News

TOPLINE:

Melatonin supplementation is linked to a reduced risk for developing age-related macular degeneration (AMD) and slowing its progression, suggesting potential as a preventive therapy.

METHODOLOGY:

• Researchers analyzed data from the TriNetX database, covering electronic medical records across the United States from December 2023 to March 2024.
• The retrospective study included patients aged ≥ 50 years, divided into groups based on their history of AMD and melatonin medication codes between November 2008 and November 2023.
• Propensity score matching was used to compare melatonin users and nonusers for the risk for developing any form of AMD or the progression to exudative AMD from the nonexudative form of the condition.

TAKEAWAY:

• Use of melatonin was associated with a 58% reduction in the risk for developing AMD, according to the researchers.
• In people with nonexudative AMD, use of the supplement was linked to a 56% lower risk for progression to exudative AMD.
• The findings were consistent across age groups, suggesting melatonin’s benefits may extend to older populations at higher risk for AMD, the researchers reported.

IN PRACTICE:

“In this cohort study of 121,523 patients with no history of AMD aged ≥ 50 years, taking melatonin was associated with a decreased risk of developing AMD,” the authors of the study wrote. “Likewise, among 66,253 patients with preexisting nonexudative AMD, melatonin supplementation was negatively associated with the rate of progression to exudative AMD.”

Studies in animals and humans have shown melatonin may be a potent antioxidant and anti-inflammatory agent and have both antiangiogenic and mitochondrial-preserving properties, the authors noted. The new findings “provide a rationale for expanding clinical research on the potential therapeutic efficacy of melatonin in preventing AMD development or its progression,” they added. 

SOURCE:

The study was led by Hejin Jeong, Case Western Reserve University School of Medicine, Cleveland, and was published online in JAMA Ophthalmology.

LIMITATIONS:

The study’s reliance on diagnostic codes may have limited the accuracy of identifying AMD progression. Variations in coding practices and the reporting of over-the-counter medications like melatonin could have influenced the results. The study did not control for all modifiable risk factors for AMD, which may have introduced healthy user bias.

DISCLOSURES:

The authors reported various potential conflicts of interest, including receiving personal fees and grants from various pharmaceutical companies. The study was funded by grants from the National Institutes of Health and the Cleveland Eye Bank Foundation.

This article was created using several editorial tools, including AI, as part of the process. Human editors reviewed this content before publication.

A version of this article appeared on Medscape.com.

TOPLINE:

Melatonin supplementation is linked to a reduced risk for developing age-related macular degeneration (AMD) and slowing its progression, suggesting potential as a preventive therapy.

METHODOLOGY:

• Researchers analyzed data from the TriNetX database, covering electronic medical records across the United States from December 2023 to March 2024.
• The retrospective study included patients aged ≥ 50 years, divided into groups based on their history of AMD and melatonin medication codes between November 2008 and November 2023.
• Propensity score matching was used to compare melatonin users and nonusers for the risk for developing any form of AMD or the progression to exudative AMD from the nonexudative form of the condition.

TAKEAWAY:

• Use of melatonin was associated with a 58% reduction in the risk for developing AMD, according to the researchers.
• In people with nonexudative AMD, use of the supplement was linked to a 56% lower risk for progression to exudative AMD.
• The findings were consistent across age groups, suggesting melatonin’s benefits may extend to older populations at higher risk for AMD, the researchers reported.

IN PRACTICE:

“In this cohort study of 121,523 patients with no history of AMD aged ≥ 50 years, taking melatonin was associated with a decreased risk of developing AMD,” the authors of the study wrote. “Likewise, among 66,253 patients with preexisting nonexudative AMD, melatonin supplementation was negatively associated with the rate of progression to exudative AMD.”

Studies in animals and humans have shown melatonin may be a potent antioxidant and anti-inflammatory agent and have both antiangiogenic and mitochondrial-preserving properties, the authors noted. The new findings “provide a rationale for expanding clinical research on the potential therapeutic efficacy of melatonin in preventing AMD development or its progression,” they added. 

SOURCE:

The study was led by Hejin Jeong, Case Western Reserve University School of Medicine, Cleveland, and was published online in JAMA Ophthalmology.

LIMITATIONS:

The study’s reliance on diagnostic codes may have limited the accuracy of identifying AMD progression. Variations in coding practices and the reporting of over-the-counter medications like melatonin could have influenced the results. The study did not control for all modifiable risk factors for AMD, which may have introduced healthy user bias.

DISCLOSURES:

The authors reported various potential conflicts of interest, including receiving personal fees and grants from various pharmaceutical companies. The study was funded by grants from the National Institutes of Health and the Cleveland Eye Bank Foundation.

This article was created using several editorial tools, including AI, as part of the process. Human editors reviewed this content before publication.

A version of this article appeared on Medscape.com.

TOPLINE:

Melatonin supplementation is linked to a reduced risk for developing age-related macular degeneration (AMD) and slowing its progression, suggesting potential as a preventive therapy.

METHODOLOGY:

• Researchers analyzed data from the TriNetX database, covering electronic medical records across the United States from December 2023 to March 2024.
• The retrospective study included patients aged ≥ 50 years, divided into groups based on their history of AMD and melatonin medication codes between November 2008 and November 2023.
• Propensity score matching was used to compare melatonin users and nonusers for the risk for developing any form of AMD or the progression to exudative AMD from the nonexudative form of the condition.

TAKEAWAY:

• Use of melatonin was associated with a 58% reduction in the risk for developing AMD, according to the researchers.
• In people with nonexudative AMD, use of the supplement was linked to a 56% lower risk for progression to exudative AMD.
• The findings were consistent across age groups, suggesting melatonin’s benefits may extend to older populations at higher risk for AMD, the researchers reported.

IN PRACTICE:

“In this cohort study of 121,523 patients with no history of AMD aged ≥ 50 years, taking melatonin was associated with a decreased risk of developing AMD,” the authors of the study wrote. “Likewise, among 66,253 patients with preexisting nonexudative AMD, melatonin supplementation was negatively associated with the rate of progression to exudative AMD.”

Studies in animals and humans have shown melatonin may be a potent antioxidant and anti-inflammatory agent and have both antiangiogenic and mitochondrial-preserving properties, the authors noted. The new findings “provide a rationale for expanding clinical research on the potential therapeutic efficacy of melatonin in preventing AMD development or its progression,” they added. 

SOURCE:

The study was led by Hejin Jeong, Case Western Reserve University School of Medicine, Cleveland, and was published online in JAMA Ophthalmology.

LIMITATIONS:

The study’s reliance on diagnostic codes may have limited the accuracy of identifying AMD progression. Variations in coding practices and the reporting of over-the-counter medications like melatonin could have influenced the results. The study did not control for all modifiable risk factors for AMD, which may have introduced healthy user bias.

DISCLOSURES:

The authors reported various potential conflicts of interest, including receiving personal fees and grants from various pharmaceutical companies. The study was funded by grants from the National Institutes of Health and the Cleveland Eye Bank Foundation.

This article was created using several editorial tools, including AI, as part of the process. Human editors reviewed this content before publication.

A version of this article appeared on Medscape.com.

TOPLINE:

Taking antidepressants in midlife was not associated with an increased risk of subsequent Alzheimer’s disease (AD) or AD-related dementias (ADRD), data from a large prospective study of US veterans show.

METHODOLOGY:

• Investigators analyzed data from 35,200 US veterans aged ≥ 55 years diagnosed with major depressive disorder from January 1, 2000, to June 1, 2022, and followed them for ≤ 20 years to track subsequent AD/ADRD diagnoses.
• Health information was pulled from electronic health records of the Veterans Health Administration (VHA) Corporate Data Warehouse, and veterans had to be at the VHA for ≥ 1 year before diagnosis.
• Participants were considered to be exposed to an antidepressant when a prescription lasted ≥ 3 months.

TAKEAWAY:

• A total of 32,500 individuals were diagnosed with MDD. The mean age was 65 years, and 91% were men. 17,000 patients received antidepressants for a median duration of 4 years. Median follow-up time was 3.2 years.
• There was no significant association between antidepressant exposure and the risk for AD/ADRD (events = 1056; hazard ratio, 0.93; 95% CI, 0.80-1.08) vs no exposure.
• In a subgroup analysis, investigators found no significant link between different classes of antidepressants and dementia risk. These included selective serotonin reuptake inhibitors, norepinephrine and dopamine reuptake inhibitors, and serotonin-norepinephrine reuptake inhibitors.
• Investigators emphasized the need for further research, particularly in populations with a larger representation of female patients.

IN PRACTICE:

“A possibility for the conflicting results in retrospective studies is that the heightened risk identified in participants on antidepressants may be attributed to depression itself, rather than the result of a potential pharmacological action. So, this and other clinical confounding factors need to be taken into account,” the investigators noted.

SOURCE:

The study was led by Jaime Ramos-Cejudo, PhD, VA Boston Healthcare System, Boston. It was published online May 8 in Alzheimer’s & Dementia.

LIMITATIONS:

The cohort’s relatively young age limited the number of dementia cases captured. Data from supplemental insurance, including Medicare, were not included, potentially limiting outcome capture.

DISCLOSURES:

The study was supported by the National Institutes of Health and the National Alzheimer’s Coordinating Center. The authors declared no conflicts of interest.

This article was created using several editorial tools, including AI, as part of the process. Human editors reviewed this content before publication.

A version of this article appeared on Medscape.com.

TOPLINE:

Taking antidepressants in midlife was not associated with an increased risk of subsequent Alzheimer’s disease (AD) or AD-related dementias (ADRD), data from a large prospective study of US veterans show.

METHODOLOGY:

• Investigators analyzed data from 35,200 US veterans aged ≥ 55 years diagnosed with major depressive disorder from January 1, 2000, to June 1, 2022, and followed them for ≤ 20 years to track subsequent AD/ADRD diagnoses.
• Health information was pulled from electronic health records of the Veterans Health Administration (VHA) Corporate Data Warehouse, and veterans had to be at the VHA for ≥ 1 year before diagnosis.
• Participants were considered to be exposed to an antidepressant when a prescription lasted ≥ 3 months.

TAKEAWAY:

• A total of 32,500 individuals were diagnosed with MDD. The mean age was 65 years, and 91% were men. 17,000 patients received antidepressants for a median duration of 4 years. Median follow-up time was 3.2 years.
• There was no significant association between antidepressant exposure and the risk for AD/ADRD (events = 1056; hazard ratio, 0.93; 95% CI, 0.80-1.08) vs no exposure.
• In a subgroup analysis, investigators found no significant link between different classes of antidepressants and dementia risk. These included selective serotonin reuptake inhibitors, norepinephrine and dopamine reuptake inhibitors, and serotonin-norepinephrine reuptake inhibitors.
• Investigators emphasized the need for further research, particularly in populations with a larger representation of female patients.

IN PRACTICE:

“A possibility for the conflicting results in retrospective studies is that the heightened risk identified in participants on antidepressants may be attributed to depression itself, rather than the result of a potential pharmacological action. So, this and other clinical confounding factors need to be taken into account,” the investigators noted.

SOURCE:

The study was led by Jaime Ramos-Cejudo, PhD, VA Boston Healthcare System, Boston. It was published online May 8 in Alzheimer’s & Dementia.

LIMITATIONS:

The cohort’s relatively young age limited the number of dementia cases captured. Data from supplemental insurance, including Medicare, were not included, potentially limiting outcome capture.

DISCLOSURES:

The study was supported by the National Institutes of Health and the National Alzheimer’s Coordinating Center. The authors declared no conflicts of interest.

This article was created using several editorial tools, including AI, as part of the process. Human editors reviewed this content before publication.

A version of this article appeared on Medscape.com.

TOPLINE:

Taking antidepressants in midlife was not associated with an increased risk of subsequent Alzheimer’s disease (AD) or AD-related dementias (ADRD), data from a large prospective study of US veterans show.

METHODOLOGY:

• Investigators analyzed data from 35,200 US veterans aged ≥ 55 years diagnosed with major depressive disorder from January 1, 2000, to June 1, 2022, and followed them for ≤ 20 years to track subsequent AD/ADRD diagnoses.
• Health information was pulled from electronic health records of the Veterans Health Administration (VHA) Corporate Data Warehouse, and veterans had to be at the VHA for ≥ 1 year before diagnosis.
• Participants were considered to be exposed to an antidepressant when a prescription lasted ≥ 3 months.

TAKEAWAY:

• A total of 32,500 individuals were diagnosed with MDD. The mean age was 65 years, and 91% were men. 17,000 patients received antidepressants for a median duration of 4 years. Median follow-up time was 3.2 years.
• There was no significant association between antidepressant exposure and the risk for AD/ADRD (events = 1056; hazard ratio, 0.93; 95% CI, 0.80-1.08) vs no exposure.
• In a subgroup analysis, investigators found no significant link between different classes of antidepressants and dementia risk. These included selective serotonin reuptake inhibitors, norepinephrine and dopamine reuptake inhibitors, and serotonin-norepinephrine reuptake inhibitors.
• Investigators emphasized the need for further research, particularly in populations with a larger representation of female patients.

IN PRACTICE:

“A possibility for the conflicting results in retrospective studies is that the heightened risk identified in participants on antidepressants may be attributed to depression itself, rather than the result of a potential pharmacological action. So, this and other clinical confounding factors need to be taken into account,” the investigators noted.

SOURCE:

The study was led by Jaime Ramos-Cejudo, PhD, VA Boston Healthcare System, Boston. It was published online May 8 in Alzheimer’s & Dementia.

LIMITATIONS:

The cohort’s relatively young age limited the number of dementia cases captured. Data from supplemental insurance, including Medicare, were not included, potentially limiting outcome capture.

DISCLOSURES:

The study was supported by the National Institutes of Health and the National Alzheimer’s Coordinating Center. The authors declared no conflicts of interest.

This article was created using several editorial tools, including AI, as part of the process. Human editors reviewed this content before publication.

A version of this article appeared on Medscape.com.

The antibody-drug conjugate trastuzumab deruxtecan, or T-DXd, is an effective first-line treatment in patients with HER2-low metastatic breast cancer, conferring an additional 5 months’ progression-free survival over chemotherapy.

HER2-low cancers express levels of human epidermal growth factor receptor 2 that are below standard thresholds for HER2-positive immunohistochemistry. In 2022, results from the DESTINY-Breast04 trial showed T-DXd (Enhertu, AstraZeneca) to be an effective second-line chemotherapy in patients with HER2-low metastatic breast cancer.

The highly awaited new findings, from the manufacturer-sponsored, open-label Phase 3 DESTINY-Breast06 trial, were presented at the annual meeting of the American Society of Clinical Oncology (ASCO) in Chicago, Illinois.

The findings not only definitively establish a role for T-DXd earlier in the treatment sequence for HER2-low cancers, they also suggest benefit in a group of patients designated for the purposes of this trial to be HER2-ultralow. These patients have cancers with only faintly detectable HER2 expression on currently used assays (J Clin Oncol 42, 2024 [suppl 17; abstr LBA 1000]).

