comorbid factors, especially vascular comorbidities such as hypertension, diabetes, or high cholesterol, that can cause white matter hyperintensities as individuals age. “This can create difficulties with using this procedure, because if you have small vessel disease at the same time you have MS, you have much more T2 lesion volume. It becomes a little bit more difficult to suss out whether the person has MS. So there’s a little bit of work that needs to be done along those lines as well,” said Dr. Patel.

With more research, the technology has the potential to improve MS diagnosis, both among community neurologists and even among specialists, according to Dr. Patel. “There are definitely cases that are rather ambiguous that even though they present at a major academic center, it’s sometimes very difficult for us to determine as to whether the person has multiple sclerosis or not. And this sort of technique can potentially help us in distinguishing those cases. Sometimes even after they see folks at tertiary centers, folks still don’t have a definitive diagnosis,” said Dr. Patel.

Dr. Sati and Dr. Patel have no relevant financial disclosures.

Multiple sclerosis (MS) remains a challenging disease to diagnose, but recent advances in magnetic resonance imaging (MRI) have the potential to improve both the sensitivity and specificity of diagnosis. One method involves use of MRI to detect central vein sign (CVS) in MRI images. The CVS is a hypointense vessel at the center of a hyperintense focal lesion, and various retrospective analyses have revealed an association between a greater percentage of lesions being CVS and a diagnosis of MS.

“This is a very frequent finding in MS patients, but it’s a very infrequent finding in non-MS patients, specifically radiological mimics or clinical mimics that are typically confused with MS at the time of clinical diagnosis, and could lead to misdiagnosis. The idea here of a central vein sign is to use it diagnostically as early as possible in the evaluation of the MS, and use it as complementary to the existing McDonald criteria to improve sensitivity and specificity,” Pascal Sati, PhD, said in an interview. Dr. Sati presented an overview of the topic at the annual meeting held by the Americas Committee for Treatment and Research in Multiple Sclerosis (ACTRIMS). He is associate professor of neurology at Cedars Sinai Medical Center in Los Angeles and the director of the neuroimaging program in the department of neurology at Cedars Sinai.

The findings could address an important issue in MS. “Misdiagnosis is a big problem in multiple sclerosis, and it has been for a long time. There are recent surveys of physicians that show that something like 95% of MS physicians have seen a case of misdiagnosis in the last year,” Kevin Patel, MD, said in an interview. Dr. Patel is assistant professor of neurology at the University of California, Los Angeles, and moderated the session where Dr. Sati presented.
 

What is the diagnostic threshold of CVS positivity?

A key question is what percentage of lesions should be CVS positive (CVS+) to predict a diagnosis of MS. One meta-analysis found that an average of 73% CVS positivity in MS patients, but levels below 40% in conditions that can mimic MS, such as migraine (22%), cerebral small vessel disease (28.5%), and neuromyelitis optica spectrum disorder (33.5%). However, both biological and technical effects can influence that percentage. The percentage is lower among older patients with MS, and those with vascular comorbidities, likely due to noninflammatory or ischemic plaques, or other lesion types, said Dr. Sati.

On the technical side, lower field strengths tend to reveal a lower proportion of CVS than higher field strengths, which are more sensitive. However, the choice of MRI technique can influence sensitivity, and the optimized T2* EPI and FLAIR* techniques have been shown to reveal higher percentages of CVS, even at lower field strengths like the commonly available 3-T.

Forty percent CVS positivity has been suggested as a diagnostic for MS, but this can be time consuming to determine in patients with large numbers of lesions. An alternative is to analyze a subset of lesions and make a diagnosis if these lesions display the CVS. For example, ‘Select 3*’ would establish an MS diagnosis if at least 3 brain lesions have the CVS, or the ‘6-lesion rule’ would establish an MS diagnosis if at least 6 out 10 brain lesions have the CVS. Recent retrospective studies have supported these simplified diagnostic criteria, suggesting that these approaches perform similarly to the 40% rule.
 

What will change clinical practice?

However, retrospective studies aren’t enough to change international diagnostic guidelines and clinical practice. Dr. Sati is part of a group of investigators from the North American Imaging in MS (NAIMS) Cooperative that is conducting a large prospective diagnostic study (CAVS-MS) with a $7.2 million grant from the National Institutes of Health, which is currently recruiting 400 patients being evaluated for MS. The MRI protocol will use the optimized T2* EPI/FLAIR* techniques developed by Dr. Sati on 3-T scanners. “It’s a twofold goal: First the evaluation of the diagnostic power of the central vein sign in a real-world cohort, and then the validation of the advanced MRI technology that we’re developing to image the central vein sign clinically,” said Dr. Sati.

Neurologists generally are becoming more aware of these techniques, according to Dr. Patel, but they aren’t yet widely used outside of research settings.

“We haven’t collected enough evidence to really warrant wide implementation. I suspect that that’s one of the major reasons why it is that we don’t see this deployed more widely. I think there’ll be a bit of time before this is integrated to the standard sequences that are done for evaluation of multiple sclerosis,” said Dr. Patel.

The technique must contend with comorbid factors, especially vascular comorbidities such as hypertension, diabetes, or high cholesterol, that can cause white matter hyperintensities as individuals age. “This can create difficulties with using this procedure, because if you have small vessel disease at the same time you have MS, you have much more T2 lesion volume. It becomes a little bit more difficult to suss out whether the person has MS. So there’s a little bit of work that needs to be done along those lines as well,” said Dr. Patel.

With more research, the technology has the potential to improve MS diagnosis, both among community neurologists and even among specialists, according to Dr. Patel. “There are definitely cases that are rather ambiguous that even though they present at a major academic center, it’s sometimes very difficult for us to determine as to whether the person has multiple sclerosis or not. And this sort of technique can potentially help us in distinguishing those cases. Sometimes even after they see folks at tertiary centers, folks still don’t have a definitive diagnosis,” said Dr. Patel.

Dr. Sati and Dr. Patel have no relevant financial disclosures.

A study of testicular cancer mortality finds worse outcomes among Hispanic men, but better outcomes among Black men.

The findings were reported at the American Society of Clinical Oncology Genitourinary Cancers Symposium.

Incidence rates for testicular cancer in the United States have increased slowly in recent decades, said Anushka Ghosh, a clinical research coordinatory with Massachusetts General Hospital, Boston. Her analysis found mortality increases from 1999 to 2019 to be significantly greater among Hispanic men. The increase was 0.0019 per 100,000, compared with a 0.0003 per 100,000 decrease among non-Hispanic men (comparison P = .010).

Among Black men, testicular cancer–specific mortality rates declined by 0.0007 per 100,000, compared with a marginally significant increase of 0.0006 per 100,000 among White men (P =.049).

“Given that testicular cancer generally has a favorable prognosis, it is concerning that the mortality rate for this disease is increasing,” said Sophia C. Kamran, MD, the study’s lead author and a radiation oncologist at Massachusetts General Hospital.

Dr. Kamran urged new efforts to understand these trends and to make testicular cancer care more accessible for all patients.

Ms. Ghosh said that other researchers have identified the same disparity among Hispanic men with prostate cancer. “Even though testicular cancer is a rare, our finding warrants further investigation to find the basis of these disparities to better serve the Hispanic community.”

Other studies have shown higher likelihood of later stage diagnosis and worse survival outcomes among Black patients.

No funding sources were reported for this study.

A study of testicular cancer mortality finds worse outcomes among Hispanic men, but better outcomes among Black men.

The findings were reported at the American Society of Clinical Oncology Genitourinary Cancers Symposium.

Incidence rates for testicular cancer in the United States have increased slowly in recent decades, said Anushka Ghosh, a clinical research coordinatory with Massachusetts General Hospital, Boston. Her analysis found mortality increases from 1999 to 2019 to be significantly greater among Hispanic men. The increase was 0.0019 per 100,000, compared with a 0.0003 per 100,000 decrease among non-Hispanic men (comparison P = .010).

Among Black men, testicular cancer–specific mortality rates declined by 0.0007 per 100,000, compared with a marginally significant increase of 0.0006 per 100,000 among White men (P =.049).

“Given that testicular cancer generally has a favorable prognosis, it is concerning that the mortality rate for this disease is increasing,” said Sophia C. Kamran, MD, the study’s lead author and a radiation oncologist at Massachusetts General Hospital.

Dr. Kamran urged new efforts to understand these trends and to make testicular cancer care more accessible for all patients.

Ms. Ghosh said that other researchers have identified the same disparity among Hispanic men with prostate cancer. “Even though testicular cancer is a rare, our finding warrants further investigation to find the basis of these disparities to better serve the Hispanic community.”

Other studies have shown higher likelihood of later stage diagnosis and worse survival outcomes among Black patients.

No funding sources were reported for this study.

A study of testicular cancer mortality finds worse outcomes among Hispanic men, but better outcomes among Black men.

The findings were reported at the American Society of Clinical Oncology Genitourinary Cancers Symposium.

Incidence rates for testicular cancer in the United States have increased slowly in recent decades, said Anushka Ghosh, a clinical research coordinatory with Massachusetts General Hospital, Boston. Her analysis found mortality increases from 1999 to 2019 to be significantly greater among Hispanic men. The increase was 0.0019 per 100,000, compared with a 0.0003 per 100,000 decrease among non-Hispanic men (comparison P = .010).

Among Black men, testicular cancer–specific mortality rates declined by 0.0007 per 100,000, compared with a marginally significant increase of 0.0006 per 100,000 among White men (P =.049).

“Given that testicular cancer generally has a favorable prognosis, it is concerning that the mortality rate for this disease is increasing,” said Sophia C. Kamran, MD, the study’s lead author and a radiation oncologist at Massachusetts General Hospital.

Dr. Kamran urged new efforts to understand these trends and to make testicular cancer care more accessible for all patients.

Ms. Ghosh said that other researchers have identified the same disparity among Hispanic men with prostate cancer. “Even though testicular cancer is a rare, our finding warrants further investigation to find the basis of these disparities to better serve the Hispanic community.”

Other studies have shown higher likelihood of later stage diagnosis and worse survival outcomes among Black patients.

No funding sources were reported for this study.

Sotorasib, an approved treatment for lung cancer, has demonstrated clinically meaningful anticancer activity and tolerability in patients with heavily pretreated KRASG12C-mutated advanced pancreatic cancer.

The findings were reported at the American Society of Clinical Oncology Genitourinary Cancers Symposium.

“This is clinically meaningful for patients because there is not an established standard therapy for these patients once they get to a third line of treatment,” said the study’s author John H Strickler, MD, of Duke University Medical Center, Durham, N.C.

The study, called CodeBreaK100, is an open-label global phase 1 and 2 trial. It consists of the largest dataset evaluating efficacy and safety of a KRASG12C inhibitor in patients with stage 4 pancreatic cancer.

Survival with Food and Drug Administration–approved second-line therapy in pancreatic ductal adenocarcinoma is 6 months with a 16% response rate. No therapies have demonstrated survival benefit after progression on first- and second-line chemotherapy. Among the 90% of pancreatic ductal adenocarcinoma tumors which harbor a KRAS mutation, 1%-2% are p.G12ac mutations. There are currently no approved treatments for KRASG12C-mutated PDAC.

The study included 38 patients (median age, 65.5 years; 76.3% male) with locally advanced or metastatic pancreatic malignancies who received oral sotorasib (960 mg once daily).

The patients in the trial received one or more prior systemic therapies (79% received two; range, one to eight) or were intolerant or ineligible for available therapies. The primary endpoint was complete plus partial response by blinded independent central review (RECIST 1.1).

Confirmed objective response were reported in 8 patients (21.1%; 95% confidence interval, 9.55%-37.22%) with disease control in 32 (84.2%; 95% CI, 68.75%-93.98%). The median duration of response was 5.7 months. After a median follow-up of 16.8 months, median progression-free survival was 4.0 months (95% CI, 2.8-5.6), and median overall survival was 6.9 months (95% CI, 5.0-9.1).