In a separate set of findings also presented at ASCO, from the randomized phase 1B open-label study, DESTINY-Breast07, T-Dxd showed efficacy in previously untreated HER2-positive metastatic breast cancer patients both alone and in combination with the monoclonal antibody pertuzumab (Perjeta, Genentech).
 

DESTINY-Breast06 Methods and Results

The DESTINY-Breast06 findings were presented by lead investigator Guiseppe Curigliano, MD, PhD, of the University of Milan and European Institute of Oncology. Dr. Curigliano and his colleagues randomized 866 patients with metastatic breast cancer: 436 to intravenous T-Dxd and 430 to the investigator’s choice of capecitabine, nab-paclitaxel, or paclitaxel chemotherapy. The investigators chose capecitabine 60% of the time.

Most patients had cancers classed as HER2 low (immunohistochemistry 1+ or 2+), while 153 had cancers classed by investigators as HER2-ultralow (IHC 0 with membrane staining or IHC under 1+). Patients enrolled in the study were those whose disease had progressed after endocrine therapy with or without targeted therapy. Patients’ median age was between 57 and 58, and all were chemotherapy-naive in the metastatic breast cancer setting.

The main outcome of the study was median progression-free survival in the HER2-low group. T-Dxd was seen improving progression-free survival, with median 13.2 months vs. 8.1 months (hazard ratio, 0.62; 95% confidence interval, 0.51-0.74; P < .0001). In the intention-to-treat population, which included the HER2 ultralow patients, the benefit was the same (HR, 0.63; 95% CI, 0.53-0.75; P < .0001). This suggested that T-DXd is also effective in these patients, and it will be extremely important going forward to identify the lowest level of HER2 expression in metastatic breast cancers that can still benefit from therapy with T-DxD, Dr. Curigliano said.

Overall survival could not be assessed in the study cohort because complete data were not yet available, Dr. Curigliano said. However, trends pointed to an advantage for T-DXd, and tumor response rates were markedly higher with T-DXd: 57% compared with 31% for standard chemotherapy in the full cohort.

Serious treatment-emergent adverse events were more common in the T-Dxd–treated patients, with 11% of that arm developing drug-related interstitial lung disease, and three patients dying of it. Five patients in the T-DXd arm died of adverse events deemed treatment-related, and none died from treatment-related adverse events in the standard chemotherapy arm. Altogether 11 patients died in the T-DXd arm and 6 in the chemotherapy arm.
 

Clinical Implications of DESTINY-Breast06

The DESTINY-Breast06 data show that “we have to again change how we think about HER2 expression. Even very low levels of HER2 expression matter, and they can be leveraged to improve the treatment for our patients,” said Ian Krop, MD, PhD, of the Yale Cancer Center in New Haven, Connecticut, during the session where the results were presented.

But T-DXd may not be an appropriate first choice for all patients, especially given the safety concerns associated with T-DXd, he continued. With overall survival and quality-of-life data still lacking, clinicians will have to determine on a case-by-case basis who should get T-DXd in the first line.

“For patients who have symptomatic metastatic disease, who need a response to address those symptoms, those in whom you think chemotherapy may not work as well because they had, for example, a short recurrence interval after their adjuvant chemotherapy — using T-DXd in that first-line setting makes perfect sense to take advantage of the substantially higher response rate compared to chemo,” Dr. Krop said. “But for patients who have asymptomatic low burdens of disease, it seems very reasonable to consider using a well-tolerated chemotherapy like capecitabine in the first line, and then using T-DXd in the second line.”

In an interview, Erica Mayer, MD, of the Dana Farber Cancer Institute in Boston, Massachusetts, said patient choice will also matter in determining whether T-DXd is a first-line option. The known toxicity of T-DXd was underscored by the latest findings, she noted, while capecitabine, one of the chemotherapy choices in the control arm of the study, “really reflects what the majority of breast cancer doctors tend to offer, both because of the efficacy of the drug, but also because it’s oral, it’s well tolerated, and you don’t lose your hair.”
 

DESTINY-Breast07 Results

The DESTINY-Breast07 findings, from a Phase 1B open-label trial measuring safety and tolerability, were presented by Fabrice Andre, MD, PhD, of Université Paris Saclay in Paris, France. Dr. Andre and his colleagues presented the first data comparing T-DXd monotherapy and T-DXd with pertuzumab — a monoclonal antibody targeting HER2 — as a first-line treatment in patients with HER2-overexpressing (immunohistochemistry 3 and above) metastatic breast cancer. (J Clin Oncol 42, 2024 [suppl 16; abstr 1009]).

Current first-line standard of care for these patients is pertuzumab, trastuzumab, and docetaxel, based on results from the 2015 CLEOPATRA trial. T-DXd is currently approved as a second-line treatment.

Dr. Andre and his colleagues randomized 75 patients to monotherapy with T-DXd and 50 to combined therapy, with a median follow-up of 2 years.

After 1 year of treatment, combination of T-DXd and pertuzumab was seen to be associated with a progression-free survival of 89% at 1 year (80% CI, 81.9-93.9), compared with 80% in patients treated with T-DXd alone (80% CI, 73.7-86.1). Objective tumor response rate was 84% for the combined therapy at 12 weeks, with 20% of patients seeing a complete response, compared with 76% and 8%, respectively, for monotherapy.

As in the DESTINY-Breast06 trial, adverse events were high, with interstitial lung disease seen in 9% of patients in the monotherapy group and in 14% of the combined-therapy patients, although no treatment-related deaths occurred.

A randomized phase 3 trial, DESTINY Breast09, will now compare the monotherapy and the combined therapy with standard care.

T-DXd has seen a rapidly expanding role in treating breast and other solid tumors. The DESTINY Breast06 findings will move up its place in the treatment algorithm for metastatic breast cancer, “allowing us to now offer T-DXd as the first chemotherapy choice for patients who are making that transition to chemotherapy over many of the traditional provider choices that we previously have offered,” Dr. Mayer said.

The results “support the use of not only this specific agent, but also the concept of antibody drug conjugates as a very effective way to treat malignancy,” she added.

Dr. Curigliano reported receiving speaker’s fees, research funding, and other support from AstraZeneca and Daiichi Sankyo, among other companies, as did most of his co-authors, of whom three were AstraZeneca employees. Dr. Fabrice disclosed receiving research funding, travel compensation, and/or advisory fees from AstraZeneca and other entities, as did several of his co-authors. Two of his co-authors were employed by AstraZeneca and Roche, manufacturers of the study drugs. Dr. Krop and Dr. Mayer disclosed relationships with AstraZeneca and others.

The antibody-drug conjugate trastuzumab deruxtecan, or T-DXd, is an effective first-line treatment in patients with HER2-low metastatic breast cancer, conferring an additional 5 months’ progression-free survival over chemotherapy.

HER2-low cancers express levels of human epidermal growth factor receptor 2 that are below standard thresholds for HER2-positive immunohistochemistry. In 2022, results from the DESTINY-Breast04 trial showed T-DXd (Enhertu, AstraZeneca) to be an effective second-line chemotherapy in patients with HER2-low metastatic breast cancer.

The highly awaited new findings, from the manufacturer-sponsored, open-label Phase 3 DESTINY-Breast06 trial, were presented at the annual meeting of the American Society of Clinical Oncology (ASCO) in Chicago, Illinois.

The findings not only definitively establish a role for T-DXd earlier in the treatment sequence for HER2-low cancers, they also suggest benefit in a group of patients designated for the purposes of this trial to be HER2-ultralow. These patients have cancers with only faintly detectable HER2 expression on currently used assays (J Clin Oncol 42, 2024 [suppl 17; abstr LBA 1000]).

In a separate set of findings also presented at ASCO, from the randomized phase 1B open-label study, DESTINY-Breast07, T-Dxd showed efficacy in previously untreated HER2-positive metastatic breast cancer patients both alone and in combination with the monoclonal antibody pertuzumab (Perjeta, Genentech).
 

DESTINY-Breast06 Methods and Results

The DESTINY-Breast06 findings were presented by lead investigator Guiseppe Curigliano, MD, PhD, of the University of Milan and European Institute of Oncology. Dr. Curigliano and his colleagues randomized 866 patients with metastatic breast cancer: 436 to intravenous T-Dxd and 430 to the investigator’s choice of capecitabine, nab-paclitaxel, or paclitaxel chemotherapy. The investigators chose capecitabine 60% of the time.

Most patients had cancers classed as HER2 low (immunohistochemistry 1+ or 2+), while 153 had cancers classed by investigators as HER2-ultralow (IHC 0 with membrane staining or IHC under 1+). Patients enrolled in the study were those whose disease had progressed after endocrine therapy with or without targeted therapy. Patients’ median age was between 57 and 58, and all were chemotherapy-naive in the metastatic breast cancer setting.

The main outcome of the study was median progression-free survival in the HER2-low group. T-Dxd was seen improving progression-free survival, with median 13.2 months vs. 8.1 months (hazard ratio, 0.62; 95% confidence interval, 0.51-0.74; P < .0001). In the intention-to-treat population, which included the HER2 ultralow patients, the benefit was the same (HR, 0.63; 95% CI, 0.53-0.75; P < .0001). This suggested that T-DXd is also effective in these patients, and it will be extremely important going forward to identify the lowest level of HER2 expression in metastatic breast cancers that can still benefit from therapy with T-DxD, Dr. Curigliano said.

Overall survival could not be assessed in the study cohort because complete data were not yet available, Dr. Curigliano said. However, trends pointed to an advantage for T-DXd, and tumor response rates were markedly higher with T-DXd: 57% compared with 31% for standard chemotherapy in the full cohort.

Serious treatment-emergent adverse events were more common in the T-Dxd–treated patients, with 11% of that arm developing drug-related interstitial lung disease, and three patients dying of it. Five patients in the T-DXd arm died of adverse events deemed treatment-related, and none died from treatment-related adverse events in the standard chemotherapy arm. Altogether 11 patients died in the T-DXd arm and 6 in the chemotherapy arm.
 

Clinical Implications of DESTINY-Breast06

The DESTINY-Breast06 data show that “we have to again change how we think about HER2 expression. Even very low levels of HER2 expression matter, and they can be leveraged to improve the treatment for our patients,” said Ian Krop, MD, PhD, of the Yale Cancer Center in New Haven, Connecticut, during the session where the results were presented.

But T-DXd may not be an appropriate first choice for all patients, especially given the safety concerns associated with T-DXd, he continued. With overall survival and quality-of-life data still lacking, clinicians will have to determine on a case-by-case basis who should get T-DXd in the first line.

“For patients who have symptomatic metastatic disease, who need a response to address those symptoms, those in whom you think chemotherapy may not work as well because they had, for example, a short recurrence interval after their adjuvant chemotherapy — using T-DXd in that first-line setting makes perfect sense to take advantage of the substantially higher response rate compared to chemo,” Dr. Krop said. “But for patients who have asymptomatic low burdens of disease, it seems very reasonable to consider using a well-tolerated chemotherapy like capecitabine in the first line, and then using T-DXd in the second line.”

In an interview, Erica Mayer, MD, of the Dana Farber Cancer Institute in Boston, Massachusetts, said patient choice will also matter in determining whether T-DXd is a first-line option. The known toxicity of T-DXd was underscored by the latest findings, she noted, while capecitabine, one of the chemotherapy choices in the control arm of the study, “really reflects what the majority of breast cancer doctors tend to offer, both because of the efficacy of the drug, but also because it’s oral, it’s well tolerated, and you don’t lose your hair.”
 

DESTINY-Breast07 Results

The DESTINY-Breast07 findings, from a Phase 1B open-label trial measuring safety and tolerability, were presented by Fabrice Andre, MD, PhD, of Université Paris Saclay in Paris, France. Dr. Andre and his colleagues presented the first data comparing T-DXd monotherapy and T-DXd with pertuzumab — a monoclonal antibody targeting HER2 — as a first-line treatment in patients with HER2-overexpressing (immunohistochemistry 3 and above) metastatic breast cancer. (J Clin Oncol 42, 2024 [suppl 16; abstr 1009]).

Current first-line standard of care for these patients is pertuzumab, trastuzumab, and docetaxel, based on results from the 2015 CLEOPATRA trial. T-DXd is currently approved as a second-line treatment.

Dr. Andre and his colleagues randomized 75 patients to monotherapy with T-DXd and 50 to combined therapy, with a median follow-up of 2 years.

After 1 year of treatment, combination of T-DXd and pertuzumab was seen to be associated with a progression-free survival of 89% at 1 year (80% CI, 81.9-93.9), compared with 80% in patients treated with T-DXd alone (80% CI, 73.7-86.1). Objective tumor response rate was 84% for the combined therapy at 12 weeks, with 20% of patients seeing a complete response, compared with 76% and 8%, respectively, for monotherapy.

As in the DESTINY-Breast06 trial, adverse events were high, with interstitial lung disease seen in 9% of patients in the monotherapy group and in 14% of the combined-therapy patients, although no treatment-related deaths occurred.

A randomized phase 3 trial, DESTINY Breast09, will now compare the monotherapy and the combined therapy with standard care.

T-DXd has seen a rapidly expanding role in treating breast and other solid tumors. The DESTINY Breast06 findings will move up its place in the treatment algorithm for metastatic breast cancer, “allowing us to now offer T-DXd as the first chemotherapy choice for patients who are making that transition to chemotherapy over many of the traditional provider choices that we previously have offered,” Dr. Mayer said.

The results “support the use of not only this specific agent, but also the concept of antibody drug conjugates as a very effective way to treat malignancy,” she added.

Dr. Curigliano reported receiving speaker’s fees, research funding, and other support from AstraZeneca and Daiichi Sankyo, among other companies, as did most of his co-authors, of whom three were AstraZeneca employees. Dr. Fabrice disclosed receiving research funding, travel compensation, and/or advisory fees from AstraZeneca and other entities, as did several of his co-authors. Two of his co-authors were employed by AstraZeneca and Roche, manufacturers of the study drugs. Dr. Krop and Dr. Mayer disclosed relationships with AstraZeneca and others.

The antibody-drug conjugate trastuzumab deruxtecan, or T-DXd, is an effective first-line treatment in patients with HER2-low metastatic breast cancer, conferring an additional 5 months’ progression-free survival over chemotherapy.

HER2-low cancers express levels of human epidermal growth factor receptor 2 that are below standard thresholds for HER2-positive immunohistochemistry. In 2022, results from the DESTINY-Breast04 trial showed T-DXd (Enhertu, AstraZeneca) to be an effective second-line chemotherapy in patients with HER2-low metastatic breast cancer.

The highly awaited new findings, from the manufacturer-sponsored, open-label Phase 3 DESTINY-Breast06 trial, were presented at the annual meeting of the American Society of Clinical Oncology (ASCO) in Chicago, Illinois.

The findings not only definitively establish a role for T-DXd earlier in the treatment sequence for HER2-low cancers, they also suggest benefit in a group of patients designated for the purposes of this trial to be HER2-ultralow. These patients have cancers with only faintly detectable HER2 expression on currently used assays (J Clin Oncol 42, 2024 [suppl 17; abstr LBA 1000]).

In a separate set of findings also presented at ASCO, from the randomized phase 1B open-label study, DESTINY-Breast07, T-Dxd showed efficacy in previously untreated HER2-positive metastatic breast cancer patients both alone and in combination with the monoclonal antibody pertuzumab (Perjeta, Genentech).
 

DESTINY-Breast06 Methods and Results

The DESTINY-Breast06 findings were presented by lead investigator Guiseppe Curigliano, MD, PhD, of the University of Milan and European Institute of Oncology. Dr. Curigliano and his colleagues randomized 866 patients with metastatic breast cancer: 436 to intravenous T-Dxd and 430 to the investigator’s choice of capecitabine, nab-paclitaxel, or paclitaxel chemotherapy. The investigators chose capecitabine 60% of the time.

Most patients had cancers classed as HER2 low (immunohistochemistry 1+ or 2+), while 153 had cancers classed by investigators as HER2-ultralow (IHC 0 with membrane staining or IHC under 1+). Patients enrolled in the study were those whose disease had progressed after endocrine therapy with or without targeted therapy. Patients’ median age was between 57 and 58, and all were chemotherapy-naive in the metastatic breast cancer setting.

The main outcome of the study was median progression-free survival in the HER2-low group. T-Dxd was seen improving progression-free survival, with median 13.2 months vs. 8.1 months (hazard ratio, 0.62; 95% confidence interval, 0.51-0.74; P < .0001). In the intention-to-treat population, which included the HER2 ultralow patients, the benefit was the same (HR, 0.63; 95% CI, 0.53-0.75; P < .0001). This suggested that T-DXd is also effective in these patients, and it will be extremely important going forward to identify the lowest level of HER2 expression in metastatic breast cancers that can still benefit from therapy with T-DxD, Dr. Curigliano said.

Overall survival could not be assessed in the study cohort because complete data were not yet available, Dr. Curigliano said. However, trends pointed to an advantage for T-DXd, and tumor response rates were markedly higher with T-DXd: 57% compared with 31% for standard chemotherapy in the full cohort.

Serious treatment-emergent adverse events were more common in the T-Dxd–treated patients, with 11% of that arm developing drug-related interstitial lung disease, and three patients dying of it. Five patients in the T-DXd arm died of adverse events deemed treatment-related, and none died from treatment-related adverse events in the standard chemotherapy arm. Altogether 11 patients died in the T-DXd arm and 6 in the chemotherapy arm.
 

Clinical Implications of DESTINY-Breast06

The DESTINY-Breast06 data show that “we have to again change how we think about HER2 expression. Even very low levels of HER2 expression matter, and they can be leveraged to improve the treatment for our patients,” said Ian Krop, MD, PhD, of the Yale Cancer Center in New Haven, Connecticut, during the session where the results were presented.

But T-DXd may not be an appropriate first choice for all patients, especially given the safety concerns associated with T-DXd, he continued. With overall survival and quality-of-life data still lacking, clinicians will have to determine on a case-by-case basis who should get T-DXd in the first line.

“For patients who have symptomatic metastatic disease, who need a response to address those symptoms, those in whom you think chemotherapy may not work as well because they had, for example, a short recurrence interval after their adjuvant chemotherapy — using T-DXd in that first-line setting makes perfect sense to take advantage of the substantially higher response rate compared to chemo,” Dr. Krop said. “But for patients who have asymptomatic low burdens of disease, it seems very reasonable to consider using a well-tolerated chemotherapy like capecitabine in the first line, and then using T-DXd in the second line.”

In an interview, Erica Mayer, MD, of the Dana Farber Cancer Institute in Boston, Massachusetts, said patient choice will also matter in determining whether T-DXd is a first-line option. The known toxicity of T-DXd was underscored by the latest findings, she noted, while capecitabine, one of the chemotherapy choices in the control arm of the study, “really reflects what the majority of breast cancer doctors tend to offer, both because of the efficacy of the drug, but also because it’s oral, it’s well tolerated, and you don’t lose your hair.”
 

DESTINY-Breast07 Results

The DESTINY-Breast07 findings, from a Phase 1B open-label trial measuring safety and tolerability, were presented by Fabrice Andre, MD, PhD, of Université Paris Saclay in Paris, France. Dr. Andre and his colleagues presented the first data comparing T-DXd monotherapy and T-DXd with pertuzumab — a monoclonal antibody targeting HER2 — as a first-line treatment in patients with HER2-overexpressing (immunohistochemistry 3 and above) metastatic breast cancer. (J Clin Oncol 42, 2024 [suppl 16; abstr 1009]).

Current first-line standard of care for these patients is pertuzumab, trastuzumab, and docetaxel, based on results from the 2015 CLEOPATRA trial. T-DXd is currently approved as a second-line treatment.

Dr. Andre and his colleagues randomized 75 patients to monotherapy with T-DXd and 50 to combined therapy, with a median follow-up of 2 years.

After 1 year of treatment, combination of T-DXd and pertuzumab was seen to be associated with a progression-free survival of 89% at 1 year (80% CI, 81.9-93.9), compared with 80% in patients treated with T-DXd alone (80% CI, 73.7-86.1). Objective tumor response rate was 84% for the combined therapy at 12 weeks, with 20% of patients seeing a complete response, compared with 76% and 8%, respectively, for monotherapy.

As in the DESTINY-Breast06 trial, adverse events were high, with interstitial lung disease seen in 9% of patients in the monotherapy group and in 14% of the combined-therapy patients, although no treatment-related deaths occurred.

A randomized phase 3 trial, DESTINY Breast09, will now compare the monotherapy and the combined therapy with standard care.

T-DXd has seen a rapidly expanding role in treating breast and other solid tumors. The DESTINY Breast06 findings will move up its place in the treatment algorithm for metastatic breast cancer, “allowing us to now offer T-DXd as the first chemotherapy choice for patients who are making that transition to chemotherapy over many of the traditional provider choices that we previously have offered,” Dr. Mayer said.

The results “support the use of not only this specific agent, but also the concept of antibody drug conjugates as a very effective way to treat malignancy,” she added.

Dr. Curigliano reported receiving speaker’s fees, research funding, and other support from AstraZeneca and Daiichi Sankyo, among other companies, as did most of his co-authors, of whom three were AstraZeneca employees. Dr. Fabrice disclosed receiving research funding, travel compensation, and/or advisory fees from AstraZeneca and other entities, as did several of his co-authors. Two of his co-authors were employed by AstraZeneca and Roche, manufacturers of the study drugs. Dr. Krop and Dr. Mayer disclosed relationships with AstraZeneca and others.

CHICAGO — Genetics and diet have been among the top theories for what may be fueling the troubling rise of colorectal cancer in young adults. Now, an early look at genetic data from people with colorectal cancer further suggests that the cause is linked to what is happening in the gut.

The findings were presented at the annual meeting of the American Society for Clinical Oncology (ASCO) by researchers from Ohio State University. For the analysis, they analyzed genetic data on tumors.

The researchers found signs that a high-fat, low-fiber diet may increase inflammation in the gut that prevents it from naturally suppressing tumors. The cells of young people with colorectal cancer also appeared to have aged more quickly — by 15 years on average — than a person’s actual age. That’s unusual, because older people with colorectal cancer don’t have the same boost in cellular aging.

The rate of colorectal cancer among young people has been rising at an alarming rate, according to a 2023 report from the American Cancer Society. In 2019, one in five colorectal cancer cases were among people younger than 55. That’s up from 1 in 10 in 1995, which means the rate has doubled in less than 30 years.
 

Need Colon Cancer Screening?

Who needs a colorectal cancer screening? Ask colorectal cancer specialist Nancy Kemeny, MD.

A 2017 analysis estimated that a person’s risk of colorectal cancer increased 12% by eating 3.5 ounces of red or processed meat daily, which is the equivalent of the size of a deck of playing cards. The same study also linked colorectal cancer risk to alcohol intake, citing its ethanol content. Eating a diet high in fiber can reduce a person’s risk.

This latest study aligned with previous findings that link bacteria called Fusobacterium to colorectal cancer. It’s not unusual for Fusobacterium to be present in a person’s mouth, but it is more likely to be found in the intestines of colorectal cancer patients, compared with those of healthy people. One study even found that people with colorectal cancer were five times more likely to have Fusobacterium in their stool, compared with healthy people.

Colorectal cancer is more common among men than women, “likely reflecting differences in risk factor prevalence, such as excess body weight and processed meat consumption,” the authors of the 2023 American Cancer Society report explained.

People younger than 45 should alert their medical provider if they have constipation, rectal bleeding, or sudden changes in bowel movements, which can be symptoms of colorectal cancer. Screening for colorectal cancer should begin for most people at age 45.

A version of this article appeared on WebMD.com.

CHICAGO — Genetics and diet have been among the top theories for what may be fueling the troubling rise of colorectal cancer in young adults. Now, an early look at genetic data from people with colorectal cancer further suggests that the cause is linked to what is happening in the gut.

The findings were presented at the annual meeting of the American Society for Clinical Oncology (ASCO) by researchers from Ohio State University. For the analysis, they analyzed genetic data on tumors.

The researchers found signs that a high-fat, low-fiber diet may increase inflammation in the gut that prevents it from naturally suppressing tumors. The cells of young people with colorectal cancer also appeared to have aged more quickly — by 15 years on average — than a person’s actual age. That’s unusual, because older people with colorectal cancer don’t have the same boost in cellular aging.

The rate of colorectal cancer among young people has been rising at an alarming rate, according to a 2023 report from the American Cancer Society. In 2019, one in five colorectal cancer cases were among people younger than 55. That’s up from 1 in 10 in 1995, which means the rate has doubled in less than 30 years.
 

Need Colon Cancer Screening?

Who needs a colorectal cancer screening? Ask colorectal cancer specialist Nancy Kemeny, MD.

A 2017 analysis estimated that a person’s risk of colorectal cancer increased 12% by eating 3.5 ounces of red or processed meat daily, which is the equivalent of the size of a deck of playing cards. The same study also linked colorectal cancer risk to alcohol intake, citing its ethanol content. Eating a diet high in fiber can reduce a person’s risk.

This latest study aligned with previous findings that link bacteria called Fusobacterium to colorectal cancer. It’s not unusual for Fusobacterium to be present in a person’s mouth, but it is more likely to be found in the intestines of colorectal cancer patients, compared with those of healthy people. One study even found that people with colorectal cancer were five times more likely to have Fusobacterium in their stool, compared with healthy people.

Colorectal cancer is more common among men than women, “likely reflecting differences in risk factor prevalence, such as excess body weight and processed meat consumption,” the authors of the 2023 American Cancer Society report explained.

People younger than 45 should alert their medical provider if they have constipation, rectal bleeding, or sudden changes in bowel movements, which can be symptoms of colorectal cancer. Screening for colorectal cancer should begin for most people at age 45.

A version of this article appeared on WebMD.com.

CHICAGO — Genetics and diet have been among the top theories for what may be fueling the troubling rise of colorectal cancer in young adults. Now, an early look at genetic data from people with colorectal cancer further suggests that the cause is linked to what is happening in the gut.

The findings were presented at the annual meeting of the American Society for Clinical Oncology (ASCO) by researchers from Ohio State University. For the analysis, they analyzed genetic data on tumors.

The researchers found signs that a high-fat, low-fiber diet may increase inflammation in the gut that prevents it from naturally suppressing tumors. The cells of young people with colorectal cancer also appeared to have aged more quickly — by 15 years on average — than a person’s actual age. That’s unusual, because older people with colorectal cancer don’t have the same boost in cellular aging.

The rate of colorectal cancer among young people has been rising at an alarming rate, according to a 2023 report from the American Cancer Society. In 2019, one in five colorectal cancer cases were among people younger than 55. That’s up from 1 in 10 in 1995, which means the rate has doubled in less than 30 years.
 

Need Colon Cancer Screening?

Who needs a colorectal cancer screening? Ask colorectal cancer specialist Nancy Kemeny, MD.

A 2017 analysis estimated that a person’s risk of colorectal cancer increased 12% by eating 3.5 ounces of red or processed meat daily, which is the equivalent of the size of a deck of playing cards. The same study also linked colorectal cancer risk to alcohol intake, citing its ethanol content. Eating a diet high in fiber can reduce a person’s risk.

This latest study aligned with previous findings that link bacteria called Fusobacterium to colorectal cancer. It’s not unusual for Fusobacterium to be present in a person’s mouth, but it is more likely to be found in the intestines of colorectal cancer patients, compared with those of healthy people. One study even found that people with colorectal cancer were five times more likely to have Fusobacterium in their stool, compared with healthy people.

Colorectal cancer is more common among men than women, “likely reflecting differences in risk factor prevalence, such as excess body weight and processed meat consumption,” the authors of the 2023 American Cancer Society report explained.

People younger than 45 should alert their medical provider if they have constipation, rectal bleeding, or sudden changes in bowel movements, which can be symptoms of colorectal cancer. Screening for colorectal cancer should begin for most people at age 45.

A version of this article appeared on WebMD.com.

TOPLINE:

Patients with early-onset colorectal cancer (EOCRC) often present with hematochezia or abdominal pain, symptoms frequently overlooked in younger populations, leading to delays in diagnosis of 4-6 months, a new analysis showed.

METHODOLOGY:

• As the number of cases of EOCRC, defined as colorectal cancer (CRC) diagnosed before age 50, continues to rise, early detection has become increasingly important. Improved recognition of presenting signs and symptoms associated with EOCRC could lead to a more timely diagnosis and better clinical outcomes.
• In a systematic review and meta-analysis of 81 studies with 24.9 million EOCRC cases, researchers sought to determine the most common presenting signs and symptoms, their association with EOCRC risk, and the time from presentation to diagnosis.
• Data extraction and quality assessment were performed independently in duplicate using PRISMA guidelines, and Joanna Briggs Institute critical appraisal tools were used to measure the risk of bias.

TAKEAWAY:

• Hematochezia was the most common presenting sign/symptom, with a pooled prevalence of 45%, followed by abdominal pain, with a pooled prevalence of 40%.
• Altered bowel habits, which included constipation, diarrhea, and alternating bowel habits, were the third most common presenting sign/symptom (pooled prevalence of 27%), followed by unexplained weight loss (pooled prevalence of 17%).
• The likelihood of EOCRC was estimated to be fivefold to 54-fold higher with hematochezia and 1.3-fold to sixfold higher with abdominal pain.
• The mean time from sign or symptom onset to EOCRC diagnosis was 6.4 months (range, 1.8-13.7 months).

IN PRACTICE:

“These findings and the increasing risk of CRC in individuals younger than 50 years highlight the urgent need to educate clinicians and patients about these signs and symptoms to ensure that diagnostic workup and resolution are not delayed. Adapting current clinical practice to identify and address these signs and symptoms through careful clinical triage and follow-up could help limit morbidity and mortality associated with EOCRC,” the authors wrote.

SOURCE:

The study, with Joshua Demb, PhD, MPH, division of gastroenterology, department of medicine, University of California, San Diego, was published online May 24 in JAMA Network Open.