Once-daily sotorasib was well tolerated. The only treatment-related adverse events above grade 2 were six (15.8%) grade 3 events, with diarrhea in two and fatigue in two (each 5.3%), and single occurrences (2.6%) of abdominal pain, ALT/AST increase, pleural effusion and pulmonary embolism. Three adverse events were serious (7.9%), and no adverse events led to sotorasib discontinuation or were fatal.

Dr. Strickler described the case of a 64-year-old female with stage IV pancreatic cancer at diagnosis, who had baseline metastatic lesions in the liver, lymph nodes, lung and peritoneum. She received prior FOLFIRINOX first line until disease progression. With once-daily sotorasib, time to treatment response was 1.3 month, duration of response was 5.8 months, progression-free survival and overall were 7.1 months each.

Pointing to the centrally confirmed objective response rate of 21.1% and the disease control rate of 84.2%, Dr. Strickler observed in an interview that the CodeBreaK100 data support further exploration of sotorasib in this population with high unmet medical need and that based on these data, the CodeBreaK 100 clinical trial will be expanded to enroll more patients with pancreatic cancer and other tumor types.

The study was funded by Amgen.

Sotorasib, an approved treatment for lung cancer, has demonstrated clinically meaningful anticancer activity and tolerability in patients with heavily pretreated KRASG12C-mutated advanced pancreatic cancer.

The findings were reported at the American Society of Clinical Oncology Genitourinary Cancers Symposium.

“This is clinically meaningful for patients because there is not an established standard therapy for these patients once they get to a third line of treatment,” said the study’s author John H Strickler, MD, of Duke University Medical Center, Durham, N.C.

The study, called CodeBreaK100, is an open-label global phase 1 and 2 trial. It consists of the largest dataset evaluating efficacy and safety of a KRASG12C inhibitor in patients with stage 4 pancreatic cancer.

Survival with Food and Drug Administration–approved second-line therapy in pancreatic ductal adenocarcinoma is 6 months with a 16% response rate. No therapies have demonstrated survival benefit after progression on first- and second-line chemotherapy. Among the 90% of pancreatic ductal adenocarcinoma tumors which harbor a KRAS mutation, 1%-2% are p.G12ac mutations. There are currently no approved treatments for KRASG12C-mutated PDAC.

The study included 38 patients (median age, 65.5 years; 76.3% male) with locally advanced or metastatic pancreatic malignancies who received oral sotorasib (960 mg once daily).

The patients in the trial received one or more prior systemic therapies (79% received two; range, one to eight) or were intolerant or ineligible for available therapies. The primary endpoint was complete plus partial response by blinded independent central review (RECIST 1.1).

Confirmed objective response were reported in 8 patients (21.1%; 95% confidence interval, 9.55%-37.22%) with disease control in 32 (84.2%; 95% CI, 68.75%-93.98%). The median duration of response was 5.7 months. After a median follow-up of 16.8 months, median progression-free survival was 4.0 months (95% CI, 2.8-5.6), and median overall survival was 6.9 months (95% CI, 5.0-9.1).

Once-daily sotorasib was well tolerated. The only treatment-related adverse events above grade 2 were six (15.8%) grade 3 events, with diarrhea in two and fatigue in two (each 5.3%), and single occurrences (2.6%) of abdominal pain, ALT/AST increase, pleural effusion and pulmonary embolism. Three adverse events were serious (7.9%), and no adverse events led to sotorasib discontinuation or were fatal.

Dr. Strickler described the case of a 64-year-old female with stage IV pancreatic cancer at diagnosis, who had baseline metastatic lesions in the liver, lymph nodes, lung and peritoneum. She received prior FOLFIRINOX first line until disease progression. With once-daily sotorasib, time to treatment response was 1.3 month, duration of response was 5.8 months, progression-free survival and overall were 7.1 months each.

Pointing to the centrally confirmed objective response rate of 21.1% and the disease control rate of 84.2%, Dr. Strickler observed in an interview that the CodeBreaK100 data support further exploration of sotorasib in this population with high unmet medical need and that based on these data, the CodeBreaK 100 clinical trial will be expanded to enroll more patients with pancreatic cancer and other tumor types.

The study was funded by Amgen.

Sotorasib, an approved treatment for lung cancer, has demonstrated clinically meaningful anticancer activity and tolerability in patients with heavily pretreated KRASG12C-mutated advanced pancreatic cancer.

The findings were reported at the American Society of Clinical Oncology Genitourinary Cancers Symposium.

“This is clinically meaningful for patients because there is not an established standard therapy for these patients once they get to a third line of treatment,” said the study’s author John H Strickler, MD, of Duke University Medical Center, Durham, N.C.

The study, called CodeBreaK100, is an open-label global phase 1 and 2 trial. It consists of the largest dataset evaluating efficacy and safety of a KRASG12C inhibitor in patients with stage 4 pancreatic cancer.

Survival with Food and Drug Administration–approved second-line therapy in pancreatic ductal adenocarcinoma is 6 months with a 16% response rate. No therapies have demonstrated survival benefit after progression on first- and second-line chemotherapy. Among the 90% of pancreatic ductal adenocarcinoma tumors which harbor a KRAS mutation, 1%-2% are p.G12ac mutations. There are currently no approved treatments for KRASG12C-mutated PDAC.

The study included 38 patients (median age, 65.5 years; 76.3% male) with locally advanced or metastatic pancreatic malignancies who received oral sotorasib (960 mg once daily).

The patients in the trial received one or more prior systemic therapies (79% received two; range, one to eight) or were intolerant or ineligible for available therapies. The primary endpoint was complete plus partial response by blinded independent central review (RECIST 1.1).

Confirmed objective response were reported in 8 patients (21.1%; 95% confidence interval, 9.55%-37.22%) with disease control in 32 (84.2%; 95% CI, 68.75%-93.98%). The median duration of response was 5.7 months. After a median follow-up of 16.8 months, median progression-free survival was 4.0 months (95% CI, 2.8-5.6), and median overall survival was 6.9 months (95% CI, 5.0-9.1).

Once-daily sotorasib was well tolerated. The only treatment-related adverse events above grade 2 were six (15.8%) grade 3 events, with diarrhea in two and fatigue in two (each 5.3%), and single occurrences (2.6%) of abdominal pain, ALT/AST increase, pleural effusion and pulmonary embolism. Three adverse events were serious (7.9%), and no adverse events led to sotorasib discontinuation or were fatal.

Dr. Strickler described the case of a 64-year-old female with stage IV pancreatic cancer at diagnosis, who had baseline metastatic lesions in the liver, lymph nodes, lung and peritoneum. She received prior FOLFIRINOX first line until disease progression. With once-daily sotorasib, time to treatment response was 1.3 month, duration of response was 5.8 months, progression-free survival and overall were 7.1 months each.

Pointing to the centrally confirmed objective response rate of 21.1% and the disease control rate of 84.2%, Dr. Strickler observed in an interview that the CodeBreaK100 data support further exploration of sotorasib in this population with high unmet medical need and that based on these data, the CodeBreaK 100 clinical trial will be expanded to enroll more patients with pancreatic cancer and other tumor types.

The study was funded by Amgen.

PHOENIX – For at least a decade, professional allergy and pediatrics societies have urged against using food IgE tests unless the patient has a history consistent with potential IgE-mediated food allergies. Yet virtually every health system offers these blood tests, and their inappropriate use – especially of panels that measure many allergens at once – remains a huge problem.

Beyond wasteful spending, excessive food IgE testing can lead patients to worry needlessly and to avoid foods they aren’t allergic to. For babies and toddlers, avoidance can drive up the risk of developing allergies to those foods later in life – a consequence that was convincingly proven by the LEAP study but has still not translated to a widespread change in practice.

“I think we all know that there’s just a lot of system-wide resistance to making these changes, and we don’t completely understand why,” Nicholas Hartog, MD, an allergist with Spectrum Health in Grand Rapids, Mich., told this news organization.

At the American Academy of Allergy, Asthma & Immunology annual meeting, one of Dr. Hartog’s residents, Courtney Cotter, DO, presented a poster detailing their team’s retrospective review of food panel ordering practices across Spectrum Health, a large, multispecialty physician group in west Michigan.

The team combed Epic health records to evaluate food IgE ordering from January 2016 to December 2021. They tracked monthly figures for the number of patients who underwent food IgE tests, the percentage of tested patients for whom food panels were available, and the number of food panels and total number of food IgE tests ordered. They compared average rates from the final 3 months with rates from the first 3 months, which predated the August 2016 establishment of an academic pediatric allergy/immunology department.

Initially, Dr. Hartog and his colleagues focused on educating doctors on appropriate use of food IgE tests through informal conversations and lectures, but, he said, “It’s really difficult to change physician behavior, so sometimes we have to go about it by making it hard to do the wrong thing.”

To that end, the team tried to eliminate the food panels. However, some lab staff feared the possibility of losing revenue if physicians decided to order these tests elsewhere. After more negotiations, the laboratory agreed in December 2019 to restrict and rework food IgE testing by dropping the number of panels from nine to two and by restricting the number of foods in those panels. For example, in the basic panel, “we limited it to just four allergens, so even if you order a panel, you’re not getting 20 results,” Dr. Hartog told this news organization. “I finally found a friendly pathologist who was very on board with this positive change.”

In December 2020, the team implemented yet another strategy: Epic alerts. Each time doctors request a food panel, they receive a pop-up message stating that panel tests are not recommended and asking if they wish to proceed.

The multipronged effort had a modest impact on the number of food panels ordered per month, which dipped from 112.7 to 84.7 for the first and last 3 months of the study. Monthly totals of individual food IgE tests showed a steeper drop, decreasing from 2,379 to 1,180 in the initial and final 3-month periods – a change Dr. Hartog attributes to the revamped food panels. They estimated the cost savings at around $40 per patient, “and we were getting on average about 200 patients a month, so it adds up,” he said.

But the Epic alerts seemed to have little effect. Over the duration of the study, the monthly number of IgE tests ordered per clinician did not change. Neither did the percentage of patients evaluated with a food panel. “The alerts pop up, but people are still ordering,” Dr. Hartog said.

On the whole, the analysis shows that, “despite major efforts to educate providers and the public about these things, it is rampantly disregarded and is a huge problem for our specialty and is likely causing harm to patients,” said allergist-immunologist Gerald Lee, MD, of Emory University in Atlanta.

Dr. Lee said that a common scenario for inappropriate food IgE testing is severe eczema. Many parents request blood tests because they assume their child’s skin condition is driven by food allergies. When the child turns up positive to various foods on panel tests, which have high false-positive rates, the physician may recommend eliminating those foods to improve the skin rash – which “actually delays introduction of the food and potentially increases the risk for food allergy,” Dr. Lee said. “That was a common practice when I was in fellowship (2011) and is widely prevalent today.”

Edwin Kim, MD, director of the UNC Food Allergy Initiative at the University of North Carolina at Chapel Hill, agrees that food IgE panels are wasteful and harmful. However, he thinks the solution is not to tell primary care physicians and pediatricians to stop using the tests. “We’re insinuating that they’re being used inappropriately, but the problem is that these are people that are patient facing, the patients are asking a question, and the appropriate tests aren’t there,” Dr. Kim said. “A big part of that problem is that the tests we have available to us are not good enough.”

The Spectrum Health analysis did not examine ICD codes associated with the food IgE tests or track which physicians ordered the tests. A 2016 retrospective review published in Pediatrics did evaluate ordering practices by specialty and found that primary care providers ordered “significantly more food allergen panels, tests for uncommon causes of food allergy, and generate higher cost per patient compared with allergists.”