LIMITATIONS:

Significant heterogeneity across studies affected the ability to meta-analyze some results. The cross-sectional data limited the ability to stratify by age, sex, race and ethnicity, or genetic ancestry. It was not possible to evaluate the impact of time to diagnosis on CRC outcomes due to a limited number of studies answering this question. Researchers were unable to examine the constellation of signs and symptoms because they lacked individual-level data from each study.

DISCLOSURES:

The authors disclosed no relevant conflicts of interest. No specific funding was disclosed.
 

A version of this article appeared on Medscape.com.

TOPLINE:

Patients with early-onset colorectal cancer (EOCRC) often present with hematochezia or abdominal pain, symptoms frequently overlooked in younger populations, leading to delays in diagnosis of 4-6 months, a new analysis showed.

METHODOLOGY:

• As the number of cases of EOCRC, defined as colorectal cancer (CRC) diagnosed before age 50, continues to rise, early detection has become increasingly important. Improved recognition of presenting signs and symptoms associated with EOCRC could lead to a more timely diagnosis and better clinical outcomes.
• In a systematic review and meta-analysis of 81 studies with 24.9 million EOCRC cases, researchers sought to determine the most common presenting signs and symptoms, their association with EOCRC risk, and the time from presentation to diagnosis.
• Data extraction and quality assessment were performed independently in duplicate using PRISMA guidelines, and Joanna Briggs Institute critical appraisal tools were used to measure the risk of bias.

TAKEAWAY:

• Hematochezia was the most common presenting sign/symptom, with a pooled prevalence of 45%, followed by abdominal pain, with a pooled prevalence of 40%.
• Altered bowel habits, which included constipation, diarrhea, and alternating bowel habits, were the third most common presenting sign/symptom (pooled prevalence of 27%), followed by unexplained weight loss (pooled prevalence of 17%).
• The likelihood of EOCRC was estimated to be fivefold to 54-fold higher with hematochezia and 1.3-fold to sixfold higher with abdominal pain.
• The mean time from sign or symptom onset to EOCRC diagnosis was 6.4 months (range, 1.8-13.7 months).

IN PRACTICE:

“These findings and the increasing risk of CRC in individuals younger than 50 years highlight the urgent need to educate clinicians and patients about these signs and symptoms to ensure that diagnostic workup and resolution are not delayed. Adapting current clinical practice to identify and address these signs and symptoms through careful clinical triage and follow-up could help limit morbidity and mortality associated with EOCRC,” the authors wrote.

SOURCE:

The study, with Joshua Demb, PhD, MPH, division of gastroenterology, department of medicine, University of California, San Diego, was published online May 24 in JAMA Network Open.

LIMITATIONS:

Significant heterogeneity across studies affected the ability to meta-analyze some results. The cross-sectional data limited the ability to stratify by age, sex, race and ethnicity, or genetic ancestry. It was not possible to evaluate the impact of time to diagnosis on CRC outcomes due to a limited number of studies answering this question. Researchers were unable to examine the constellation of signs and symptoms because they lacked individual-level data from each study.

DISCLOSURES:

The authors disclosed no relevant conflicts of interest. No specific funding was disclosed.
 

A version of this article appeared on Medscape.com.

TOPLINE:

Patients with early-onset colorectal cancer (EOCRC) often present with hematochezia or abdominal pain, symptoms frequently overlooked in younger populations, leading to delays in diagnosis of 4-6 months, a new analysis showed.

METHODOLOGY:

• As the number of cases of EOCRC, defined as colorectal cancer (CRC) diagnosed before age 50, continues to rise, early detection has become increasingly important. Improved recognition of presenting signs and symptoms associated with EOCRC could lead to a more timely diagnosis and better clinical outcomes.
• In a systematic review and meta-analysis of 81 studies with 24.9 million EOCRC cases, researchers sought to determine the most common presenting signs and symptoms, their association with EOCRC risk, and the time from presentation to diagnosis.
• Data extraction and quality assessment were performed independently in duplicate using PRISMA guidelines, and Joanna Briggs Institute critical appraisal tools were used to measure the risk of bias.

TAKEAWAY:

• Hematochezia was the most common presenting sign/symptom, with a pooled prevalence of 45%, followed by abdominal pain, with a pooled prevalence of 40%.
• Altered bowel habits, which included constipation, diarrhea, and alternating bowel habits, were the third most common presenting sign/symptom (pooled prevalence of 27%), followed by unexplained weight loss (pooled prevalence of 17%).
• The likelihood of EOCRC was estimated to be fivefold to 54-fold higher with hematochezia and 1.3-fold to sixfold higher with abdominal pain.
• The mean time from sign or symptom onset to EOCRC diagnosis was 6.4 months (range, 1.8-13.7 months).

IN PRACTICE:

“These findings and the increasing risk of CRC in individuals younger than 50 years highlight the urgent need to educate clinicians and patients about these signs and symptoms to ensure that diagnostic workup and resolution are not delayed. Adapting current clinical practice to identify and address these signs and symptoms through careful clinical triage and follow-up could help limit morbidity and mortality associated with EOCRC,” the authors wrote.

SOURCE:

The study, with Joshua Demb, PhD, MPH, division of gastroenterology, department of medicine, University of California, San Diego, was published online May 24 in JAMA Network Open.

LIMITATIONS:

Significant heterogeneity across studies affected the ability to meta-analyze some results. The cross-sectional data limited the ability to stratify by age, sex, race and ethnicity, or genetic ancestry. It was not possible to evaluate the impact of time to diagnosis on CRC outcomes due to a limited number of studies answering this question. Researchers were unable to examine the constellation of signs and symptoms because they lacked individual-level data from each study.

DISCLOSURES:

The authors disclosed no relevant conflicts of interest. No specific funding was disclosed.
 

A version of this article appeared on Medscape.com.

BOSTON — Use of over-the-counter arthritis supplements containing undisclosed glucocorticoids can lead to iatrogenic adrenal dysfunction, Cushing syndrome, and/or adrenal insufficiency (AI). 

Patients who have been taking these supplements for prolonged periods must slowly taper off them with corticosteroid replacement, because abruptly stopping the supplement can precipitate AI, Kevin S. Wei, MD, said in a presentation of 12 cases — the largest such series to date of the phenomenon — at the annual meeting of the Endocrine Society.

The specific supplements used were Artri King in eight of the patients, Ardosons in two, and Ajo Rey in one. In April 2022, the US Food and Drug Administration issued a warning that Artri King contains diclofenac and dexamethasone not listed on the product label. In July 2023, the agency issued an expanded warning about that product and others including Ajo Rey.

The supplements are not believed to be sold in the United States, but they are available in Mexico and can be ordered online, said Dr. Wei, a second-year resident at the Keck School of Medicine at the University of California, Los Angeles.

“We found that quite a lot of patients after they’ve been on the Artri King or some other over the counter arthritis supplement, started developing these cushingoid features seen in the physical exam, such as rounded facial features or stretch marks of their abdomen,” he said.

And “when patients are abruptly taken off those supplements … sometimes this can cause them to go into signs or symptoms of adrenal insufficiency. That can occasionally be life-threatening if it’s not addressed in an inpatient setting,” Dr. Wei said.

In an interview, session moderator Sharon L. Wardlaw, MD, professor of medicine at Columbia University Irving Medical Center, New York, explained that when a person takes these drugs containing hidden glucocorticoids, “they won’t be picked up in a cortisol assay, but they’ll suppress the [adrenocorticotropic hormone] and the person’s own cortisol production. They look like they have Cushing, but when you measure their hormone levels, they’re undetectable. And then people wonder what’s going on. Well, their [hypothalamic-pituitary-adrenal] axis is suppressed.”

But if the product is suddenly stopped without cortisol replacement “If they get an infection they can die because they can’t mount a cortisol response.”

The takeaway message, she said, is “always ask patients to show you their supplements and look at them. In many cases, that’s why they work so well for pain relief because they have ingredients that people shouldn’t be taking.”

Twelve Patients Seen During 2022-2023

The 12 patients were seen during 2022-2023 at an endocrinology consult service in an urban safety net hospital. Their median age was 52 years, and one third were women. All had started using the supplements for joint pain, with a median of about 6 months of use prior to cessation.

Presenting symptoms included nausea/vomiting in 42%, fatigue in 42%, abdominal pain in 33%, and dizziness in 17%. Physical exam findings included moon facies in 66%, central adiposity in 66%, abdominal striae in 50%, dorsocervical fat pad in 33%, and bruising in 33%. Three required intensive care admission.

Cortisol testing was performed in 11 of the patients and was normal (≥ 16 mcg/dL) in just one. AI (≤ 3 mcg/dL) was found in three, while the rest had indeterminate results. Of those seven patients, subsequent cosyntropin-stimulation testing suggested AI (cortisol < 16 mcg/dL at 60 minutes post stimulation) in four patients, while the other two showed reduced but normal responses (cortisol 18.2-18.4 mcg/dL).

Ten of the 12 patients were prescribed glucocorticoid tapering replacements to avoid precipitating adrenal crisis, most commonly twice-daily hydrocortisone. Of those ten, eight continued to take the replacement steroids 1-2 years later, Dr. Wei said.

Dr. Wei and Dr. Wardlaw had no disclosures.

A version of this article appeared on Medscape.com.

BOSTON — Use of over-the-counter arthritis supplements containing undisclosed glucocorticoids can lead to iatrogenic adrenal dysfunction, Cushing syndrome, and/or adrenal insufficiency (AI). 

Patients who have been taking these supplements for prolonged periods must slowly taper off them with corticosteroid replacement, because abruptly stopping the supplement can precipitate AI, Kevin S. Wei, MD, said in a presentation of 12 cases — the largest such series to date of the phenomenon — at the annual meeting of the Endocrine Society.

The specific supplements used were Artri King in eight of the patients, Ardosons in two, and Ajo Rey in one. In April 2022, the US Food and Drug Administration issued a warning that Artri King contains diclofenac and dexamethasone not listed on the product label. In July 2023, the agency issued an expanded warning about that product and others including Ajo Rey.

The supplements are not believed to be sold in the United States, but they are available in Mexico and can be ordered online, said Dr. Wei, a second-year resident at the Keck School of Medicine at the University of California, Los Angeles.

“We found that quite a lot of patients after they’ve been on the Artri King or some other over the counter arthritis supplement, started developing these cushingoid features seen in the physical exam, such as rounded facial features or stretch marks of their abdomen,” he said.

And “when patients are abruptly taken off those supplements … sometimes this can cause them to go into signs or symptoms of adrenal insufficiency. That can occasionally be life-threatening if it’s not addressed in an inpatient setting,” Dr. Wei said.

In an interview, session moderator Sharon L. Wardlaw, MD, professor of medicine at Columbia University Irving Medical Center, New York, explained that when a person takes these drugs containing hidden glucocorticoids, “they won’t be picked up in a cortisol assay, but they’ll suppress the [adrenocorticotropic hormone] and the person’s own cortisol production. They look like they have Cushing, but when you measure their hormone levels, they’re undetectable. And then people wonder what’s going on. Well, their [hypothalamic-pituitary-adrenal] axis is suppressed.”

But if the product is suddenly stopped without cortisol replacement “If they get an infection they can die because they can’t mount a cortisol response.”

The takeaway message, she said, is “always ask patients to show you their supplements and look at them. In many cases, that’s why they work so well for pain relief because they have ingredients that people shouldn’t be taking.”

Twelve Patients Seen During 2022-2023

The 12 patients were seen during 2022-2023 at an endocrinology consult service in an urban safety net hospital. Their median age was 52 years, and one third were women. All had started using the supplements for joint pain, with a median of about 6 months of use prior to cessation.

Presenting symptoms included nausea/vomiting in 42%, fatigue in 42%, abdominal pain in 33%, and dizziness in 17%. Physical exam findings included moon facies in 66%, central adiposity in 66%, abdominal striae in 50%, dorsocervical fat pad in 33%, and bruising in 33%. Three required intensive care admission.

Cortisol testing was performed in 11 of the patients and was normal (≥ 16 mcg/dL) in just one. AI (≤ 3 mcg/dL) was found in three, while the rest had indeterminate results. Of those seven patients, subsequent cosyntropin-stimulation testing suggested AI (cortisol < 16 mcg/dL at 60 minutes post stimulation) in four patients, while the other two showed reduced but normal responses (cortisol 18.2-18.4 mcg/dL).

Ten of the 12 patients were prescribed glucocorticoid tapering replacements to avoid precipitating adrenal crisis, most commonly twice-daily hydrocortisone. Of those ten, eight continued to take the replacement steroids 1-2 years later, Dr. Wei said.

Dr. Wei and Dr. Wardlaw had no disclosures.

A version of this article appeared on Medscape.com.

BOSTON — Use of over-the-counter arthritis supplements containing undisclosed glucocorticoids can lead to iatrogenic adrenal dysfunction, Cushing syndrome, and/or adrenal insufficiency (AI). 

Patients who have been taking these supplements for prolonged periods must slowly taper off them with corticosteroid replacement, because abruptly stopping the supplement can precipitate AI, Kevin S. Wei, MD, said in a presentation of 12 cases — the largest such series to date of the phenomenon — at the annual meeting of the Endocrine Society.

The specific supplements used were Artri King in eight of the patients, Ardosons in two, and Ajo Rey in one. In April 2022, the US Food and Drug Administration issued a warning that Artri King contains diclofenac and dexamethasone not listed on the product label. In July 2023, the agency issued an expanded warning about that product and others including Ajo Rey.

The supplements are not believed to be sold in the United States, but they are available in Mexico and can be ordered online, said Dr. Wei, a second-year resident at the Keck School of Medicine at the University of California, Los Angeles.

“We found that quite a lot of patients after they’ve been on the Artri King or some other over the counter arthritis supplement, started developing these cushingoid features seen in the physical exam, such as rounded facial features or stretch marks of their abdomen,” he said.

And “when patients are abruptly taken off those supplements … sometimes this can cause them to go into signs or symptoms of adrenal insufficiency. That can occasionally be life-threatening if it’s not addressed in an inpatient setting,” Dr. Wei said.

In an interview, session moderator Sharon L. Wardlaw, MD, professor of medicine at Columbia University Irving Medical Center, New York, explained that when a person takes these drugs containing hidden glucocorticoids, “they won’t be picked up in a cortisol assay, but they’ll suppress the [adrenocorticotropic hormone] and the person’s own cortisol production. They look like they have Cushing, but when you measure their hormone levels, they’re undetectable. And then people wonder what’s going on. Well, their [hypothalamic-pituitary-adrenal] axis is suppressed.”

But if the product is suddenly stopped without cortisol replacement “If they get an infection they can die because they can’t mount a cortisol response.”

The takeaway message, she said, is “always ask patients to show you their supplements and look at them. In many cases, that’s why they work so well for pain relief because they have ingredients that people shouldn’t be taking.”

Twelve Patients Seen During 2022-2023

The 12 patients were seen during 2022-2023 at an endocrinology consult service in an urban safety net hospital. Their median age was 52 years, and one third were women. All had started using the supplements for joint pain, with a median of about 6 months of use prior to cessation.