Given the immense challenges with implementing system-wide changes, sometimes it can help to educate parents and families. “When you sit down and take 2 or 3 minutes to explain why this is a bad test and that I care about your kid but just don’t want inappropriate testing, they’re okay with it. They understand,” Dr. Hartog said. “When I teach residents, I make sure to emphasize that we have these conversations all the time.”

Dr. Hartog reports financial relationships with Binding Site (speaker), Regeneron (advisory board), Genentech (advisory board), Horizon Pharmaceuticals (advisory board, consulting, speaker), Takeda (speaker, advisory board) and Pharming Healthcare (advisory board, scientific steering committee, consulting), though none related to food allergy. Dr. Lee has disclosed no relevant financial relationships. Dr. Kim reports consultancy with Aimmune Therapeutics, Allako, AllerGenis, Belhaven Pharma, DBV Technologies, Duke Clinical Research Institute, and Nutricia; advisory board membership with ALK, DBV Technologies, Kenota Health, and Ukko; and grant support from the National Institute of Allergy and Infectious Diseases and the Immune Tolerance Network; the National Center for Complementary and Integrative Health; Food Allergy Research and Education; and the Wallace Research Foundation.

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

PHOENIX – For at least a decade, professional allergy and pediatrics societies have urged against using food IgE tests unless the patient has a history consistent with potential IgE-mediated food allergies. Yet virtually every health system offers these blood tests, and their inappropriate use – especially of panels that measure many allergens at once – remains a huge problem.

Beyond wasteful spending, excessive food IgE testing can lead patients to worry needlessly and to avoid foods they aren’t allergic to. For babies and toddlers, avoidance can drive up the risk of developing allergies to those foods later in life – a consequence that was convincingly proven by the LEAP study but has still not translated to a widespread change in practice.

“I think we all know that there’s just a lot of system-wide resistance to making these changes, and we don’t completely understand why,” Nicholas Hartog, MD, an allergist with Spectrum Health in Grand Rapids, Mich., told this news organization.

At the American Academy of Allergy, Asthma & Immunology annual meeting, one of Dr. Hartog’s residents, Courtney Cotter, DO, presented a poster detailing their team’s retrospective review of food panel ordering practices across Spectrum Health, a large, multispecialty physician group in west Michigan.

The team combed Epic health records to evaluate food IgE ordering from January 2016 to December 2021. They tracked monthly figures for the number of patients who underwent food IgE tests, the percentage of tested patients for whom food panels were available, and the number of food panels and total number of food IgE tests ordered. They compared average rates from the final 3 months with rates from the first 3 months, which predated the August 2016 establishment of an academic pediatric allergy/immunology department.

Initially, Dr. Hartog and his colleagues focused on educating doctors on appropriate use of food IgE tests through informal conversations and lectures, but, he said, “It’s really difficult to change physician behavior, so sometimes we have to go about it by making it hard to do the wrong thing.”

To that end, the team tried to eliminate the food panels. However, some lab staff feared the possibility of losing revenue if physicians decided to order these tests elsewhere. After more negotiations, the laboratory agreed in December 2019 to restrict and rework food IgE testing by dropping the number of panels from nine to two and by restricting the number of foods in those panels. For example, in the basic panel, “we limited it to just four allergens, so even if you order a panel, you’re not getting 20 results,” Dr. Hartog told this news organization. “I finally found a friendly pathologist who was very on board with this positive change.”

In December 2020, the team implemented yet another strategy: Epic alerts. Each time doctors request a food panel, they receive a pop-up message stating that panel tests are not recommended and asking if they wish to proceed.

The multipronged effort had a modest impact on the number of food panels ordered per month, which dipped from 112.7 to 84.7 for the first and last 3 months of the study. Monthly totals of individual food IgE tests showed a steeper drop, decreasing from 2,379 to 1,180 in the initial and final 3-month periods – a change Dr. Hartog attributes to the revamped food panels. They estimated the cost savings at around $40 per patient, “and we were getting on average about 200 patients a month, so it adds up,” he said.

But the Epic alerts seemed to have little effect. Over the duration of the study, the monthly number of IgE tests ordered per clinician did not change. Neither did the percentage of patients evaluated with a food panel. “The alerts pop up, but people are still ordering,” Dr. Hartog said.

On the whole, the analysis shows that, “despite major efforts to educate providers and the public about these things, it is rampantly disregarded and is a huge problem for our specialty and is likely causing harm to patients,” said allergist-immunologist Gerald Lee, MD, of Emory University in Atlanta.

Dr. Lee said that a common scenario for inappropriate food IgE testing is severe eczema. Many parents request blood tests because they assume their child’s skin condition is driven by food allergies. When the child turns up positive to various foods on panel tests, which have high false-positive rates, the physician may recommend eliminating those foods to improve the skin rash – which “actually delays introduction of the food and potentially increases the risk for food allergy,” Dr. Lee said. “That was a common practice when I was in fellowship (2011) and is widely prevalent today.”

Edwin Kim, MD, director of the UNC Food Allergy Initiative at the University of North Carolina at Chapel Hill, agrees that food IgE panels are wasteful and harmful. However, he thinks the solution is not to tell primary care physicians and pediatricians to stop using the tests. “We’re insinuating that they’re being used inappropriately, but the problem is that these are people that are patient facing, the patients are asking a question, and the appropriate tests aren’t there,” Dr. Kim said. “A big part of that problem is that the tests we have available to us are not good enough.”

The Spectrum Health analysis did not examine ICD codes associated with the food IgE tests or track which physicians ordered the tests. A 2016 retrospective review published in Pediatrics did evaluate ordering practices by specialty and found that primary care providers ordered “significantly more food allergen panels, tests for uncommon causes of food allergy, and generate higher cost per patient compared with allergists.”

Given the immense challenges with implementing system-wide changes, sometimes it can help to educate parents and families. “When you sit down and take 2 or 3 minutes to explain why this is a bad test and that I care about your kid but just don’t want inappropriate testing, they’re okay with it. They understand,” Dr. Hartog said. “When I teach residents, I make sure to emphasize that we have these conversations all the time.”

Dr. Hartog reports financial relationships with Binding Site (speaker), Regeneron (advisory board), Genentech (advisory board), Horizon Pharmaceuticals (advisory board, consulting, speaker), Takeda (speaker, advisory board) and Pharming Healthcare (advisory board, scientific steering committee, consulting), though none related to food allergy. Dr. Lee has disclosed no relevant financial relationships. Dr. Kim reports consultancy with Aimmune Therapeutics, Allako, AllerGenis, Belhaven Pharma, DBV Technologies, Duke Clinical Research Institute, and Nutricia; advisory board membership with ALK, DBV Technologies, Kenota Health, and Ukko; and grant support from the National Institute of Allergy and Infectious Diseases and the Immune Tolerance Network; the National Center for Complementary and Integrative Health; Food Allergy Research and Education; and the Wallace Research Foundation.

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

PHOENIX – For at least a decade, professional allergy and pediatrics societies have urged against using food IgE tests unless the patient has a history consistent with potential IgE-mediated food allergies. Yet virtually every health system offers these blood tests, and their inappropriate use – especially of panels that measure many allergens at once – remains a huge problem.

Beyond wasteful spending, excessive food IgE testing can lead patients to worry needlessly and to avoid foods they aren’t allergic to. For babies and toddlers, avoidance can drive up the risk of developing allergies to those foods later in life – a consequence that was convincingly proven by the LEAP study but has still not translated to a widespread change in practice.

“I think we all know that there’s just a lot of system-wide resistance to making these changes, and we don’t completely understand why,” Nicholas Hartog, MD, an allergist with Spectrum Health in Grand Rapids, Mich., told this news organization.

At the American Academy of Allergy, Asthma & Immunology annual meeting, one of Dr. Hartog’s residents, Courtney Cotter, DO, presented a poster detailing their team’s retrospective review of food panel ordering practices across Spectrum Health, a large, multispecialty physician group in west Michigan.

The team combed Epic health records to evaluate food IgE ordering from January 2016 to December 2021. They tracked monthly figures for the number of patients who underwent food IgE tests, the percentage of tested patients for whom food panels were available, and the number of food panels and total number of food IgE tests ordered. They compared average rates from the final 3 months with rates from the first 3 months, which predated the August 2016 establishment of an academic pediatric allergy/immunology department.

Initially, Dr. Hartog and his colleagues focused on educating doctors on appropriate use of food IgE tests through informal conversations and lectures, but, he said, “It’s really difficult to change physician behavior, so sometimes we have to go about it by making it hard to do the wrong thing.”

To that end, the team tried to eliminate the food panels. However, some lab staff feared the possibility of losing revenue if physicians decided to order these tests elsewhere. After more negotiations, the laboratory agreed in December 2019 to restrict and rework food IgE testing by dropping the number of panels from nine to two and by restricting the number of foods in those panels. For example, in the basic panel, “we limited it to just four allergens, so even if you order a panel, you’re not getting 20 results,” Dr. Hartog told this news organization. “I finally found a friendly pathologist who was very on board with this positive change.”

In December 2020, the team implemented yet another strategy: Epic alerts. Each time doctors request a food panel, they receive a pop-up message stating that panel tests are not recommended and asking if they wish to proceed.

The multipronged effort had a modest impact on the number of food panels ordered per month, which dipped from 112.7 to 84.7 for the first and last 3 months of the study. Monthly totals of individual food IgE tests showed a steeper drop, decreasing from 2,379 to 1,180 in the initial and final 3-month periods – a change Dr. Hartog attributes to the revamped food panels. They estimated the cost savings at around $40 per patient, “and we were getting on average about 200 patients a month, so it adds up,” he said.

But the Epic alerts seemed to have little effect. Over the duration of the study, the monthly number of IgE tests ordered per clinician did not change. Neither did the percentage of patients evaluated with a food panel. “The alerts pop up, but people are still ordering,” Dr. Hartog said.

On the whole, the analysis shows that, “despite major efforts to educate providers and the public about these things, it is rampantly disregarded and is a huge problem for our specialty and is likely causing harm to patients,” said allergist-immunologist Gerald Lee, MD, of Emory University in Atlanta.

Dr. Lee said that a common scenario for inappropriate food IgE testing is severe eczema. Many parents request blood tests because they assume their child’s skin condition is driven by food allergies. When the child turns up positive to various foods on panel tests, which have high false-positive rates, the physician may recommend eliminating those foods to improve the skin rash – which “actually delays introduction of the food and potentially increases the risk for food allergy,” Dr. Lee said. “That was a common practice when I was in fellowship (2011) and is widely prevalent today.”

Edwin Kim, MD, director of the UNC Food Allergy Initiative at the University of North Carolina at Chapel Hill, agrees that food IgE panels are wasteful and harmful. However, he thinks the solution is not to tell primary care physicians and pediatricians to stop using the tests. “We’re insinuating that they’re being used inappropriately, but the problem is that these are people that are patient facing, the patients are asking a question, and the appropriate tests aren’t there,” Dr. Kim said. “A big part of that problem is that the tests we have available to us are not good enough.”

The Spectrum Health analysis did not examine ICD codes associated with the food IgE tests or track which physicians ordered the tests. A 2016 retrospective review published in Pediatrics did evaluate ordering practices by specialty and found that primary care providers ordered “significantly more food allergen panels, tests for uncommon causes of food allergy, and generate higher cost per patient compared with allergists.”

Given the immense challenges with implementing system-wide changes, sometimes it can help to educate parents and families. “When you sit down and take 2 or 3 minutes to explain why this is a bad test and that I care about your kid but just don’t want inappropriate testing, they’re okay with it. They understand,” Dr. Hartog said. “When I teach residents, I make sure to emphasize that we have these conversations all the time.”