Presenting symptoms included nausea/vomiting in 42%, fatigue in 42%, abdominal pain in 33%, and dizziness in 17%. Physical exam findings included moon facies in 66%, central adiposity in 66%, abdominal striae in 50%, dorsocervical fat pad in 33%, and bruising in 33%. Three required intensive care admission.

Cortisol testing was performed in 11 of the patients and was normal (≥ 16 mcg/dL) in just one. AI (≤ 3 mcg/dL) was found in three, while the rest had indeterminate results. Of those seven patients, subsequent cosyntropin-stimulation testing suggested AI (cortisol < 16 mcg/dL at 60 minutes post stimulation) in four patients, while the other two showed reduced but normal responses (cortisol 18.2-18.4 mcg/dL).

Ten of the 12 patients were prescribed glucocorticoid tapering replacements to avoid precipitating adrenal crisis, most commonly twice-daily hydrocortisone. Of those ten, eight continued to take the replacement steroids 1-2 years later, Dr. Wei said.

Dr. Wei and Dr. Wardlaw had no disclosures.

A version of this article appeared on Medscape.com.

Adding durvalumab as consolidation treatment following concurrent chemoradiation (cCRT) adds 2 years of life and increases progression-free survival by 24%, compared with placebo, in patients with limited stage small cell lung cancer (LS-SCLC).

These are results of the ADRIATIC trial, the first planned interim analysis of the randomized, phase 3, double-blind, placebo-controlled multicenter study comparing the PD-L 1 antibody durvalumab vs placebo in patients with stage I-III limited stage disease and prior concurrent chemoradiotherapy.

Lead author David R. Spigel, MD, drew several rounds of applause from an enthusiastic audience when he presented this data, at the plenary session of the annual meeting of the American Society for Clinical Oncology (ASCO) in Chicago.

“ADRIATIC is the first positive, global phase 3 trial of immunotherapy in limited stage SCLC,” said Lauren Byers, MD, the discussant in the session.

“This groundbreaking trial sets a new standard of care with consolidative durvalumab following concurrent chemoradiation,” continued Dr. Byers, who is professor and thoracic section chief in the Department of Thoracic/Head and Neck Medical Oncology at the University of Texas MD Andersen Cancer Center in Houston, Texas.
 

ADRIATIC Methods and Results

The new study enrolled 730 patients and randomized them between 1 and 42 days after concurrent chemoradiation to one of three treatments: durvalumab 1500 mg; durvalumab plus tremelimumab 75 mg; or placebo. Treatment was continued for a maximum of 24 months, or until progression or intolerable toxicity.

The study had dual primary endpoints of overall survival (OS) and progression-free survival (PFS) for durvalumab vs placebo. The researchers have not yet looked at the results for the secondary endpoints of OS and PFS for patients treated with durvalumab plus tremelimumab vs placebo.

After a median follow-up of 3 years, there was a median OS of 55.9 months in the durvalumab-treated patients, compared with 33.4 months in the placebo arm (hazard ratio [HR], 0.73), and, at a median follow-up of 2 years, there was median PFS of 16.6 months vs 9.2 months respectively (HR, 0.76).
 

New Standard of Care for Patients with LS-SCLC

“This study had a very good safety profile,” said Dr. Spigel, who is also a medical oncologist and the chief scientific officer at Sarah Cannon Research Institute in Nashville, Tennessee, during his presentation.

“Looking at severe grade 3 or 4 events, these were nearly identical in either arm at 24%. Looking at any-grade immune-mediated AEs, these were 31.2% and 10.2% respectively, and then looking at radiation pneumonitis or pneumonitis, the rates were 38.2% in the durvalumab arm, compared with 30.2% in the placebo arm,” Dr. Spigel said.

Noting that there have been no major advances in the treatment of LS-SCLC for several decades, with most patients experiencing recurrences within 2 years of the cCRT standard of care, Dr. Spigel said “consolidation durvalumab will become the new standard of care for patients with LS-SCLC who have not progressed after cCRT.”

Toby Campbell, MD, a thoracic oncologist, who is professor and chief of Palliative Care at the University of Wisconsin, in Madison, Wisconsin, agrees.

“I take care of patients with small cell lung cancer, an aggressive cancer with high symptom burden that devastates patients and families in its wake,” said Dr. Campbell, during an interview. “About 15% of patients luckily present when the cancer is still contained in the chest and is potentially curable. However, with current treatments we give, which include chemotherapy together with radiation, we are ‘successful’ at curing one in four people.

“This study presents a new treatment option which makes a big difference to patients like mine,” Dr. Campbell continued. “For example, at the 2-year time point, nearly half of patients are still cancer-free. These folks have the opportunity to live their lives more fully, unburdened by the symptoms and dread this disease brings. If approved, I think this treatment would immediately be appropriate to use in clinic.

“Further, oncologists are comfortable using this medication as it is already FDA-approved and used similarly in non–small cell lung cancer.”

The study was funded by AstraZeneca. Dr. Spigel discloses consulting or advisory roles with Abbvie, Amgen, AstraZeneca, Bristol-Myers Squibb, Genentech/Roche, GlaxoSmithKline, Ipsen, Jazz Pharmaceuticals, Lyell Immunopharma, MedImmune, Monte Rosa Therapeutics, Novartis, Novocure, and Sanofi/Aventis. He has also received research funding from many companies, and travel, accommodations, and other expense reimbursements from AstraZeneca, Genentech, and Novartis.

Dr. Byers discloses honoraria from and consulting or advisory roles with Abbvie, Amgen, Arrowhead Pharmaceuticals, AstraZeneca, Beigene, Boehringer Ingelheim, Chugai Pharma, Daiichi Sankyo, Genentech, Jazz Pharmaceuticals, Merck, Dohme, Novartis, and Puma Biotechnology. He also has received research funding from Amgen, AstraZeneca, and Jazz Pharmaceuticals.

Dr. Campbell has served as an advisor for Novocure and Genentech.

Adding durvalumab as consolidation treatment following concurrent chemoradiation (cCRT) adds 2 years of life and increases progression-free survival by 24%, compared with placebo, in patients with limited stage small cell lung cancer (LS-SCLC).

These are results of the ADRIATIC trial, the first planned interim analysis of the randomized, phase 3, double-blind, placebo-controlled multicenter study comparing the PD-L 1 antibody durvalumab vs placebo in patients with stage I-III limited stage disease and prior concurrent chemoradiotherapy.

Lead author David R. Spigel, MD, drew several rounds of applause from an enthusiastic audience when he presented this data, at the plenary session of the annual meeting of the American Society for Clinical Oncology (ASCO) in Chicago.

“ADRIATIC is the first positive, global phase 3 trial of immunotherapy in limited stage SCLC,” said Lauren Byers, MD, the discussant in the session.

“This groundbreaking trial sets a new standard of care with consolidative durvalumab following concurrent chemoradiation,” continued Dr. Byers, who is professor and thoracic section chief in the Department of Thoracic/Head and Neck Medical Oncology at the University of Texas MD Andersen Cancer Center in Houston, Texas.
 

ADRIATIC Methods and Results

The new study enrolled 730 patients and randomized them between 1 and 42 days after concurrent chemoradiation to one of three treatments: durvalumab 1500 mg; durvalumab plus tremelimumab 75 mg; or placebo. Treatment was continued for a maximum of 24 months, or until progression or intolerable toxicity.

The study had dual primary endpoints of overall survival (OS) and progression-free survival (PFS) for durvalumab vs placebo. The researchers have not yet looked at the results for the secondary endpoints of OS and PFS for patients treated with durvalumab plus tremelimumab vs placebo.

After a median follow-up of 3 years, there was a median OS of 55.9 months in the durvalumab-treated patients, compared with 33.4 months in the placebo arm (hazard ratio [HR], 0.73), and, at a median follow-up of 2 years, there was median PFS of 16.6 months vs 9.2 months respectively (HR, 0.76).
 

New Standard of Care for Patients with LS-SCLC

“This study had a very good safety profile,” said Dr. Spigel, who is also a medical oncologist and the chief scientific officer at Sarah Cannon Research Institute in Nashville, Tennessee, during his presentation.

“Looking at severe grade 3 or 4 events, these were nearly identical in either arm at 24%. Looking at any-grade immune-mediated AEs, these were 31.2% and 10.2% respectively, and then looking at radiation pneumonitis or pneumonitis, the rates were 38.2% in the durvalumab arm, compared with 30.2% in the placebo arm,” Dr. Spigel said.

Noting that there have been no major advances in the treatment of LS-SCLC for several decades, with most patients experiencing recurrences within 2 years of the cCRT standard of care, Dr. Spigel said “consolidation durvalumab will become the new standard of care for patients with LS-SCLC who have not progressed after cCRT.”

Toby Campbell, MD, a thoracic oncologist, who is professor and chief of Palliative Care at the University of Wisconsin, in Madison, Wisconsin, agrees.

“I take care of patients with small cell lung cancer, an aggressive cancer with high symptom burden that devastates patients and families in its wake,” said Dr. Campbell, during an interview. “About 15% of patients luckily present when the cancer is still contained in the chest and is potentially curable. However, with current treatments we give, which include chemotherapy together with radiation, we are ‘successful’ at curing one in four people.

“This study presents a new treatment option which makes a big difference to patients like mine,” Dr. Campbell continued. “For example, at the 2-year time point, nearly half of patients are still cancer-free. These folks have the opportunity to live their lives more fully, unburdened by the symptoms and dread this disease brings. If approved, I think this treatment would immediately be appropriate to use in clinic.

“Further, oncologists are comfortable using this medication as it is already FDA-approved and used similarly in non–small cell lung cancer.”

The study was funded by AstraZeneca. Dr. Spigel discloses consulting or advisory roles with Abbvie, Amgen, AstraZeneca, Bristol-Myers Squibb, Genentech/Roche, GlaxoSmithKline, Ipsen, Jazz Pharmaceuticals, Lyell Immunopharma, MedImmune, Monte Rosa Therapeutics, Novartis, Novocure, and Sanofi/Aventis. He has also received research funding from many companies, and travel, accommodations, and other expense reimbursements from AstraZeneca, Genentech, and Novartis.

Dr. Byers discloses honoraria from and consulting or advisory roles with Abbvie, Amgen, Arrowhead Pharmaceuticals, AstraZeneca, Beigene, Boehringer Ingelheim, Chugai Pharma, Daiichi Sankyo, Genentech, Jazz Pharmaceuticals, Merck, Dohme, Novartis, and Puma Biotechnology. He also has received research funding from Amgen, AstraZeneca, and Jazz Pharmaceuticals.

Dr. Campbell has served as an advisor for Novocure and Genentech.

Adding durvalumab as consolidation treatment following concurrent chemoradiation (cCRT) adds 2 years of life and increases progression-free survival by 24%, compared with placebo, in patients with limited stage small cell lung cancer (LS-SCLC).

These are results of the ADRIATIC trial, the first planned interim analysis of the randomized, phase 3, double-blind, placebo-controlled multicenter study comparing the PD-L 1 antibody durvalumab vs placebo in patients with stage I-III limited stage disease and prior concurrent chemoradiotherapy.

Lead author David R. Spigel, MD, drew several rounds of applause from an enthusiastic audience when he presented this data, at the plenary session of the annual meeting of the American Society for Clinical Oncology (ASCO) in Chicago.

“ADRIATIC is the first positive, global phase 3 trial of immunotherapy in limited stage SCLC,” said Lauren Byers, MD, the discussant in the session.

“This groundbreaking trial sets a new standard of care with consolidative durvalumab following concurrent chemoradiation,” continued Dr. Byers, who is professor and thoracic section chief in the Department of Thoracic/Head and Neck Medical Oncology at the University of Texas MD Andersen Cancer Center in Houston, Texas.
 

ADRIATIC Methods and Results

The new study enrolled 730 patients and randomized them between 1 and 42 days after concurrent chemoradiation to one of three treatments: durvalumab 1500 mg; durvalumab plus tremelimumab 75 mg; or placebo. Treatment was continued for a maximum of 24 months, or until progression or intolerable toxicity.

The study had dual primary endpoints of overall survival (OS) and progression-free survival (PFS) for durvalumab vs placebo. The researchers have not yet looked at the results for the secondary endpoints of OS and PFS for patients treated with durvalumab plus tremelimumab vs placebo.

After a median follow-up of 3 years, there was a median OS of 55.9 months in the durvalumab-treated patients, compared with 33.4 months in the placebo arm (hazard ratio [HR], 0.73), and, at a median follow-up of 2 years, there was median PFS of 16.6 months vs 9.2 months respectively (HR, 0.76).
 

New Standard of Care for Patients with LS-SCLC

“This study had a very good safety profile,” said Dr. Spigel, who is also a medical oncologist and the chief scientific officer at Sarah Cannon Research Institute in Nashville, Tennessee, during his presentation.

“Looking at severe grade 3 or 4 events, these were nearly identical in either arm at 24%. Looking at any-grade immune-mediated AEs, these were 31.2% and 10.2% respectively, and then looking at radiation pneumonitis or pneumonitis, the rates were 38.2% in the durvalumab arm, compared with 30.2% in the placebo arm,” Dr. Spigel said.

Noting that there have been no major advances in the treatment of LS-SCLC for several decades, with most patients experiencing recurrences within 2 years of the cCRT standard of care, Dr. Spigel said “consolidation durvalumab will become the new standard of care for patients with LS-SCLC who have not progressed after cCRT.”

Toby Campbell, MD, a thoracic oncologist, who is professor and chief of Palliative Care at the University of Wisconsin, in Madison, Wisconsin, agrees.

“I take care of patients with small cell lung cancer, an aggressive cancer with high symptom burden that devastates patients and families in its wake,” said Dr. Campbell, during an interview. “About 15% of patients luckily present when the cancer is still contained in the chest and is potentially curable. However, with current treatments we give, which include chemotherapy together with radiation, we are ‘successful’ at curing one in four people.

“This study presents a new treatment option which makes a big difference to patients like mine,” Dr. Campbell continued. “For example, at the 2-year time point, nearly half of patients are still cancer-free. These folks have the opportunity to live their lives more fully, unburdened by the symptoms and dread this disease brings. If approved, I think this treatment would immediately be appropriate to use in clinic.

“Further, oncologists are comfortable using this medication as it is already FDA-approved and used similarly in non–small cell lung cancer.”

The study was funded by AstraZeneca. Dr. Spigel discloses consulting or advisory roles with Abbvie, Amgen, AstraZeneca, Bristol-Myers Squibb, Genentech/Roche, GlaxoSmithKline, Ipsen, Jazz Pharmaceuticals, Lyell Immunopharma, MedImmune, Monte Rosa Therapeutics, Novartis, Novocure, and Sanofi/Aventis. He has also received research funding from many companies, and travel, accommodations, and other expense reimbursements from AstraZeneca, Genentech, and Novartis.

Dr. Byers discloses honoraria from and consulting or advisory roles with Abbvie, Amgen, Arrowhead Pharmaceuticals, AstraZeneca, Beigene, Boehringer Ingelheim, Chugai Pharma, Daiichi Sankyo, Genentech, Jazz Pharmaceuticals, Merck, Dohme, Novartis, and Puma Biotechnology. He also has received research funding from Amgen, AstraZeneca, and Jazz Pharmaceuticals.