Dr. Hartog reports financial relationships with Binding Site (speaker), Regeneron (advisory board), Genentech (advisory board), Horizon Pharmaceuticals (advisory board, consulting, speaker), Takeda (speaker, advisory board) and Pharming Healthcare (advisory board, scientific steering committee, consulting), though none related to food allergy. Dr. Lee has disclosed no relevant financial relationships. Dr. Kim reports consultancy with Aimmune Therapeutics, Allako, AllerGenis, Belhaven Pharma, DBV Technologies, Duke Clinical Research Institute, and Nutricia; advisory board membership with ALK, DBV Technologies, Kenota Health, and Ukko; and grant support from the National Institute of Allergy and Infectious Diseases and the Immune Tolerance Network; the National Center for Complementary and Integrative Health; Food Allergy Research and Education; and the Wallace Research Foundation.

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

The selective Janus kinase (JAK) inhibitor upadacitinib resolved more extraintestinal manifestations (EIMs) of ulcerative colitis than placebo, according to an analysis of phase 3 study findings.

The 45-mg induction dose of upadacitinib, for example, resolved more anemia, peripheral arthropathy, and axial arthropathy than placebo. The 15-mg and 30-mg maintenance doses were also associated with greater resolution of EIMs, with the higher dose producing a significantly greater reduction in comparison with placebo.

“Upadacitinib was highly effective in decreasing ulcerative colitis activity, which is triggering the extraintestinal manifestations,” lead author Jean-Frederick Colombel, MD, told this news organization.

Dr. Colombel, a gastroenterologist and professor of medicine at Mount Sinai Icahn School of Medicine, New York, said he was not surprised to see this, given that the oral JAK inhibitor “has also demonstrated efficacy in rheumatoid arthritis, psoriatic arthritis, atopic dermatitis, and ankylosing spondylitis.”

He presented the study findings during an oral presentation Feb. 19 at the 17th congress of the European Crohn’s and Colitis Organisation.

In the United States, AbbVie is seeking approval from the U.S. Food and Drug Administration for upadacitinib (RINVOQ) to treat active, moderate to severe ulcerative colitis. The company submitted regulatory applications in September 2021 for this indication.
 

About 1 in 4 report EIMs

The researchers evaluated the U-ACHIEVE and U-ACCOMPLISH 8-week induction studies, in which 660 participants were randomly assigned to receive upadacitinib 45 mg and 328 patients were assigned to receive placebo. At baseline, 25% of treated patients and 27% of the placebo group had experienced at least one EIM.

The researchers also assessed outcomes of the 52-week U-ACHIEVE maintenance trial, in which 154 people with ulcerative colitis were randomly assigned to receive 30-mg upadacitinib, 148 to receive 15-mg upadacitinib, and 149 to receive placebo. Between 24% and 27% of participants in these groups reported at least one EIM at baseline.
 

Key findings

In the pooled induction studies, a higher proportion of participants in the upadacitinib group achieved resolution of any EIM at 8 weeks, compared with the placebo group (40% vs. 33%).

Regarding specific EIMs, a higher proportion of those in the upadacitinib group had achieved resolution of peripheral or axial arthropathies at 8 weeks, compared with the placebo group (55% vs. 42%), and more participants experienced resolution of anemia (38% vs. 33%).

Similar effects were observed in the maintenance study. Resolution of any EIM at 52 weeks was experienced by 66% of those in the 30-mg upadacitinib group, compared with 42% in the 15-mg upadacitinib group and 24% in the placebo group. The 30-mg results were significantly different than placebo (P < .001).

Regarding specific EIMs, a higher proportion of the 30-mg upadacitinib group experienced resolution of peripheral or axial arthropathies at week 52, compared with the 15-mg and placebo groups (67% vs. 39% vs. 22%). The difference was statistically significant between the 30-mg and placebo groups (P = .010) but not between the 15-mg and placebo groups.

More participants in the 30-mg group also experienced resolution of anemia, compared with the 15-mg group and the placebo group (71% vs. 50% vs. 36%). Once again, the difference between 30-mg group and placebo was significant (P = .019).

When asked what physicians should be most concerned about when prescribing upadacitinib, Dr. Colombel pointed to the risks of serious infections, including herpes zoster. He added that there are potential risks of cardiovascular events, deep vein thrombosis, and cancers, “but it is too early to tell.”

Dr. Colombel advised physicians to follow the prescribing information for upadacitinib following FDA approval.
 

An ‘excellent presentation’

“Upadacitinib is a promising new option for patients with ulcerative colitis,” ECCO 2022 session cochair Annemarie de Vries, MD, PhD, told this news organization.

“The excellent presentation by Prof. Colombel further supports the high expectations by providing evidence on the effect of upadacitinib on extraintestinal manifestations,” said Dr. De Vries, a gastroenterologist at Erasmus Medical Center, Rotterdam, the Netherlands.

“For further conclusions on drug positioning, we have to await real-world data and head-to-head trials versus anti-TNF agents and vedolizumab,” she added.

The study was sponsored by AbbVie. Dr. Colombel has received research support from and is a speaker and consultant for AbbVie. Dr. De Vries reports no relevant financial relationships.

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

The selective Janus kinase (JAK) inhibitor upadacitinib resolved more extraintestinal manifestations (EIMs) of ulcerative colitis than placebo, according to an analysis of phase 3 study findings.

The 45-mg induction dose of upadacitinib, for example, resolved more anemia, peripheral arthropathy, and axial arthropathy than placebo. The 15-mg and 30-mg maintenance doses were also associated with greater resolution of EIMs, with the higher dose producing a significantly greater reduction in comparison with placebo.

“Upadacitinib was highly effective in decreasing ulcerative colitis activity, which is triggering the extraintestinal manifestations,” lead author Jean-Frederick Colombel, MD, told this news organization.

Dr. Colombel, a gastroenterologist and professor of medicine at Mount Sinai Icahn School of Medicine, New York, said he was not surprised to see this, given that the oral JAK inhibitor “has also demonstrated efficacy in rheumatoid arthritis, psoriatic arthritis, atopic dermatitis, and ankylosing spondylitis.”

He presented the study findings during an oral presentation Feb. 19 at the 17th congress of the European Crohn’s and Colitis Organisation.

In the United States, AbbVie is seeking approval from the U.S. Food and Drug Administration for upadacitinib (RINVOQ) to treat active, moderate to severe ulcerative colitis. The company submitted regulatory applications in September 2021 for this indication.
 

About 1 in 4 report EIMs

The researchers evaluated the U-ACHIEVE and U-ACCOMPLISH 8-week induction studies, in which 660 participants were randomly assigned to receive upadacitinib 45 mg and 328 patients were assigned to receive placebo. At baseline, 25% of treated patients and 27% of the placebo group had experienced at least one EIM.

The researchers also assessed outcomes of the 52-week U-ACHIEVE maintenance trial, in which 154 people with ulcerative colitis were randomly assigned to receive 30-mg upadacitinib, 148 to receive 15-mg upadacitinib, and 149 to receive placebo. Between 24% and 27% of participants in these groups reported at least one EIM at baseline.
 

Key findings

In the pooled induction studies, a higher proportion of participants in the upadacitinib group achieved resolution of any EIM at 8 weeks, compared with the placebo group (40% vs. 33%).

Regarding specific EIMs, a higher proportion of those in the upadacitinib group had achieved resolution of peripheral or axial arthropathies at 8 weeks, compared with the placebo group (55% vs. 42%), and more participants experienced resolution of anemia (38% vs. 33%).

Similar effects were observed in the maintenance study. Resolution of any EIM at 52 weeks was experienced by 66% of those in the 30-mg upadacitinib group, compared with 42% in the 15-mg upadacitinib group and 24% in the placebo group. The 30-mg results were significantly different than placebo (P < .001).

Regarding specific EIMs, a higher proportion of the 30-mg upadacitinib group experienced resolution of peripheral or axial arthropathies at week 52, compared with the 15-mg and placebo groups (67% vs. 39% vs. 22%). The difference was statistically significant between the 30-mg and placebo groups (P = .010) but not between the 15-mg and placebo groups.

More participants in the 30-mg group also experienced resolution of anemia, compared with the 15-mg group and the placebo group (71% vs. 50% vs. 36%). Once again, the difference between 30-mg group and placebo was significant (P = .019).

When asked what physicians should be most concerned about when prescribing upadacitinib, Dr. Colombel pointed to the risks of serious infections, including herpes zoster. He added that there are potential risks of cardiovascular events, deep vein thrombosis, and cancers, “but it is too early to tell.”

Dr. Colombel advised physicians to follow the prescribing information for upadacitinib following FDA approval.
 

An ‘excellent presentation’

“Upadacitinib is a promising new option for patients with ulcerative colitis,” ECCO 2022 session cochair Annemarie de Vries, MD, PhD, told this news organization.

“The excellent presentation by Prof. Colombel further supports the high expectations by providing evidence on the effect of upadacitinib on extraintestinal manifestations,” said Dr. De Vries, a gastroenterologist at Erasmus Medical Center, Rotterdam, the Netherlands.

“For further conclusions on drug positioning, we have to await real-world data and head-to-head trials versus anti-TNF agents and vedolizumab,” she added.

The study was sponsored by AbbVie. Dr. Colombel has received research support from and is a speaker and consultant for AbbVie. Dr. De Vries reports no relevant financial relationships.

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

The selective Janus kinase (JAK) inhibitor upadacitinib resolved more extraintestinal manifestations (EIMs) of ulcerative colitis than placebo, according to an analysis of phase 3 study findings.

The 45-mg induction dose of upadacitinib, for example, resolved more anemia, peripheral arthropathy, and axial arthropathy than placebo. The 15-mg and 30-mg maintenance doses were also associated with greater resolution of EIMs, with the higher dose producing a significantly greater reduction in comparison with placebo.

“Upadacitinib was highly effective in decreasing ulcerative colitis activity, which is triggering the extraintestinal manifestations,” lead author Jean-Frederick Colombel, MD, told this news organization.

Dr. Colombel, a gastroenterologist and professor of medicine at Mount Sinai Icahn School of Medicine, New York, said he was not surprised to see this, given that the oral JAK inhibitor “has also demonstrated efficacy in rheumatoid arthritis, psoriatic arthritis, atopic dermatitis, and ankylosing spondylitis.”

He presented the study findings during an oral presentation Feb. 19 at the 17th congress of the European Crohn’s and Colitis Organisation.

In the United States, AbbVie is seeking approval from the U.S. Food and Drug Administration for upadacitinib (RINVOQ) to treat active, moderate to severe ulcerative colitis. The company submitted regulatory applications in September 2021 for this indication.
 

About 1 in 4 report EIMs

The researchers evaluated the U-ACHIEVE and U-ACCOMPLISH 8-week induction studies, in which 660 participants were randomly assigned to receive upadacitinib 45 mg and 328 patients were assigned to receive placebo. At baseline, 25% of treated patients and 27% of the placebo group had experienced at least one EIM.

The researchers also assessed outcomes of the 52-week U-ACHIEVE maintenance trial, in which 154 people with ulcerative colitis were randomly assigned to receive 30-mg upadacitinib, 148 to receive 15-mg upadacitinib, and 149 to receive placebo. Between 24% and 27% of participants in these groups reported at least one EIM at baseline.
 

Key findings

In the pooled induction studies, a higher proportion of participants in the upadacitinib group achieved resolution of any EIM at 8 weeks, compared with the placebo group (40% vs. 33%).

Regarding specific EIMs, a higher proportion of those in the upadacitinib group had achieved resolution of peripheral or axial arthropathies at 8 weeks, compared with the placebo group (55% vs. 42%), and more participants experienced resolution of anemia (38% vs. 33%).