Dr. Campbell has served as an advisor for Novocure and Genentech.

BOSTON — New Endocrine Society guidelines call for limiting vitamin D supplementation beyond the daily recommended intake to specific risk groups and advises against routine 25-hydroxyvitamin D [25(OH)D] testing in healthy individuals. 

The evidence-based document was presented on June 3, 2024, at the Endocrine Society annual meeting, and simultaneously published in The Journal of Clinical Endocrinology and Metabolism. It advises that people who may benefit from vitamin D supplementation include: 

• Children aged 1-18 years to prevent rickets and to potentially lower the risk for respiratory tract infections
• Pregnant people to lower the risk for maternal and fetal or neonatal complications
• Adults older than 75 years to lower the risk for mortality
• Adults with prediabetes to lower the risk for type 2 diabetes

In those groups, the recommendation is for daily (rather than intermittent) empiric vitamin D supplementation of more than what was recommended in 2011 by the National Academy of Medicine (NAM), which was then called the Institute of Medicine (IOM): 600 IU/d for those aged 1-70 years and 800 IU/d for those older than 70 years. The document acknowledges that the optimal dose for these populations isn’t known, but it provides the dose ranges that were used in the trials cited as evidence for the recommendations. 

In contrast, the document advises against more vitamin D than the recommended daily intake for most healthier adults younger than 75 years and recommends against testing for blood vitamin D levels in the general population, including those with obesity or darker complexions. 

Guideline author Anastassios G. Pittas, MD, professor of medicine at Tufts University School of Medicine, Boston, told this news organization, “this guideline refers to people who are otherwise healthy, and there’s no clear indication for vitamin D, such as people with already established osteoporosis. This guideline is not relevant to them.”

Dr. Pittas also noted, “there’s no single question and single answer about the role of vitamin D in health and disease, which is what people often want to know. There are many questions, and we cannot answer all of them.”

Panel Chair Marie B. Demay, MD, professor of medicine at Harvard Medical School, Boston, told this news organization that indeed the panel was limited by lack of randomized clinical trial evidence to answer many important questions. “There is a paucity of data regarding definition of optimal levels and optimal intake of vitamin D for preventing specific diseases ... What we really need are large scale clinical trials and biomarkers so we can predict disease outcome before it happens.”

Overall, Dr. Demay said, “The recommendations are that populations adhere to the [NAM/IOM] dietary recommended intakes, and there are certain populations that will likely benefit from levels of intake above [those].” 

Asked to comment, session moderator Clifford J. Rosen, MD, director of Clinical and Translational Research and senior scientist at Maine Medical Center Research Institute, Scarborough, Maine, noted that screening for vitamin D is quite common in clinical practice, but the recommendation against doing so makes sense. 

“When clinicians measure vitamin D, then they’re forced to make a decision what to do about it. That’s where questions about the levels come in. And that’s a big problem. So what the panel’s saying is, don’t screen ... This really gets to the heart of the issue, because we have no data that there’s anything about screening that allows us to improve quality of life ... Screening is probably not worthwhile in any age group.”

Dr. Rosen, who was an author on the 2011 NAM/IOM dietary reference intakes, said that since then, new data have come out regarding the role of vitamin D in mortality in people older than 75 years, benefit in children with regard to respiratory illness, and the potential benefit of vitamin D in pregnancy. “Otherwise, I think we’re going over a lot of the same stuff that we’ve talked about since I was on the IOM panel 15 years ago ... But I think the level of evidence and rigor with which they did it is really impressive.”

However, Simeon I. Taylor, MD, professor of medicine at the University of Maryland, Baltimore, expressed disappointment that the document was limited to healthy people. “Although acknowledging challenges in managing vitamin D status in patients with several diseases, [such as] chronic kidney disease or inflammatory bowel disease, the new guidelines do not provide sufficient guidance for practicing physicians about how to manage these complex patients.”

In addition, Dr. Taylor said that the guidelines “do not explicitly consider the literature suggesting that alternative testing strategies may provide more relevant insights into vitamin D status. Just as variation in levels of thyroid-binding globulin have convinced endocrinologists not to rely on measurement of total thyroxine; interindividual variation in levels of vitamin D binding protein must be accounted for to interpret measurements of total levels of 25(OH)D. It would have been useful to explicitly consider the possible value of measuring vitamin D binding protein-independent indices of vitamin D status.”

Dr. Taylor also raised the same point as an audience member did during the Q&A period regarding patients with osteoporosis or osteopenia. “The value and utility of the new guidelines would be greatly strengthened by providing guidance for how to approach this important and very large group of individuals.”

Dr. Taylor did say that the document has “several strengths, including the fact that they acknowledge the major limitations of the quality of relevant evidence derived from clinical trials.” 

In an accompanying commentary, the guideline authors delve into the issues of skin pigmentation and race as they pertain to vitamin D metabolism, writing: 

The panel discovered that no randomized clinical trials have directly assessed vitamin D related patient-important outcomes based on participants’ skin pigmentation, although race and ethnicity often served as presumed proxies for skin pigmentation in the literature. In their deliberations, guideline panel members and selected Endocrine Society leaders underscored the critical need to distinguish between skin pigmentation as a biological variable and race and ethnicity as socially determined constructs. This differentiation is vital to maximize scientific rigor and, thus, the validity of resulting recommendations.

Dr. Pittas and Dr. Demay have no disclosures relevant to this clinical practice guideline. Dr. Rosen has no disclosures. Dr. Taylor serves as a consultant for Ionis Pharmaceuticals.
 

A version of this article appeared on Medscape.com.

BOSTON — New Endocrine Society guidelines call for limiting vitamin D supplementation beyond the daily recommended intake to specific risk groups and advises against routine 25-hydroxyvitamin D [25(OH)D] testing in healthy individuals. 

The evidence-based document was presented on June 3, 2024, at the Endocrine Society annual meeting, and simultaneously published in The Journal of Clinical Endocrinology and Metabolism. It advises that people who may benefit from vitamin D supplementation include: 

• Children aged 1-18 years to prevent rickets and to potentially lower the risk for respiratory tract infections
• Pregnant people to lower the risk for maternal and fetal or neonatal complications
• Adults older than 75 years to lower the risk for mortality
• Adults with prediabetes to lower the risk for type 2 diabetes

In those groups, the recommendation is for daily (rather than intermittent) empiric vitamin D supplementation of more than what was recommended in 2011 by the National Academy of Medicine (NAM), which was then called the Institute of Medicine (IOM): 600 IU/d for those aged 1-70 years and 800 IU/d for those older than 70 years. The document acknowledges that the optimal dose for these populations isn’t known, but it provides the dose ranges that were used in the trials cited as evidence for the recommendations. 

In contrast, the document advises against more vitamin D than the recommended daily intake for most healthier adults younger than 75 years and recommends against testing for blood vitamin D levels in the general population, including those with obesity or darker complexions. 

Guideline author Anastassios G. Pittas, MD, professor of medicine at Tufts University School of Medicine, Boston, told this news organization, “this guideline refers to people who are otherwise healthy, and there’s no clear indication for vitamin D, such as people with already established osteoporosis. This guideline is not relevant to them.”

Dr. Pittas also noted, “there’s no single question and single answer about the role of vitamin D in health and disease, which is what people often want to know. There are many questions, and we cannot answer all of them.”

Panel Chair Marie B. Demay, MD, professor of medicine at Harvard Medical School, Boston, told this news organization that indeed the panel was limited by lack of randomized clinical trial evidence to answer many important questions. “There is a paucity of data regarding definition of optimal levels and optimal intake of vitamin D for preventing specific diseases ... What we really need are large scale clinical trials and biomarkers so we can predict disease outcome before it happens.”

Overall, Dr. Demay said, “The recommendations are that populations adhere to the [NAM/IOM] dietary recommended intakes, and there are certain populations that will likely benefit from levels of intake above [those].” 

Asked to comment, session moderator Clifford J. Rosen, MD, director of Clinical and Translational Research and senior scientist at Maine Medical Center Research Institute, Scarborough, Maine, noted that screening for vitamin D is quite common in clinical practice, but the recommendation against doing so makes sense. 

“When clinicians measure vitamin D, then they’re forced to make a decision what to do about it. That’s where questions about the levels come in. And that’s a big problem. So what the panel’s saying is, don’t screen ... This really gets to the heart of the issue, because we have no data that there’s anything about screening that allows us to improve quality of life ... Screening is probably not worthwhile in any age group.”

Dr. Rosen, who was an author on the 2011 NAM/IOM dietary reference intakes, said that since then, new data have come out regarding the role of vitamin D in mortality in people older than 75 years, benefit in children with regard to respiratory illness, and the potential benefit of vitamin D in pregnancy. “Otherwise, I think we’re going over a lot of the same stuff that we’ve talked about since I was on the IOM panel 15 years ago ... But I think the level of evidence and rigor with which they did it is really impressive.”

However, Simeon I. Taylor, MD, professor of medicine at the University of Maryland, Baltimore, expressed disappointment that the document was limited to healthy people. “Although acknowledging challenges in managing vitamin D status in patients with several diseases, [such as] chronic kidney disease or inflammatory bowel disease, the new guidelines do not provide sufficient guidance for practicing physicians about how to manage these complex patients.”

In addition, Dr. Taylor said that the guidelines “do not explicitly consider the literature suggesting that alternative testing strategies may provide more relevant insights into vitamin D status. Just as variation in levels of thyroid-binding globulin have convinced endocrinologists not to rely on measurement of total thyroxine; interindividual variation in levels of vitamin D binding protein must be accounted for to interpret measurements of total levels of 25(OH)D. It would have been useful to explicitly consider the possible value of measuring vitamin D binding protein-independent indices of vitamin D status.”

Dr. Taylor also raised the same point as an audience member did during the Q&A period regarding patients with osteoporosis or osteopenia. “The value and utility of the new guidelines would be greatly strengthened by providing guidance for how to approach this important and very large group of individuals.”

Dr. Taylor did say that the document has “several strengths, including the fact that they acknowledge the major limitations of the quality of relevant evidence derived from clinical trials.” 

In an accompanying commentary, the guideline authors delve into the issues of skin pigmentation and race as they pertain to vitamin D metabolism, writing: 

The panel discovered that no randomized clinical trials have directly assessed vitamin D related patient-important outcomes based on participants’ skin pigmentation, although race and ethnicity often served as presumed proxies for skin pigmentation in the literature. In their deliberations, guideline panel members and selected Endocrine Society leaders underscored the critical need to distinguish between skin pigmentation as a biological variable and race and ethnicity as socially determined constructs. This differentiation is vital to maximize scientific rigor and, thus, the validity of resulting recommendations.

Dr. Pittas and Dr. Demay have no disclosures relevant to this clinical practice guideline. Dr. Rosen has no disclosures. Dr. Taylor serves as a consultant for Ionis Pharmaceuticals.
 

A version of this article appeared on Medscape.com.

BOSTON — New Endocrine Society guidelines call for limiting vitamin D supplementation beyond the daily recommended intake to specific risk groups and advises against routine 25-hydroxyvitamin D [25(OH)D] testing in healthy individuals. 

The evidence-based document was presented on June 3, 2024, at the Endocrine Society annual meeting, and simultaneously published in The Journal of Clinical Endocrinology and Metabolism. It advises that people who may benefit from vitamin D supplementation include: 

• Children aged 1-18 years to prevent rickets and to potentially lower the risk for respiratory tract infections
• Pregnant people to lower the risk for maternal and fetal or neonatal complications
• Adults older than 75 years to lower the risk for mortality
• Adults with prediabetes to lower the risk for type 2 diabetes

In those groups, the recommendation is for daily (rather than intermittent) empiric vitamin D supplementation of more than what was recommended in 2011 by the National Academy of Medicine (NAM), which was then called the Institute of Medicine (IOM): 600 IU/d for those aged 1-70 years and 800 IU/d for those older than 70 years. The document acknowledges that the optimal dose for these populations isn’t known, but it provides the dose ranges that were used in the trials cited as evidence for the recommendations. 

In contrast, the document advises against more vitamin D than the recommended daily intake for most healthier adults younger than 75 years and recommends against testing for blood vitamin D levels in the general population, including those with obesity or darker complexions. 

Guideline author Anastassios G. Pittas, MD, professor of medicine at Tufts University School of Medicine, Boston, told this news organization, “this guideline refers to people who are otherwise healthy, and there’s no clear indication for vitamin D, such as people with already established osteoporosis. This guideline is not relevant to them.”

Dr. Pittas also noted, “there’s no single question and single answer about the role of vitamin D in health and disease, which is what people often want to know. There are many questions, and we cannot answer all of them.”

Panel Chair Marie B. Demay, MD, professor of medicine at Harvard Medical School, Boston, told this news organization that indeed the panel was limited by lack of randomized clinical trial evidence to answer many important questions. “There is a paucity of data regarding definition of optimal levels and optimal intake of vitamin D for preventing specific diseases ... What we really need are large scale clinical trials and biomarkers so we can predict disease outcome before it happens.”

Overall, Dr. Demay said, “The recommendations are that populations adhere to the [NAM/IOM] dietary recommended intakes, and there are certain populations that will likely benefit from levels of intake above [those].” 

Asked to comment, session moderator Clifford J. Rosen, MD, director of Clinical and Translational Research and senior scientist at Maine Medical Center Research Institute, Scarborough, Maine, noted that screening for vitamin D is quite common in clinical practice, but the recommendation against doing so makes sense. 

“When clinicians measure vitamin D, then they’re forced to make a decision what to do about it. That’s where questions about the levels come in. And that’s a big problem. So what the panel’s saying is, don’t screen ... This really gets to the heart of the issue, because we have no data that there’s anything about screening that allows us to improve quality of life ... Screening is probably not worthwhile in any age group.”

Dr. Rosen, who was an author on the 2011 NAM/IOM dietary reference intakes, said that since then, new data have come out regarding the role of vitamin D in mortality in people older than 75 years, benefit in children with regard to respiratory illness, and the potential benefit of vitamin D in pregnancy. “Otherwise, I think we’re going over a lot of the same stuff that we’ve talked about since I was on the IOM panel 15 years ago ... But I think the level of evidence and rigor with which they did it is really impressive.”

However, Simeon I. Taylor, MD, professor of medicine at the University of Maryland, Baltimore, expressed disappointment that the document was limited to healthy people. “Although acknowledging challenges in managing vitamin D status in patients with several diseases, [such as] chronic kidney disease or inflammatory bowel disease, the new guidelines do not provide sufficient guidance for practicing physicians about how to manage these complex patients.”

In addition, Dr. Taylor said that the guidelines “do not explicitly consider the literature suggesting that alternative testing strategies may provide more relevant insights into vitamin D status. Just as variation in levels of thyroid-binding globulin have convinced endocrinologists not to rely on measurement of total thyroxine; interindividual variation in levels of vitamin D binding protein must be accounted for to interpret measurements of total levels of 25(OH)D. It would have been useful to explicitly consider the possible value of measuring vitamin D binding protein-independent indices of vitamin D status.”

Dr. Taylor also raised the same point as an audience member did during the Q&A period regarding patients with osteoporosis or osteopenia. “The value and utility of the new guidelines would be greatly strengthened by providing guidance for how to approach this important and very large group of individuals.”

Dr. Taylor did say that the document has “several strengths, including the fact that they acknowledge the major limitations of the quality of relevant evidence derived from clinical trials.” 

In an accompanying commentary, the guideline authors delve into the issues of skin pigmentation and race as they pertain to vitamin D metabolism, writing: 

The panel discovered that no randomized clinical trials have directly assessed vitamin D related patient-important outcomes based on participants’ skin pigmentation, although race and ethnicity often served as presumed proxies for skin pigmentation in the literature. In their deliberations, guideline panel members and selected Endocrine Society leaders underscored the critical need to distinguish between skin pigmentation as a biological variable and race and ethnicity as socially determined constructs. This differentiation is vital to maximize scientific rigor and, thus, the validity of resulting recommendations.

Dr. Pittas and Dr. Demay have no disclosures relevant to this clinical practice guideline. Dr. Rosen has no disclosures. Dr. Taylor serves as a consultant for Ionis Pharmaceuticals.
 

A version of this article appeared on Medscape.com.

Almost sixty percent of patients with macroscopic stage III melanoma who were randomized to 6 weeks of neoadjuvant immunotherapy needed no further treatment after therapeutic lymph node dissection in the phase 3 NADINA trial.

These results set a new standard of care in this patient population, the study’s lead author, Christian U. Blank, MD, PhD, reported at the annual meeting of the American Society of Clinical Oncology in Chicago.

Dr. Blank, a hematologist/oncologist from the Netherlands Cancer Institute in Amsterdam, called the result “very special,” noting that the trial included an active comparator, rather than a placebo control.

“When we treat these patients with surgery only, the outcome … is very bad: The 5-year relapse-free survival is only 30% and the overall survival is only 50%. Adjuvant therapy improves relapse-free survival but not overall survival ...Thus, there is an urgent need for these patients for novel therapy approaches,” he said during a press conference at the meeting.
 

Study Methods and Results

The study included 423 patients with stage III de novo or recurrent pathologically proven resectable melanoma with at least 1 lymph node metastasis. Patients were randomized to either the experimental neoadjuvant arm (n = 212), or the standard treatment control arm (n = 211), which consisted of therapeutic lymph node dissection (TLND) followed by 12 cycles of adjuvant nivolumab (NIVO 480 mg every 4 weeks).

Patients in the experimental arm received two cycles of neoadjuvant ipilimumab (IPI 80 mg every 3 weeks) plus NIVO 240 mg for 3 weeks followed by TLND. Those with a major pathologic response (MPR), defined as less than 10% vital tumor cells in the post-neoadjuvant resection specimen, went straight to follow-up.

Those without an MPR received adjuvant therapy. For patients with BRAF wild-type, this involved 11 cycles of adjuvant NIVO (480 mg every 4 weeks), while BRAF-mutated patients received dabrafenib plus trametinib (150 mg b.i.d./2 mg once a day; 46 weeks).

The study met its primary endpoint — event-free survival (EFS) — at the first interim analysis. After a median follow-up of 9.9 months, the estimated EFS was 83.7% for neoadjuvant immunotherapy versus 57.2% for standard of care, (P less than .0001, hazard ratio [HR] = 0.32).

“When we look into the subgroups, for example BRAF-mutated status or BRAF-wild-type status ... you see for both groups also a highly statistically significant outcome favoring the neoadjuvant therapy with hazard ratios of 0.29 and 0.35,” said Dr. Blank.

In total, 59% of patients in the experimental arm had an MPR needing no further treatment. “This is important, because the patients that achieve a major pathologic response have excellent outcomes, with an EFS of 95%,” said Dr. Blank.

He added that those with a partial response had an EFS of 76%, and among those who had “nonresponse,” the EFS was 57% — the same as that of patients in the control arm.

Toxicities were considered transient and acceptable, with systemic treatment-related grade 3 or 4 events in 29.7% of the neoadjuvant arm and 14.7% of the adjuvant arm.

NADINA is the first neoadjuvant checkpoint inhibitor phase 3 study in melanoma and the first phase 3 trial in oncology testing a checkpoint inhibitor without chemotherapy, noted Dr. Blank.

“At the moment we see only additions of immunotherapy to the chemotherapy neoadjuvant arms, but here you see that we can also treat patients with pure immunotherapy.”
 

Neoadjuvant Therapy Defined as Standard of Care

When considered along with evidence from the phase 2 SWOG 1801 study (N Engl J Med. 2023;388:813-8), “NADINA defines neoadjuvant therapy as the new standard of care for macroscopic stage III melanoma “which means that all trials currently ongoing need to be amended from adjuvant comparators to neoadjuvant comparators,” he said.

Dr. Blank called the trial a “new template for other malignancies implementing a neoadjuvant immunotherapy regimen followed by a response-driven adjuvant therapy.

“I think we see at the moment only sandwich designs, and this is more sales driven than patient driven, because what we have seen is that if a patient achieves a really deep response, the patient doesn’t need an adjuvant part,” he said.

Commenting during the press conference, Michael Lowe, MD, said the result “confirms and shows for the first time in a phase 3 study that giving immunotherapy before surgery results in superior outcomes to giving immunotherapy only after surgery.”

Dr. Lowe, associate professor in the Division of Surgical Oncology, at Emory University School of Medicine, Atlanta, added that the study “also confirms that giving two immunotherapy drugs before surgery results in excellent responses.”

However, he cautioned that “we cannot make comparisons to trials in which patients only got one immunotherapy. But this study confirms that consistency that patients who receive ipilimumab and nivolumab have superior responses compared to single-agent immunotherapy.”

He noted that all of the patients in the new study had all of their lymph nodes removed and called for doing that to remain the standard of care in terms of surgical approach.

“With short follow-up, it is too early to tell if some patients may have benefited from that adjuvant therapy. However, NADINA confirms that immunotherapy should be given to all patients with advanced melanoma before surgery, when possible, and establishes dual therapy with nivolumab and ipilimumab, as the standard of care in the appropriate patient,” Dr. Lowe said.
 

EFS Improvement Exceeds Expectations

In an interview, Rodabe N. Amaria, MD, a medical oncologist and professor at The University of Texas MD Anderson Cancer Center in Houston, agreed with Dr. Lowe’s assessment of the findings.

“For years we have been doing neoadjuvant immunotherapy trials, all with favorable results, but all relatively small, with data that was intriguing, but not necessarily definitive,” she said. “I see the data from the NADINA trial as being definitive and true evidence of the many advantages of neoadjuvant immunotherapy for clinical stage 3 melanoma ... This work builds on the data from the SWOG 1801 trial but also exceeds expectations with the 68% improvement in EFS appreciated with the dual combination immunotherapy regimen compared to adjuvant nivolumab.”

Additionally, the approximately 30% grade 3 or higher immune-mediated toxicity is reasonable and in keeping with known data, and this trial demonstrates clearly that neoadjuvant immunotherapy does not increase the rate of surgical complications, she said.

Dr. Amaria also considered that 59% of patients who achieved a major pathologic response were observed in the neoadjuvant setting to be a key finding.

This indicates thats “over half the patients could be spared additional immunotherapy and risk of further immune-mediated toxicities by having only two doses of neoadjuvant immunotherapy, she said.

The results “demonstrate the superiority of a neoadjuvant combination immunotherapy approach for patients with clinical stage III melanoma,” she added.

The study was funded by Bristol Myers-Squibb and the Australian government.

Dr. Blank disclosed ties with Immagene, Signature Oncology, AstraZeneca, Bristol-Myers Squibb, GenMab, GlaxoSmithKline, Lilly, MSD Oncology, Novartis, Pfizer, Pierre Fabre, Roche/Genentech, Third Rock Ventures, 4SC, NanoString Technologies, WO 2021/177822 A1, and Freshfields Bruckhaus Deringer. No other experts reported any relevant disclosures.

Almost sixty percent of patients with macroscopic stage III melanoma who were randomized to 6 weeks of neoadjuvant immunotherapy needed no further treatment after therapeutic lymph node dissection in the phase 3 NADINA trial.

These results set a new standard of care in this patient population, the study’s lead author, Christian U. Blank, MD, PhD, reported at the annual meeting of the American Society of Clinical Oncology in Chicago.

Dr. Blank, a hematologist/oncologist from the Netherlands Cancer Institute in Amsterdam, called the result “very special,” noting that the trial included an active comparator, rather than a placebo control.

“When we treat these patients with surgery only, the outcome … is very bad: The 5-year relapse-free survival is only 30% and the overall survival is only 50%. Adjuvant therapy improves relapse-free survival but not overall survival ...Thus, there is an urgent need for these patients for novel therapy approaches,” he said during a press conference at the meeting.
 

Study Methods and Results

The study included 423 patients with stage III de novo or recurrent pathologically proven resectable melanoma with at least 1 lymph node metastasis. Patients were randomized to either the experimental neoadjuvant arm (n = 212), or the standard treatment control arm (n = 211), which consisted of therapeutic lymph node dissection (TLND) followed by 12 cycles of adjuvant nivolumab (NIVO 480 mg every 4 weeks).

Patients in the experimental arm received two cycles of neoadjuvant ipilimumab (IPI 80 mg every 3 weeks) plus NIVO 240 mg for 3 weeks followed by TLND. Those with a major pathologic response (MPR), defined as less than 10% vital tumor cells in the post-neoadjuvant resection specimen, went straight to follow-up.

Those without an MPR received adjuvant therapy. For patients with BRAF wild-type, this involved 11 cycles of adjuvant NIVO (480 mg every 4 weeks), while BRAF-mutated patients received dabrafenib plus trametinib (150 mg b.i.d./2 mg once a day; 46 weeks).

The study met its primary endpoint — event-free survival (EFS) — at the first interim analysis. After a median follow-up of 9.9 months, the estimated EFS was 83.7% for neoadjuvant immunotherapy versus 57.2% for standard of care, (P less than .0001, hazard ratio [HR] = 0.32).

“When we look into the subgroups, for example BRAF-mutated status or BRAF-wild-type status ... you see for both groups also a highly statistically significant outcome favoring the neoadjuvant therapy with hazard ratios of 0.29 and 0.35,” said Dr. Blank.

In total, 59% of patients in the experimental arm had an MPR needing no further treatment. “This is important, because the patients that achieve a major pathologic response have excellent outcomes, with an EFS of 95%,” said Dr. Blank.

He added that those with a partial response had an EFS of 76%, and among those who had “nonresponse,” the EFS was 57% — the same as that of patients in the control arm.

Toxicities were considered transient and acceptable, with systemic treatment-related grade 3 or 4 events in 29.7% of the neoadjuvant arm and 14.7% of the adjuvant arm.

NADINA is the first neoadjuvant checkpoint inhibitor phase 3 study in melanoma and the first phase 3 trial in oncology testing a checkpoint inhibitor without chemotherapy, noted Dr. Blank.

“At the moment we see only additions of immunotherapy to the chemotherapy neoadjuvant arms, but here you see that we can also treat patients with pure immunotherapy.”
 

Neoadjuvant Therapy Defined as Standard of Care

When considered along with evidence from the phase 2 SWOG 1801 study (N Engl J Med. 2023;388:813-8), “NADINA defines neoadjuvant therapy as the new standard of care for macroscopic stage III melanoma “which means that all trials currently ongoing need to be amended from adjuvant comparators to neoadjuvant comparators,” he said.

Dr. Blank called the trial a “new template for other malignancies implementing a neoadjuvant immunotherapy regimen followed by a response-driven adjuvant therapy.

“I think we see at the moment only sandwich designs, and this is more sales driven than patient driven, because what we have seen is that if a patient achieves a really deep response, the patient doesn’t need an adjuvant part,” he said.

Commenting during the press conference, Michael Lowe, MD, said the result “confirms and shows for the first time in a phase 3 study that giving immunotherapy before surgery results in superior outcomes to giving immunotherapy only after surgery.”

Dr. Lowe, associate professor in the Division of Surgical Oncology, at Emory University School of Medicine, Atlanta, added that the study “also confirms that giving two immunotherapy drugs before surgery results in excellent responses.”

However, he cautioned that “we cannot make comparisons to trials in which patients only got one immunotherapy. But this study confirms that consistency that patients who receive ipilimumab and nivolumab have superior responses compared to single-agent immunotherapy.”

He noted that all of the patients in the new study had all of their lymph nodes removed and called for doing that to remain the standard of care in terms of surgical approach.

“With short follow-up, it is too early to tell if some patients may have benefited from that adjuvant therapy. However, NADINA confirms that immunotherapy should be given to all patients with advanced melanoma before surgery, when possible, and establishes dual therapy with nivolumab and ipilimumab, as the standard of care in the appropriate patient,” Dr. Lowe said.
 

EFS Improvement Exceeds Expectations

In an interview, Rodabe N. Amaria, MD, a medical oncologist and professor at The University of Texas MD Anderson Cancer Center in Houston, agreed with Dr. Lowe’s assessment of the findings.

“For years we have been doing neoadjuvant immunotherapy trials, all with favorable results, but all relatively small, with data that was intriguing, but not necessarily definitive,” she said. “I see the data from the NADINA trial as being definitive and true evidence of the many advantages of neoadjuvant immunotherapy for clinical stage 3 melanoma ... This work builds on the data from the SWOG 1801 trial but also exceeds expectations with the 68% improvement in EFS appreciated with the dual combination immunotherapy regimen compared to adjuvant nivolumab.”

Additionally, the approximately 30% grade 3 or higher immune-mediated toxicity is reasonable and in keeping with known data, and this trial demonstrates clearly that neoadjuvant immunotherapy does not increase the rate of surgical complications, she said.

Dr. Amaria also considered that 59% of patients who achieved a major pathologic response were observed in the neoadjuvant setting to be a key finding.

This indicates thats “over half the patients could be spared additional immunotherapy and risk of further immune-mediated toxicities by having only two doses of neoadjuvant immunotherapy, she said.

The results “demonstrate the superiority of a neoadjuvant combination immunotherapy approach for patients with clinical stage III melanoma,” she added.

The study was funded by Bristol Myers-Squibb and the Australian government.

Dr. Blank disclosed ties with Immagene, Signature Oncology, AstraZeneca, Bristol-Myers Squibb, GenMab, GlaxoSmithKline, Lilly, MSD Oncology, Novartis, Pfizer, Pierre Fabre, Roche/Genentech, Third Rock Ventures, 4SC, NanoString Technologies, WO 2021/177822 A1, and Freshfields Bruckhaus Deringer. No other experts reported any relevant disclosures.

Almost sixty percent of patients with macroscopic stage III melanoma who were randomized to 6 weeks of neoadjuvant immunotherapy needed no further treatment after therapeutic lymph node dissection in the phase 3 NADINA trial.

These results set a new standard of care in this patient population, the study’s lead author, Christian U. Blank, MD, PhD, reported at the annual meeting of the American Society of Clinical Oncology in Chicago.