Similar effects were observed in the maintenance study. Resolution of any EIM at 52 weeks was experienced by 66% of those in the 30-mg upadacitinib group, compared with 42% in the 15-mg upadacitinib group and 24% in the placebo group. The 30-mg results were significantly different than placebo (P < .001).

Regarding specific EIMs, a higher proportion of the 30-mg upadacitinib group experienced resolution of peripheral or axial arthropathies at week 52, compared with the 15-mg and placebo groups (67% vs. 39% vs. 22%). The difference was statistically significant between the 30-mg and placebo groups (P = .010) but not between the 15-mg and placebo groups.

More participants in the 30-mg group also experienced resolution of anemia, compared with the 15-mg group and the placebo group (71% vs. 50% vs. 36%). Once again, the difference between 30-mg group and placebo was significant (P = .019).

When asked what physicians should be most concerned about when prescribing upadacitinib, Dr. Colombel pointed to the risks of serious infections, including herpes zoster. He added that there are potential risks of cardiovascular events, deep vein thrombosis, and cancers, “but it is too early to tell.”

Dr. Colombel advised physicians to follow the prescribing information for upadacitinib following FDA approval.
 

An ‘excellent presentation’

“Upadacitinib is a promising new option for patients with ulcerative colitis,” ECCO 2022 session cochair Annemarie de Vries, MD, PhD, told this news organization.

“The excellent presentation by Prof. Colombel further supports the high expectations by providing evidence on the effect of upadacitinib on extraintestinal manifestations,” said Dr. De Vries, a gastroenterologist at Erasmus Medical Center, Rotterdam, the Netherlands.

“For further conclusions on drug positioning, we have to await real-world data and head-to-head trials versus anti-TNF agents and vedolizumab,” she added.

The study was sponsored by AbbVie. Dr. Colombel has received research support from and is a speaker and consultant for AbbVie. Dr. De Vries reports no relevant financial relationships.

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

Earlier menopause appears to be associated with a higher risk of dementia, and earlier onset of dementia, compared with menopause at normal age or later, according to a large study.

“Being aware of this increased risk can help women practice strategies to prevent dementia and to work with their physicians to closely monitor their cognitive status as they age,” study investigator Wenting Hao, MD, with Shandong University, Jinan, China, says in a news release.

The findings were presented in an e-poster March 1 at the Epidemiology, Prevention, Lifestyle & Cardiometabolic Health (EPI|Lifestyle) 2022 conference sponsored by the American Heart Association.
 

UK Biobank data

Dr. Hao and colleagues examined health data for 153,291 women who were 60 years old on average when they became participants in the UK Biobank.

Age at menopause was categorized as premature (younger than age 40), early (40 to 44 years), reference (45 to 51), 52 to 55 years, and 55+ years.

Compared with women who entered menopause around age 50 years (reference), women who experienced premature menopause were 35% more likely to develop some type of dementia later in life (hazard ratio, 1.35; 95% confidence interval, 1.22 to 1.91).

Women with early menopause were also more likely to develop early-onset dementia, that is, before age 65 (HR, 1.31; 95% confidence interval, 1.07 to 1.72).

Women who entered menopause later (at age 52+) had dementia risk similar to women who entered menopause at the average age of 50 to 51 years.

The results were adjusted for relevant cofactors, including age at last exam, race, educational level, cigarette and alcohol use, body mass index, cardiovascular disease, diabetes, income, and leisure and physical activities.

Blame it on estrogen?

Reduced estrogen levels may be a factor in the possible connection between early menopause and dementia, Dr. Hao and her colleagues say.

Estradiol plays a key role in a range of neurological functions, so the reduction of endogenous estrogen at menopause may aggravate brain changes related to neurodegenerative disease and speed up progression of dementia, they explain.

“We know that the lack of estrogen over the long term enhances oxidative stress, which may increase brain aging and lead to cognitive impairment,” Dr. Hao adds.

Limitations of the study include reliance on self-reported information about age at menopause onset.

Also, the researchers did not evaluate dementia rates in women who had a naturally occurring early menopause separate from the women with surgery-induced menopause, which may affect the results.

Finally, the data used for this study included mostly White women living in the U.K. and may not generalize to other populations.
 

Supportive evidence, critical area of research

The U.K. study supports results of a previously reported Kaiser Permanente study, which showed women who entered menopause at age 45 or younger were at 28% greater dementia risk, compared with women who experienced menopause after age 45.

Reached for comment, Heather Snyder, PhD, Alzheimer’s Association vice president of medical and scientific relations, noted that nearly two-thirds of Americans with Alzheimer’s are women.

“We know Alzheimer’s and other dementias impact a greater number of women than men, but we don’t know why,” she told this news organization.

“Lifelong differences in women may affect their risk or affect what is contributing to their underlying biology of the disease, and we need more research to better understand what may be these contributing factors,” said Dr. Snyder.

“Reproductive history is one critical area being studied. The physical and hormonal changes that occur during menopause – as well as other hormonal changes throughout life – are considerable, and it’s important to understand what impact, if any, these changes may have on the brain,” Dr. Snyder added.

“The potential link between reproduction history and brain health is intriguing, but much more research in this area is needed to understand these links,” she said.

The study was funded by the Start-up Foundation for Scientific Research at Shandong University. Dr. Hao and Dr. Snyder have disclosed no relevant financial relationships.

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

Earlier menopause appears to be associated with a higher risk of dementia, and earlier onset of dementia, compared with menopause at normal age or later, according to a large study.

“Being aware of this increased risk can help women practice strategies to prevent dementia and to work with their physicians to closely monitor their cognitive status as they age,” study investigator Wenting Hao, MD, with Shandong University, Jinan, China, says in a news release.

The findings were presented in an e-poster March 1 at the Epidemiology, Prevention, Lifestyle & Cardiometabolic Health (EPI|Lifestyle) 2022 conference sponsored by the American Heart Association.
 

UK Biobank data

Dr. Hao and colleagues examined health data for 153,291 women who were 60 years old on average when they became participants in the UK Biobank.

Age at menopause was categorized as premature (younger than age 40), early (40 to 44 years), reference (45 to 51), 52 to 55 years, and 55+ years.

Compared with women who entered menopause around age 50 years (reference), women who experienced premature menopause were 35% more likely to develop some type of dementia later in life (hazard ratio, 1.35; 95% confidence interval, 1.22 to 1.91).

Women with early menopause were also more likely to develop early-onset dementia, that is, before age 65 (HR, 1.31; 95% confidence interval, 1.07 to 1.72).

Women who entered menopause later (at age 52+) had dementia risk similar to women who entered menopause at the average age of 50 to 51 years.

The results were adjusted for relevant cofactors, including age at last exam, race, educational level, cigarette and alcohol use, body mass index, cardiovascular disease, diabetes, income, and leisure and physical activities.

Blame it on estrogen?

Reduced estrogen levels may be a factor in the possible connection between early menopause and dementia, Dr. Hao and her colleagues say.

Estradiol plays a key role in a range of neurological functions, so the reduction of endogenous estrogen at menopause may aggravate brain changes related to neurodegenerative disease and speed up progression of dementia, they explain.

“We know that the lack of estrogen over the long term enhances oxidative stress, which may increase brain aging and lead to cognitive impairment,” Dr. Hao adds.

Limitations of the study include reliance on self-reported information about age at menopause onset.

Also, the researchers did not evaluate dementia rates in women who had a naturally occurring early menopause separate from the women with surgery-induced menopause, which may affect the results.

Finally, the data used for this study included mostly White women living in the U.K. and may not generalize to other populations.
 

Supportive evidence, critical area of research

The U.K. study supports results of a previously reported Kaiser Permanente study, which showed women who entered menopause at age 45 or younger were at 28% greater dementia risk, compared with women who experienced menopause after age 45.

Reached for comment, Heather Snyder, PhD, Alzheimer’s Association vice president of medical and scientific relations, noted that nearly two-thirds of Americans with Alzheimer’s are women.

“We know Alzheimer’s and other dementias impact a greater number of women than men, but we don’t know why,” she told this news organization.

“Lifelong differences in women may affect their risk or affect what is contributing to their underlying biology of the disease, and we need more research to better understand what may be these contributing factors,” said Dr. Snyder.

“Reproductive history is one critical area being studied. The physical and hormonal changes that occur during menopause – as well as other hormonal changes throughout life – are considerable, and it’s important to understand what impact, if any, these changes may have on the brain,” Dr. Snyder added.

“The potential link between reproduction history and brain health is intriguing, but much more research in this area is needed to understand these links,” she said.

The study was funded by the Start-up Foundation for Scientific Research at Shandong University. Dr. Hao and Dr. Snyder have disclosed no relevant financial relationships.

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

Earlier menopause appears to be associated with a higher risk of dementia, and earlier onset of dementia, compared with menopause at normal age or later, according to a large study.

“Being aware of this increased risk can help women practice strategies to prevent dementia and to work with their physicians to closely monitor their cognitive status as they age,” study investigator Wenting Hao, MD, with Shandong University, Jinan, China, says in a news release.

The findings were presented in an e-poster March 1 at the Epidemiology, Prevention, Lifestyle & Cardiometabolic Health (EPI|Lifestyle) 2022 conference sponsored by the American Heart Association.
 

UK Biobank data

Dr. Hao and colleagues examined health data for 153,291 women who were 60 years old on average when they became participants in the UK Biobank.

Age at menopause was categorized as premature (younger than age 40), early (40 to 44 years), reference (45 to 51), 52 to 55 years, and 55+ years.

Compared with women who entered menopause around age 50 years (reference), women who experienced premature menopause were 35% more likely to develop some type of dementia later in life (hazard ratio, 1.35; 95% confidence interval, 1.22 to 1.91).

Women with early menopause were also more likely to develop early-onset dementia, that is, before age 65 (HR, 1.31; 95% confidence interval, 1.07 to 1.72).

Women who entered menopause later (at age 52+) had dementia risk similar to women who entered menopause at the average age of 50 to 51 years.

The results were adjusted for relevant cofactors, including age at last exam, race, educational level, cigarette and alcohol use, body mass index, cardiovascular disease, diabetes, income, and leisure and physical activities.

Blame it on estrogen?

Reduced estrogen levels may be a factor in the possible connection between early menopause and dementia, Dr. Hao and her colleagues say.

Estradiol plays a key role in a range of neurological functions, so the reduction of endogenous estrogen at menopause may aggravate brain changes related to neurodegenerative disease and speed up progression of dementia, they explain.

“We know that the lack of estrogen over the long term enhances oxidative stress, which may increase brain aging and lead to cognitive impairment,” Dr. Hao adds.

Limitations of the study include reliance on self-reported information about age at menopause onset.

Also, the researchers did not evaluate dementia rates in women who had a naturally occurring early menopause separate from the women with surgery-induced menopause, which may affect the results.

Finally, the data used for this study included mostly White women living in the U.K. and may not generalize to other populations.
 

Supportive evidence, critical area of research

The U.K. study supports results of a previously reported Kaiser Permanente study, which showed women who entered menopause at age 45 or younger were at 28% greater dementia risk, compared with women who experienced menopause after age 45.

Reached for comment, Heather Snyder, PhD, Alzheimer’s Association vice president of medical and scientific relations, noted that nearly two-thirds of Americans with Alzheimer’s are women.

“We know Alzheimer’s and other dementias impact a greater number of women than men, but we don’t know why,” she told this news organization.

“Lifelong differences in women may affect their risk or affect what is contributing to their underlying biology of the disease, and we need more research to better understand what may be these contributing factors,” said Dr. Snyder.

“Reproductive history is one critical area being studied. The physical and hormonal changes that occur during menopause – as well as other hormonal changes throughout life – are considerable, and it’s important to understand what impact, if any, these changes may have on the brain,” Dr. Snyder added.

“The potential link between reproduction history and brain health is intriguing, but much more research in this area is needed to understand these links,” she said.

The study was funded by the Start-up Foundation for Scientific Research at Shandong University. Dr. Hao and Dr. Snyder have disclosed no relevant financial relationships.

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

Both tofacitinib (Xeljanz) and vedolizumab (Entyvio) are effective options for people with ulcerative colitis (UC) who fail at least one antitumor necrosis factor (anti-TNF) therapy, a real-world study in France revealed.

However, response was superior with tofacitinib among people after primary failure to biologics and multiple therapeutic failure, the researchers report, including endoscopic improvement and mucosal healing.  

Anthony Buisson, MD, presented the results Feb. 18 at the 17th congress of the European Crohn’s and Colitis Organisation.
 

The French comparison

Although multiple therapeutic options are available to treat ulcerative colitis after anti-TNF failure, “there are no data comparing tofacitinib to vedolizumab in the real world,” said Dr. Buisson, a gastroenterologist at Clermont Auvergne University, Clermont-Ferrand, France.

In addition, network meta-analysis data are inconclusive, he said.

This led Dr. Buisson and colleagues to study adults with symptomatic UC with prior exposure to at least one anti-TNF treatment. They assessed 126 patients in a tofacitinib group and 178 in a vedolizumab group. The groups were comparable except for higher disease activity at baseline in the tofacitinib group.

The retrospective study was conducted at nine academic centers. Patients started either tofacitinib or vedolizumab between January 2019 and June 2021.

The primary endpoint, corticosteroid-free clinical remission at 16 weeks, was achieved by 45% of the tofacitinib group and 40% of the vedolizumab group. This difference was not statistically significant.

However, endoscopic improvement at week 16 did differ significantly and was achieved by 24% of the tofacitinib group versus 7% of the vedolizumab group (P = .0036).

“Tofacitinib and vedolizumab are effective to induce corticosteroid-free clinical remission at week 16 in patients with UC who failed at least one anti-TNF agent,” Dr. Buisson said.

“Vedolizumab seems to be less effective in cases of more severe UC and prior history of primary failure to any biologic,” he added.

Dr. Buisson said he and his colleagues plan to continue the study beyond 16 weeks to look at longterm outcomes.
 

The science from Spain

In another study presented at ECCO ‘22 Virtual, investigators from Spain compared vedolizumab to ustekinumab (Stelara) after at least one anti-TNF treatment failure, this time among people with Crohn’s disease.

Finding effective treatments after an anti-TNF failure is essential, Maria Jose Garcia, MD, said when presenting the results of the VERSUS-CD trial. “Over 20%-30% of Crohn’s disease patients are nonresponders or develop intolerance to anti-TNF therapies. Also, anti-TNF responders can experience a loss of response over time.”

Both vedolizumab and ustekinumab are effective for Crohn’s, she said. “But no clinical trial has compared both treatments, and limited data exist in real life.”

To remedy this situation, Dr. Garcia and colleagues studied 755 people from 30 medical centers in a national database in Spain who failed a previous anti-TNF agent, including 195 people switched to vedolizumab and 560 switched to ustekinumab. Luminal activity, perianal disease, or postoperative recurrence of Crohn’s were the indications for treatment.

The study’s main objective was to compare the short- and long-term treatment survival rate of vedolizumab and ustekinumab after anti-TNF therapy failure in clinical practice. Evaluating efficacy and safety were secondary aims.

“The treatment survival rate with ustekinumab was higher than with vedolizumab” over 5 years of follow-up, said Dr. Garcia, a gastroenterologist at Hospital Universitario Marqués de Valdecilla-IDIVAL, Santander, Spain. The difference was statistically significant (P < .001).

Just less than half (43%) of the 327 patients discontinued treatment over time, including 142 in the vedolizumab group and 185 in the ustekinumab group. The most frequent cause was primarily nonresponse.

Infection, arthralgia, and infusion reactions were the most common adverse events. The safety profile was similar between groups, Dr. Garcia said.

“In clinical practice, vedolizumab and ustekinumab are both effective after anti-TNF failure or intolerance in CD,” Dr. Garcia said, adding that, “the retention rate of ustekinumab was higher compared to vedolizumab.”

When asked if the results will change how she practices, Dr. Garcia responded, “This confirms the first choice is ustekinumab more than vedolizumab in clinical practice, because it seems the clinical remission and durability of the treatment is superior.”
 

More options means more questions

“Looking back almost 25 years ago, the struggle was how to work with just one biologic and how to make it last for patients who have already failed all the available therapies. All these years later, we have such riches that the question we most often deal with is ‘What’s my first treatment?’ for patients with inflammatory bowel disease,” Arun Swaminath, MD, said, when asked to comment on both studies.

“Increasingly, we are seeing industry do head-to-head trials of drugs, but this is a time-consuming and expensive process,” added Dr. Swaminath, chief of gastroenterology and director of the inflammatory bowel diseases program at Lenox Hill Hospital, New York.

The study from Dr. Buisson and colleagues in UC approaches the design of a head-to-head trial, Dr. Swaminath said. “In the end, their primary endpoint was a statistical dead heat between the two options.”

In the VERSUS-CD study, vedolizumab was compared with ustekinumab, “with more patients not discontinuing ustekinumab therapy compared to vedolizumab,” he said. “This study also seems to favor sicker patients being treated with ustekinumab.”

“In both cases, we are starting to see the ‘order’ of treatments take shape, even before the benefit of head-to-head trials,” Dr. Swaminath said.

Dr. Buisson reports receiving grant support from AbbVie, Celltrion, Pfizer, and Takeda, as well as personal fees from AbbVie, Amgen, Arena, Biogen, Celltrion, Ferring, Janssen, MSD, Nexbiome, Pfizer, Roche, sanofi-aventis, Takeda, Tillots, and Vifor Pharma. Dr. Garcia reports receiving financial support for traveling and educational activities from MSD, Janssen, AbbVie, Takeda, and Ferring. Dr. Swaminath reports receiving advanced IBD fellowship support from Janssen and Takeda and is on the advisory board for Boehringer Ingelheim.

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

Both tofacitinib (Xeljanz) and vedolizumab (Entyvio) are effective options for people with ulcerative colitis (UC) who fail at least one antitumor necrosis factor (anti-TNF) therapy, a real-world study in France revealed.

However, response was superior with tofacitinib among people after primary failure to biologics and multiple therapeutic failure, the researchers report, including endoscopic improvement and mucosal healing.  

Anthony Buisson, MD, presented the results Feb. 18 at the 17th congress of the European Crohn’s and Colitis Organisation.
 

The French comparison

Although multiple therapeutic options are available to treat ulcerative colitis after anti-TNF failure, “there are no data comparing tofacitinib to vedolizumab in the real world,” said Dr. Buisson, a gastroenterologist at Clermont Auvergne University, Clermont-Ferrand, France.

In addition, network meta-analysis data are inconclusive, he said.

This led Dr. Buisson and colleagues to study adults with symptomatic UC with prior exposure to at least one anti-TNF treatment. They assessed 126 patients in a tofacitinib group and 178 in a vedolizumab group. The groups were comparable except for higher disease activity at baseline in the tofacitinib group.

The retrospective study was conducted at nine academic centers. Patients started either tofacitinib or vedolizumab between January 2019 and June 2021.

The primary endpoint, corticosteroid-free clinical remission at 16 weeks, was achieved by 45% of the tofacitinib group and 40% of the vedolizumab group. This difference was not statistically significant.

However, endoscopic improvement at week 16 did differ significantly and was achieved by 24% of the tofacitinib group versus 7% of the vedolizumab group (P = .0036).

“Tofacitinib and vedolizumab are effective to induce corticosteroid-free clinical remission at week 16 in patients with UC who failed at least one anti-TNF agent,” Dr. Buisson said.

“Vedolizumab seems to be less effective in cases of more severe UC and prior history of primary failure to any biologic,” he added.

Dr. Buisson said he and his colleagues plan to continue the study beyond 16 weeks to look at longterm outcomes.
 

The science from Spain

In another study presented at ECCO ‘22 Virtual, investigators from Spain compared vedolizumab to ustekinumab (Stelara) after at least one anti-TNF treatment failure, this time among people with Crohn’s disease.

Finding effective treatments after an anti-TNF failure is essential, Maria Jose Garcia, MD, said when presenting the results of the VERSUS-CD trial. “Over 20%-30% of Crohn’s disease patients are nonresponders or develop intolerance to anti-TNF therapies. Also, anti-TNF responders can experience a loss of response over time.”

Both vedolizumab and ustekinumab are effective for Crohn’s, she said. “But no clinical trial has compared both treatments, and limited data exist in real life.”

To remedy this situation, Dr. Garcia and colleagues studied 755 people from 30 medical centers in a national database in Spain who failed a previous anti-TNF agent, including 195 people switched to vedolizumab and 560 switched to ustekinumab. Luminal activity, perianal disease, or postoperative recurrence of Crohn’s were the indications for treatment.

The study’s main objective was to compare the short- and long-term treatment survival rate of vedolizumab and ustekinumab after anti-TNF therapy failure in clinical practice. Evaluating efficacy and safety were secondary aims.

“The treatment survival rate with ustekinumab was higher than with vedolizumab” over 5 years of follow-up, said Dr. Garcia, a gastroenterologist at Hospital Universitario Marqués de Valdecilla-IDIVAL, Santander, Spain. The difference was statistically significant (P < .001).

Just less than half (43%) of the 327 patients discontinued treatment over time, including 142 in the vedolizumab group and 185 in the ustekinumab group. The most frequent cause was primarily nonresponse.

Infection, arthralgia, and infusion reactions were the most common adverse events. The safety profile was similar between groups, Dr. Garcia said.

“In clinical practice, vedolizumab and ustekinumab are both effective after anti-TNF failure or intolerance in CD,” Dr. Garcia said, adding that, “the retention rate of ustekinumab was higher compared to vedolizumab.”

When asked if the results will change how she practices, Dr. Garcia responded, “This confirms the first choice is ustekinumab more than vedolizumab in clinical practice, because it seems the clinical remission and durability of the treatment is superior.”
 

More options means more questions

“Looking back almost 25 years ago, the struggle was how to work with just one biologic and how to make it last for patients who have already failed all the available therapies. All these years later, we have such riches that the question we most often deal with is ‘What’s my first treatment?’ for patients with inflammatory bowel disease,” Arun Swaminath, MD, said, when asked to comment on both studies.

“Increasingly, we are seeing industry do head-to-head trials of drugs, but this is a time-consuming and expensive process,” added Dr. Swaminath, chief of gastroenterology and director of the inflammatory bowel diseases program at Lenox Hill Hospital, New York.

The study from Dr. Buisson and colleagues in UC approaches the design of a head-to-head trial, Dr. Swaminath said. “In the end, their primary endpoint was a statistical dead heat between the two options.”

In the VERSUS-CD study, vedolizumab was compared with ustekinumab, “with more patients not discontinuing ustekinumab therapy compared to vedolizumab,” he said. “This study also seems to favor sicker patients being treated with ustekinumab.”

“In both cases, we are starting to see the ‘order’ of treatments take shape, even before the benefit of head-to-head trials,” Dr. Swaminath said.

Dr. Buisson reports receiving grant support from AbbVie, Celltrion, Pfizer, and Takeda, as well as personal fees from AbbVie, Amgen, Arena, Biogen, Celltrion, Ferring, Janssen, MSD, Nexbiome, Pfizer, Roche, sanofi-aventis, Takeda, Tillots, and Vifor Pharma. Dr. Garcia reports receiving financial support for traveling and educational activities from MSD, Janssen, AbbVie, Takeda, and Ferring. Dr. Swaminath reports receiving advanced IBD fellowship support from Janssen and Takeda and is on the advisory board for Boehringer Ingelheim.

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

Both tofacitinib (Xeljanz) and vedolizumab (Entyvio) are effective options for people with ulcerative colitis (UC) who fail at least one antitumor necrosis factor (anti-TNF) therapy, a real-world study in France revealed.

However, response was superior with tofacitinib among people after primary failure to biologics and multiple therapeutic failure, the researchers report, including endoscopic improvement and mucosal healing.  

Anthony Buisson, MD, presented the results Feb. 18 at the 17th congress of the European Crohn’s and Colitis Organisation.
 

The French comparison

Although multiple therapeutic options are available to treat ulcerative colitis after anti-TNF failure, “there are no data comparing tofacitinib to vedolizumab in the real world,” said Dr. Buisson, a gastroenterologist at Clermont Auvergne University, Clermont-Ferrand, France.

In addition, network meta-analysis data are inconclusive, he said.

This led Dr. Buisson and colleagues to study adults with symptomatic UC with prior exposure to at least one anti-TNF treatment. They assessed 126 patients in a tofacitinib group and 178 in a vedolizumab group. The groups were comparable except for higher disease activity at baseline in the tofacitinib group.

The retrospective study was conducted at nine academic centers. Patients started either tofacitinib or vedolizumab between January 2019 and June 2021.

The primary endpoint, corticosteroid-free clinical remission at 16 weeks, was achieved by 45% of the tofacitinib group and 40% of the vedolizumab group. This difference was not statistically significant.

However, endoscopic improvement at week 16 did differ significantly and was achieved by 24% of the tofacitinib group versus 7% of the vedolizumab group (P = .0036).

“Tofacitinib and vedolizumab are effective to induce corticosteroid-free clinical remission at week 16 in patients with UC who failed at least one anti-TNF agent,” Dr. Buisson said.

“Vedolizumab seems to be less effective in cases of more severe UC and prior history of primary failure to any biologic,” he added.

Dr. Buisson said he and his colleagues plan to continue the study beyond 16 weeks to look at longterm outcomes.
 

The science from Spain

In another study presented at ECCO ‘22 Virtual, investigators from Spain compared vedolizumab to ustekinumab (Stelara) after at least one anti-TNF treatment failure, this time among people with Crohn’s disease.

Finding effective treatments after an anti-TNF failure is essential, Maria Jose Garcia, MD, said when presenting the results of the VERSUS-CD trial. “Over 20%-30% of Crohn’s disease patients are nonresponders or develop intolerance to anti-TNF therapies. Also, anti-TNF responders can experience a loss of response over time.”

Both vedolizumab and ustekinumab are effective for Crohn’s, she said. “But no clinical trial has compared both treatments, and limited data exist in real life.”

To remedy this situation, Dr. Garcia and colleagues studied 755 people from 30 medical centers in a national database in Spain who failed a previous anti-TNF agent, including 195 people switched to vedolizumab and 560 switched to ustekinumab. Luminal activity, perianal disease, or postoperative recurrence of Crohn’s were the indications for treatment.

The study’s main objective was to compare the short- and long-term treatment survival rate of vedolizumab and ustekinumab after anti-TNF therapy failure in clinical practice. Evaluating efficacy and safety were secondary aims.

“The treatment survival rate with ustekinumab was higher than with vedolizumab” over 5 years of follow-up, said Dr. Garcia, a gastroenterologist at Hospital Universitario Marqués de Valdecilla-IDIVAL, Santander, Spain. The difference was statistically significant (P < .001).

Just less than half (43%) of the 327 patients discontinued treatment over time, including 142 in the vedolizumab group and 185 in the ustekinumab group. The most frequent cause was primarily nonresponse.

Infection, arthralgia, and infusion reactions were the most common adverse events. The safety profile was similar between groups, Dr. Garcia said.

“In clinical practice, vedolizumab and ustekinumab are both effective after anti-TNF failure or intolerance in CD,” Dr. Garcia said, adding that, “the retention rate of ustekinumab was higher compared to vedolizumab.”

When asked if the results will change how she practices, Dr. Garcia responded, “This confirms the first choice is ustekinumab more than vedolizumab in clinical practice, because it seems the clinical remission and durability of the treatment is superior.”
 

More options means more questions

“Looking back almost 25 years ago, the struggle was how to work with just one biologic and how to make it last for patients who have already failed all the available therapies. All these years later, we have such riches that the question we most often deal with is ‘What’s my first treatment?’ for patients with inflammatory bowel disease,” Arun Swaminath, MD, said, when asked to comment on both studies.

“Increasingly, we are seeing industry do head-to-head trials of drugs, but this is a time-consuming and expensive process,” added Dr. Swaminath, chief of gastroenterology and director of the inflammatory bowel diseases program at Lenox Hill Hospital, New York.

The study from Dr. Buisson and colleagues in UC approaches the design of a head-to-head trial, Dr. Swaminath said. “In the end, their primary endpoint was a statistical dead heat between the two options.”

In the VERSUS-CD study, vedolizumab was compared with ustekinumab, “with more patients not discontinuing ustekinumab therapy compared to vedolizumab,” he said. “This study also seems to favor sicker patients being treated with ustekinumab.”

“In both cases, we are starting to see the ‘order’ of treatments take shape, even before the benefit of head-to-head trials,” Dr. Swaminath said.

Dr. Buisson reports receiving grant support from AbbVie, Celltrion, Pfizer, and Takeda, as well as personal fees from AbbVie, Amgen, Arena, Biogen, Celltrion, Ferring, Janssen, MSD, Nexbiome, Pfizer, Roche, sanofi-aventis, Takeda, Tillots, and Vifor Pharma. Dr. Garcia reports receiving financial support for traveling and educational activities from MSD, Janssen, AbbVie, Takeda, and Ferring. Dr. Swaminath reports receiving advanced IBD fellowship support from Janssen and Takeda and is on the advisory board for Boehringer Ingelheim.

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

LAS VEGAS – Someday, pharmacogenomics will advance precision psychiatry, but in the opinion of Erika L. Nurmi, MD, PhD, routine use of genetic testing to guide clinical treatment decisions is not indicated.

“It’s misleading to rely on results of genetic tests to drive clinical treatment,” Dr. Nurmi, a child and adolescent psychiatrist in the department of psychiatry and biobehavioral sciences at the University of California, Los Angeles, said during an annual psychopharmacology update held by the Nevada Psychiatric Association. “There’s a lot of hope and promise there. But currently, we only know the tip of the iceberg about how drugs work and the genetics influencing these effects. Current testing is probably a very poor reflection of the complexity of drug effects.”

According to Dr. Nurmi, there are at least 165 Food and Drug Administration–approved drugs with pharmacogenetic information on 64 different biomarkers – 37% with CYP p450 notations. Of these, 32 psychiatric drugs have pharmacogenetic information, and most of them are dosing recommendations based on whether a patient has the variant. However, there is wide public acceptance of genetic testing in preventing the wrong drug from being used, in selecting the best drug dose, and avoiding side effects (Pharmacogenomics 2012;12[3]:197-204). “Most people have a lot of hope [for genetic testing in psychiatry],” Dr. Nurmi said. “But is the science really there? It doesn’t matter, because these companies are doing it, and you are being shown these reports from patients. Whether or not the science supports it, we’re going to have to interpret these reports and explain them to our patients – even if we don’t order them.”

Currently, she continued, clinicians practice trial and error prescribing where they might try one treatment in a class that they think that will work based on previous literature. If nothing works, they try another one. If that’s intolerable, they try a third treatment, and so on. “When we finally find the right treatment, it can take some time to get the dosing right,” Dr. Nurmi said. “So, it can take many months to get a child on the right medication. Precision treatment, on the other hand, would start off by taking a saliva or blood sample to get a printout that lets physicians know which drugs might be used with caution because they might lack efficacy at standard doses, which ones would likely have adverse effects at standard doses, and which are the best choices and what are the dosing recommendations for those choices. If we could get all the information to guide us, that would be a useful product, but right now, we don’t know enough to be able to make these determinations.”

Current evidence-based genetic testing supports a limited role for CYP2D6 and CYP2C19 genotyping because most psychiatric drugs are metabolized by those two enzymes. Poor metabolizers have two dysfunctional copies of the enzyme-encoding gene. This results in increased drug plasma levels with a potentially increased rate of adverse effects.

“Intermediate and extensive metabolizers usually have a normal phenotype, but you can also have ultrarapid metabolizers who have duplications or other enhancing mutations of the CYP gene,” Dr. Nurmi said. “This can result in lower bioavailability and possibly efficacy. Psychiatrists treat poor metabolizers and ultrarapid metabolizers all the time, because the variants are very common.” An estimated 10% of White people are poor metabolizers at the CYP2D6 gene while about 7% are ultrarapid metabolizers. At the same time, an estimated 20% of Asians, Africans, and Whites are poor metabolizers at the CYP2C19 gene. “So, you’re seeing a lot of this in your practice, and you’re probably changing dosing based on genetic differences in metabolism,” she said.

The only FDA pharmacodynamic treatment guideline is for the risk of Stevens-Johnson syndrome (SJS) with the use of carbamazepine. In a study of 44 patients with SJS, all were positive for the HLA-B*1502 variant, compared with 3% of carbamazepine-tolerant patients (Nature 2004;428[6982]:486). The frequency of carrying this variant is an estimated 1:10,000 among Whites and 1:1,000 among Asians. In 2007, the FDA recommended that patients of Asian ancestry should be screened for HLA-B*1502 prior to starting carbamazepine.

Genetic variation also predicts clinical outcome with atomoxetine use. “Most child psychiatrists I know think atomoxetine doesn’t work as a second-line nonstimulant medication for ADHD,” Dr. Nurmi said. “I’d like to convince you that why you think it doesn’t work is because of the genetics.” In a study published in 2019, Dr. Nurmi and colleagues reviewed medical literature and provided therapeutic recommendations for atomoxetine therapy based on CYP2D6 genotype (Clin Pharmacol Ther 2019 Jul;106[1]:94-102). They observed 10- to 30-fold plasma differences in drug exposure between normal metabolizers and poor metabolizers.

“Poor metabolizers therefore get more benefit, but they are also going to get more side effects,” she said. “FDA recommended doses are inadequate for normal metabolizers, so they had to make guidelines based on poor metabolizers because there would be too much risk for them at higher doses. One-third of individuals require doses above the FDA limit to achieve a therapeutic drug level.”

Dr. Nurmi warned that the existing evidence base for using these genetic tests in children “is really poor. There is no data in adults with any diagnosis other than depression, and even those studies are plagued by concerns. When you’re implementing decision support tools in your practice, the key factors are patient presentation, history and symptoms, your clinical skills, the evidence base, FDA recommendations, and patient autonomy. Appropriate incorporation of genetic data should include avoiding a medication with high toxicity (like SJS), titration planning (dose and titration speed adjustments), and choosing between medications in the same class with an indication or evidence base for the target disorder.” She added that while the benefit of current genetic testing is limited, it may help some patients feel more comfortable tolerating a medication. “For example, being able to tell someone with anxiety that their genetics suggests that they will not have side effects could be very powerful,” she said.

In a 2018 safety communication, the FDA warned the public about its concerns with companies making claims about how to use genetic test results to manage medication treatments that are not supported by recommendations in the FDA-approved drug labeling or other scientific evidence. The American Academy of Child and Adolescent Psychiatry also published a guide for patients and families.

Dr. Nurmi disclosed that she is an unpaid advisory board member for Myriad Genetics and the Tourette Association of America, a paid adviser for Teva Pharmaceuticals, and a recipient of research support from Emalex Pharmaceuticals. She has received research funding from the National Institutes Health, the International OCD Foundation, the Tourette Association of America, and the Brain & Behavior Research Foundation.

LAS VEGAS – Someday, pharmacogenomics will advance precision psychiatry, but in the opinion of Erika L. Nurmi, MD, PhD, routine use of genetic testing to guide clinical treatment decisions is not indicated.

“It’s misleading to rely on results of genetic tests to drive clinical treatment,” Dr. Nurmi, a child and adolescent psychiatrist in the department of psychiatry and biobehavioral sciences at the University of California, Los Angeles, said during an annual psychopharmacology update held by the Nevada Psychiatric Association. “There’s a lot of hope and promise there. But currently, we only know the tip of the iceberg about how drugs work and the genetics influencing these effects. Current testing is probably a very poor reflection of the complexity of drug effects.”

According to Dr. Nurmi, there are at least 165 Food and Drug Administration–approved drugs with pharmacogenetic information on 64 different biomarkers – 37% with CYP p450 notations. Of these, 32 psychiatric drugs have pharmacogenetic information, and most of them are dosing recommendations based on whether a patient has the variant. However, there is wide public acceptance of genetic testing in preventing the wrong drug from being used, in selecting the best drug dose, and avoiding side effects (Pharmacogenomics 2012;12[3]:197-204). “Most people have a lot of hope [for genetic testing in psychiatry],” Dr. Nurmi said. “But is the science really there? It doesn’t matter, because these companies are doing it, and you are being shown these reports from patients. Whether or not the science supports it, we’re going to have to interpret these reports and explain them to our patients – even if we don’t order them.”

Currently, she continued, clinicians practice trial and error prescribing where they might try one treatment in a class that they think that will work based on previous literature. If nothing works, they try another one. If that’s intolerable, they try a third treatment, and so on. “When we finally find the right treatment, it can take some time to get the dosing right,” Dr. Nurmi said. “So, it can take many months to get a child on the right medication. Precision treatment, on the other hand, would start off by taking a saliva or blood sample to get a printout that lets physicians know which drugs might be used with caution because they might lack efficacy at standard doses, which ones would likely have adverse effects at standard doses, and which are the best choices and what are the dosing recommendations for those choices. If we could get all the information to guide us, that would be a useful product, but right now, we don’t know enough to be able to make these determinations.”

Current evidence-based genetic testing supports a limited role for CYP2D6 and CYP2C19 genotyping because most psychiatric drugs are metabolized by those two enzymes. Poor metabolizers have two dysfunctional copies of the enzyme-encoding gene. This results in increased drug plasma levels with a potentially increased rate of adverse effects.

“Intermediate and extensive metabolizers usually have a normal phenotype, but you can also have ultrarapid metabolizers who have duplications or other enhancing mutations of the CYP gene,” Dr. Nurmi said. “This can result in lower bioavailability and possibly efficacy. Psychiatrists treat poor metabolizers and ultrarapid metabolizers all the time, because the variants are very common.” An estimated 10% of White people are poor metabolizers at the CYP2D6 gene while about 7% are ultrarapid metabolizers. At the same time, an estimated 20% of Asians, Africans, and Whites are poor metabolizers at the CYP2C19 gene. “So, you’re seeing a lot of this in your practice, and you’re probably changing dosing based on genetic differences in metabolism,” she said.

The only FDA pharmacodynamic treatment guideline is for the risk of Stevens-Johnson syndrome (SJS) with the use of carbamazepine. In a study of 44 patients with SJS, all were positive for the HLA-B*1502 variant, compared with 3% of carbamazepine-tolerant patients (Nature 2004;428[6982]:486). The frequency of carrying this variant is an estimated 1:10,000 among Whites and 1:1,000 among Asians. In 2007, the FDA recommended that patients of Asian ancestry should be screened for HLA-B*1502 prior to starting carbamazepine.

Genetic variation also predicts clinical outcome with atomoxetine use. “Most child psychiatrists I know think atomoxetine doesn’t work as a second-line nonstimulant medication for ADHD,” Dr. Nurmi said. “I’d like to convince you that why you think it doesn’t work is because of the genetics.” In a study published in 2019, Dr. Nurmi and colleagues reviewed medical literature and provided therapeutic recommendations for atomoxetine therapy based on CYP2D6 genotype (Clin Pharmacol Ther 2019 Jul;106[1]:94-102). They observed 10- to 30-fold plasma differences in drug exposure between normal metabolizers and poor metabolizers.

“Poor metabolizers therefore get more benefit, but they are also going to get more side effects,” she said. “FDA recommended doses are inadequate for normal metabolizers, so they had to make guidelines based on poor metabolizers because there would be too much risk for them at higher doses. One-third of individuals require doses above the FDA limit to achieve a therapeutic drug level.”

Dr. Nurmi warned that the existing evidence base for using these genetic tests in children “is really poor. There is no data in adults with any diagnosis other than depression, and even those studies are plagued by concerns. When you’re implementing decision support tools in your practice, the key factors are patient presentation, history and symptoms, your clinical skills, the evidence base, FDA recommendations, and patient autonomy. Appropriate incorporation of genetic data should include avoiding a medication with high toxicity (like SJS), titration planning (dose and titration speed adjustments), and choosing between medications in the same class with an indication or evidence base for the target disorder.” She added that while the benefit of current genetic testing is limited, it may help some patients feel more comfortable tolerating a medication. “For example, being able to tell someone with anxiety that their genetics suggests that they will not have side effects could be very powerful,” she said.

In a 2018 safety communication, the FDA warned the public about its concerns with companies making claims about how to use genetic test results to manage medication treatments that are not supported by recommendations in the FDA-approved drug labeling or other scientific evidence. The American Academy of Child and Adolescent Psychiatry also published a guide for patients and families.

Dr. Nurmi disclosed that she is an unpaid advisory board member for Myriad Genetics and the Tourette Association of America, a paid adviser for Teva Pharmaceuticals, and a recipient of research support from Emalex Pharmaceuticals. She has received research funding from the National Institutes Health, the International OCD Foundation, the Tourette Association of America, and the Brain & Behavior Research Foundation.

LAS VEGAS – Someday, pharmacogenomics will advance precision psychiatry, but in the opinion of Erika L. Nurmi, MD, PhD, routine use of genetic testing to guide clinical treatment decisions is not indicated.

“It’s misleading to rely on results of genetic tests to drive clinical treatment,” Dr. Nurmi, a child and adolescent psychiatrist in the department of psychiatry and biobehavioral sciences at the University of California, Los Angeles, said during an annual psychopharmacology update held by the Nevada Psychiatric Association. “There’s a lot of hope and promise there. But currently, we only know the tip of the iceberg about how drugs work and the genetics influencing these effects. Current testing is probably a very poor reflection of the complexity of drug effects.”

According to Dr. Nurmi, there are at least 165 Food and Drug Administration–approved drugs with pharmacogenetic information on 64 different biomarkers – 37% with CYP p450 notations. Of these, 32 psychiatric drugs have pharmacogenetic information, and most of them are dosing recommendations based on whether a patient has the variant. However, there is wide public acceptance of genetic testing in preventing the wrong drug from being used, in selecting the best drug dose, and avoiding side effects (Pharmacogenomics 2012;12[3]:197-204). “Most people have a lot of hope [for genetic testing in psychiatry],” Dr. Nurmi said. “But is the science really there? It doesn’t matter, because these companies are doing it, and you are being shown these reports from patients. Whether or not the science supports it, we’re going to have to interpret these reports and explain them to our patients – even if we don’t order them.”

Currently, she continued, clinicians practice trial and error prescribing where they might try one treatment in a class that they think that will work based on previous literature. If nothing works, they try another one. If that’s intolerable, they try a third treatment, and so on. “When we finally find the right treatment, it can take some time to get the dosing right,” Dr. Nurmi said. “So, it can take many months to get a child on the right medication. Precision treatment, on the other hand, would start off by taking a saliva or blood sample to get a printout that lets physicians know which drugs might be used with caution because they might lack efficacy at standard doses, which ones would likely have adverse effects at standard doses, and which are the best choices and what are the dosing recommendations for those choices. If we could get all the information to guide us, that would be a useful product, but right now, we don’t know enough to be able to make these determinations.”

Current evidence-based genetic testing supports a limited role for CYP2D6 and CYP2C19 genotyping because most psychiatric drugs are metabolized by those two enzymes. Poor metabolizers have two dysfunctional copies of the enzyme-encoding gene. This results in increased drug plasma levels with a potentially increased rate of adverse effects.

“Intermediate and extensive metabolizers usually have a normal phenotype, but you can also have ultrarapid metabolizers who have duplications or other enhancing mutations of the CYP gene,” Dr. Nurmi said. “This can result in lower bioavailability and possibly efficacy. Psychiatrists treat poor metabolizers and ultrarapid metabolizers all the time, because the variants are very common.” An estimated 10% of White people are poor metabolizers at the CYP2D6 gene while about 7% are ultrarapid metabolizers. At the same time, an estimated 20% of Asians, Africans, and Whites are poor metabolizers at the CYP2C19 gene. “So, you’re seeing a lot of this in your practice, and you’re probably changing dosing based on genetic differences in metabolism,” she said.

The only FDA pharmacodynamic treatment guideline is for the risk of Stevens-Johnson syndrome (SJS) with the use of carbamazepine. In a study of 44 patients with SJS, all were positive for the HLA-B*1502 variant, compared with 3% of carbamazepine-tolerant patients (Nature 2004;428[6982]:486). The frequency of carrying this variant is an estimated 1:10,000 among Whites and 1:1,000 among Asians. In 2007, the FDA recommended that patients of Asian ancestry should be screened for HLA-B*1502 prior to starting carbamazepine.

Genetic variation also predicts clinical outcome with atomoxetine use. “Most child psychiatrists I know think atomoxetine doesn’t work as a second-line nonstimulant medication for ADHD,” Dr. Nurmi said. “I’d like to convince you that why you think it doesn’t work is because of the genetics.” In a study published in 2019, Dr. Nurmi and colleagues reviewed medical literature and provided therapeutic recommendations for atomoxetine therapy based on CYP2D6 genotype (Clin Pharmacol Ther 2019 Jul;106[1]:94-102). They observed 10- to 30-fold plasma differences in drug exposure between normal metabolizers and poor metabolizers.

“Poor metabolizers therefore get more benefit, but they are also going to get more side effects,” she said. “FDA recommended doses are inadequate for normal metabolizers, so they had to make guidelines based on poor metabolizers because there would be too much risk for them at higher doses. One-third of individuals require doses above the FDA limit to achieve a therapeutic drug level.”

Dr. Nurmi warned that the existing evidence base for using these genetic tests in children “is really poor. There is no data in adults with any diagnosis other than depression, and even those studies are plagued by concerns. When you’re implementing decision support tools in your practice, the key factors are patient presentation, history and symptoms, your clinical skills, the evidence base, FDA recommendations, and patient autonomy. Appropriate incorporation of genetic data should include avoiding a medication with high toxicity (like SJS), titration planning (dose and titration speed adjustments), and choosing between medications in the same class with an indication or evidence base for the target disorder.” She added that while the benefit of current genetic testing is limited, it may help some patients feel more comfortable tolerating a medication. “For example, being able to tell someone with anxiety that their genetics suggests that they will not have side effects could be very powerful,” she said.

In a 2018 safety communication, the FDA warned the public about its concerns with companies making claims about how to use genetic test results to manage medication treatments that are not supported by recommendations in the FDA-approved drug labeling or other scientific evidence. The American Academy of Child and Adolescent Psychiatry also published a guide for patients and families.

Dr. Nurmi disclosed that she is an unpaid advisory board member for Myriad Genetics and the Tourette Association of America, a paid adviser for Teva Pharmaceuticals, and a recipient of research support from Emalex Pharmaceuticals. She has received research funding from the National Institutes Health, the International OCD Foundation, the Tourette Association of America, and the Brain & Behavior Research Foundation.