Dr. Blank, a hematologist/oncologist from the Netherlands Cancer Institute in Amsterdam, called the result “very special,” noting that the trial included an active comparator, rather than a placebo control.

“When we treat these patients with surgery only, the outcome … is very bad: The 5-year relapse-free survival is only 30% and the overall survival is only 50%. Adjuvant therapy improves relapse-free survival but not overall survival ...Thus, there is an urgent need for these patients for novel therapy approaches,” he said during a press conference at the meeting.
 

Study Methods and Results

The study included 423 patients with stage III de novo or recurrent pathologically proven resectable melanoma with at least 1 lymph node metastasis. Patients were randomized to either the experimental neoadjuvant arm (n = 212), or the standard treatment control arm (n = 211), which consisted of therapeutic lymph node dissection (TLND) followed by 12 cycles of adjuvant nivolumab (NIVO 480 mg every 4 weeks).

Patients in the experimental arm received two cycles of neoadjuvant ipilimumab (IPI 80 mg every 3 weeks) plus NIVO 240 mg for 3 weeks followed by TLND. Those with a major pathologic response (MPR), defined as less than 10% vital tumor cells in the post-neoadjuvant resection specimen, went straight to follow-up.

Those without an MPR received adjuvant therapy. For patients with BRAF wild-type, this involved 11 cycles of adjuvant NIVO (480 mg every 4 weeks), while BRAF-mutated patients received dabrafenib plus trametinib (150 mg b.i.d./2 mg once a day; 46 weeks).

The study met its primary endpoint — event-free survival (EFS) — at the first interim analysis. After a median follow-up of 9.9 months, the estimated EFS was 83.7% for neoadjuvant immunotherapy versus 57.2% for standard of care, (P less than .0001, hazard ratio [HR] = 0.32).

“When we look into the subgroups, for example BRAF-mutated status or BRAF-wild-type status ... you see for both groups also a highly statistically significant outcome favoring the neoadjuvant therapy with hazard ratios of 0.29 and 0.35,” said Dr. Blank.

In total, 59% of patients in the experimental arm had an MPR needing no further treatment. “This is important, because the patients that achieve a major pathologic response have excellent outcomes, with an EFS of 95%,” said Dr. Blank.

He added that those with a partial response had an EFS of 76%, and among those who had “nonresponse,” the EFS was 57% — the same as that of patients in the control arm.

Toxicities were considered transient and acceptable, with systemic treatment-related grade 3 or 4 events in 29.7% of the neoadjuvant arm and 14.7% of the adjuvant arm.

NADINA is the first neoadjuvant checkpoint inhibitor phase 3 study in melanoma and the first phase 3 trial in oncology testing a checkpoint inhibitor without chemotherapy, noted Dr. Blank.

“At the moment we see only additions of immunotherapy to the chemotherapy neoadjuvant arms, but here you see that we can also treat patients with pure immunotherapy.”
 

Neoadjuvant Therapy Defined as Standard of Care

When considered along with evidence from the phase 2 SWOG 1801 study (N Engl J Med. 2023;388:813-8), “NADINA defines neoadjuvant therapy as the new standard of care for macroscopic stage III melanoma “which means that all trials currently ongoing need to be amended from adjuvant comparators to neoadjuvant comparators,” he said.

Dr. Blank called the trial a “new template for other malignancies implementing a neoadjuvant immunotherapy regimen followed by a response-driven adjuvant therapy.

“I think we see at the moment only sandwich designs, and this is more sales driven than patient driven, because what we have seen is that if a patient achieves a really deep response, the patient doesn’t need an adjuvant part,” he said.

Commenting during the press conference, Michael Lowe, MD, said the result “confirms and shows for the first time in a phase 3 study that giving immunotherapy before surgery results in superior outcomes to giving immunotherapy only after surgery.”

Dr. Lowe, associate professor in the Division of Surgical Oncology, at Emory University School of Medicine, Atlanta, added that the study “also confirms that giving two immunotherapy drugs before surgery results in excellent responses.”

However, he cautioned that “we cannot make comparisons to trials in which patients only got one immunotherapy. But this study confirms that consistency that patients who receive ipilimumab and nivolumab have superior responses compared to single-agent immunotherapy.”

He noted that all of the patients in the new study had all of their lymph nodes removed and called for doing that to remain the standard of care in terms of surgical approach.

“With short follow-up, it is too early to tell if some patients may have benefited from that adjuvant therapy. However, NADINA confirms that immunotherapy should be given to all patients with advanced melanoma before surgery, when possible, and establishes dual therapy with nivolumab and ipilimumab, as the standard of care in the appropriate patient,” Dr. Lowe said.
 

EFS Improvement Exceeds Expectations

In an interview, Rodabe N. Amaria, MD, a medical oncologist and professor at The University of Texas MD Anderson Cancer Center in Houston, agreed with Dr. Lowe’s assessment of the findings.

“For years we have been doing neoadjuvant immunotherapy trials, all with favorable results, but all relatively small, with data that was intriguing, but not necessarily definitive,” she said. “I see the data from the NADINA trial as being definitive and true evidence of the many advantages of neoadjuvant immunotherapy for clinical stage 3 melanoma ... This work builds on the data from the SWOG 1801 trial but also exceeds expectations with the 68% improvement in EFS appreciated with the dual combination immunotherapy regimen compared to adjuvant nivolumab.”

Additionally, the approximately 30% grade 3 or higher immune-mediated toxicity is reasonable and in keeping with known data, and this trial demonstrates clearly that neoadjuvant immunotherapy does not increase the rate of surgical complications, she said.

Dr. Amaria also considered that 59% of patients who achieved a major pathologic response were observed in the neoadjuvant setting to be a key finding.

This indicates thats “over half the patients could be spared additional immunotherapy and risk of further immune-mediated toxicities by having only two doses of neoadjuvant immunotherapy, she said.

The results “demonstrate the superiority of a neoadjuvant combination immunotherapy approach for patients with clinical stage III melanoma,” she added.

The study was funded by Bristol Myers-Squibb and the Australian government.

Dr. Blank disclosed ties with Immagene, Signature Oncology, AstraZeneca, Bristol-Myers Squibb, GenMab, GlaxoSmithKline, Lilly, MSD Oncology, Novartis, Pfizer, Pierre Fabre, Roche/Genentech, Third Rock Ventures, 4SC, NanoString Technologies, WO 2021/177822 A1, and Freshfields Bruckhaus Deringer. No other experts reported any relevant disclosures.

A reformulation of the multiple cancer drugs in the combination treatment known as BEACOPP boosted progression free survival vs. the original therapy in adult patients with advanced-stage classical Hodgkin lymphoma, a large, open-label, phase III trial found.

At a median follow-up of 4 years, progression-free survival for the new treatment, known as BrECADD, was 94.3% vs. 90.9% for BEACOPP (hazard ratio, 0.66, 95% CI, P = .035), researchers led by Peter Borchmann, MD, assistant medical director of hematology and oncology at the University Hospital of Cologne, Germany, reported at the annual meeting of the American Society of Clinical Oncology (ASCO).

“These results are really striking,” said hematologist-oncologist Oreofe O. Odejide, MD, MPH, of the Dana-Farber Cancer Institute and Harvard Medical School, Boston, who was not involved in the study and commented on it during an ASCO news briefing. “This is really poised to impact the standard-of-care treatment for patients with advanced-stage classical Hodgkin lymphoma.”

As Dr. Borchmann explained at the briefing, Hodgkin lymphoma is the most common cancer among young adults. “The median age at onset is around 30 years, and it can be primarily cured with chemotherapy. Intensified chemotherapy probably is better primary lymphoma control than less intensive treatment, but this comes at the cost of treatment-related adverse events.”

Dr. Borchmann and colleagues developed the existing treatment known as BEACOPP, a combination of bleomycin, etoposide, doxorubicin, cyclophosphamide, vincristine, procarbazine, and prednisone. “It’s our standard of care due to its high primary cure rate, which is reflected by compelling progression-free survival,” he said.

However, he said, “it’s a high burden of treatment.” The investigational treatment, BrECADD, includes six drugs instead of seven: brentuximab vedotin, etoposide, cyclophosphamide, doxorubicin, dacarbazine, and dexamethasone. Two of the additions — brentuximab vedotin and dacarbazine — are cancer drugs, and dexamethasone is a steroid. There is one fewer cancer drug in the new formulation.

In the international HD21 trial (9 countries, 233 sites), researchers recruited patients aged 18-60 who received four or six cycles of either BEACOPP or BrECADD. The doses were guided by PET2 findings.

In the intention-to-treat cohort of 1,482 subjects (median age 31.1, 44% female), 742 were assigned to BrECADD and 740 to BEACOPP.

There were few early treatment failures in the BrECADD group vs. BEACOPP. The numbers who had primary progression within the first 3 months were 5 vs. 15, respectively, and the numbers reaching early relapse between months 3 and 12 were 11 vs. 23, respectively.

Four-year overall survival rates in the groups were nearly identical at 98.5% for BrECADD and 98.2% for BEACOPP. In regard to fertility, follicle-stimulating hormone recovery rates after 1 year were higher in the BrECADD group in both men (67% vs. 24%, respectively) and women (89% vs. 68%, respectively). Birth rates were also higher in the BrECADD group (n = 60 vs. n = 43 in the BEACOPP group).

Nearly two-thirds of those in BrECADD group (64%) required 12 weeks of therapy — four cycles. As for treatment-related morbidity toxicities, they were less common in the BrECADD group vs. the BEACOPP group (42% vs. 59%, respectively, P < .0001), and 1% of BrECADD-treated had them at 1 year.

Oncologist Julie R. Gralow, MD, chief medical officer and executive vice president of ASCO, welcomed the findings at the ACO news briefing. “By replacing some pretty toxic chemo with an antibody-drug conjugate [brentuximab vedotin], and changing the regimen a bit, and using PET scan to determine the number of cycles received, the long-term outcomes were maintained, if not even improved upon,” said Dr. Dr. Gralow, who was not involved in the study.

In addition, she said, the findings about fertility are good news because “these are young people who probably haven’t started a family yet, and we’re increasing the odds that they will be able to do so after survival.”

Moving forward, she said, “we will need to have some discussion on how this relates to ABVD, which is a more commonly used regimen in the United States right now.” ABVD refers to a combination of doxorubicin hydrochloride, bleomycin sulfate, vinblastine sulfate, and dacarbazine.

Takeda funded the study. Dr. Borchmann reported ties with BMS, GmbH & Co, Incyte, MSD/Merck, Roche, Takeda/Millennium, Miltenyi, Amgen, and Novartis. Some of the other study authors reported various disclosures. Dr. Odejide and Dr. Gralow have no disclosures.

A reformulation of the multiple cancer drugs in the combination treatment known as BEACOPP boosted progression free survival vs. the original therapy in adult patients with advanced-stage classical Hodgkin lymphoma, a large, open-label, phase III trial found.

At a median follow-up of 4 years, progression-free survival for the new treatment, known as BrECADD, was 94.3% vs. 90.9% for BEACOPP (hazard ratio, 0.66, 95% CI, P = .035), researchers led by Peter Borchmann, MD, assistant medical director of hematology and oncology at the University Hospital of Cologne, Germany, reported at the annual meeting of the American Society of Clinical Oncology (ASCO).

“These results are really striking,” said hematologist-oncologist Oreofe O. Odejide, MD, MPH, of the Dana-Farber Cancer Institute and Harvard Medical School, Boston, who was not involved in the study and commented on it during an ASCO news briefing. “This is really poised to impact the standard-of-care treatment for patients with advanced-stage classical Hodgkin lymphoma.”

As Dr. Borchmann explained at the briefing, Hodgkin lymphoma is the most common cancer among young adults. “The median age at onset is around 30 years, and it can be primarily cured with chemotherapy. Intensified chemotherapy probably is better primary lymphoma control than less intensive treatment, but this comes at the cost of treatment-related adverse events.”

Dr. Borchmann and colleagues developed the existing treatment known as BEACOPP, a combination of bleomycin, etoposide, doxorubicin, cyclophosphamide, vincristine, procarbazine, and prednisone. “It’s our standard of care due to its high primary cure rate, which is reflected by compelling progression-free survival,” he said.

However, he said, “it’s a high burden of treatment.” The investigational treatment, BrECADD, includes six drugs instead of seven: brentuximab vedotin, etoposide, cyclophosphamide, doxorubicin, dacarbazine, and dexamethasone. Two of the additions — brentuximab vedotin and dacarbazine — are cancer drugs, and dexamethasone is a steroid. There is one fewer cancer drug in the new formulation.

In the international HD21 trial (9 countries, 233 sites), researchers recruited patients aged 18-60 who received four or six cycles of either BEACOPP or BrECADD. The doses were guided by PET2 findings.

In the intention-to-treat cohort of 1,482 subjects (median age 31.1, 44% female), 742 were assigned to BrECADD and 740 to BEACOPP.

There were few early treatment failures in the BrECADD group vs. BEACOPP. The numbers who had primary progression within the first 3 months were 5 vs. 15, respectively, and the numbers reaching early relapse between months 3 and 12 were 11 vs. 23, respectively.

Four-year overall survival rates in the groups were nearly identical at 98.5% for BrECADD and 98.2% for BEACOPP. In regard to fertility, follicle-stimulating hormone recovery rates after 1 year were higher in the BrECADD group in both men (67% vs. 24%, respectively) and women (89% vs. 68%, respectively). Birth rates were also higher in the BrECADD group (n = 60 vs. n = 43 in the BEACOPP group).

Nearly two-thirds of those in BrECADD group (64%) required 12 weeks of therapy — four cycles. As for treatment-related morbidity toxicities, they were less common in the BrECADD group vs. the BEACOPP group (42% vs. 59%, respectively, P < .0001), and 1% of BrECADD-treated had them at 1 year.

Oncologist Julie R. Gralow, MD, chief medical officer and executive vice president of ASCO, welcomed the findings at the ACO news briefing. “By replacing some pretty toxic chemo with an antibody-drug conjugate [brentuximab vedotin], and changing the regimen a bit, and using PET scan to determine the number of cycles received, the long-term outcomes were maintained, if not even improved upon,” said Dr. Dr. Gralow, who was not involved in the study.

In addition, she said, the findings about fertility are good news because “these are young people who probably haven’t started a family yet, and we’re increasing the odds that they will be able to do so after survival.”

Moving forward, she said, “we will need to have some discussion on how this relates to ABVD, which is a more commonly used regimen in the United States right now.” ABVD refers to a combination of doxorubicin hydrochloride, bleomycin sulfate, vinblastine sulfate, and dacarbazine.

Takeda funded the study. Dr. Borchmann reported ties with BMS, GmbH & Co, Incyte, MSD/Merck, Roche, Takeda/Millennium, Miltenyi, Amgen, and Novartis. Some of the other study authors reported various disclosures. Dr. Odejide and Dr. Gralow have no disclosures.

A reformulation of the multiple cancer drugs in the combination treatment known as BEACOPP boosted progression free survival vs. the original therapy in adult patients with advanced-stage classical Hodgkin lymphoma, a large, open-label, phase III trial found.

At a median follow-up of 4 years, progression-free survival for the new treatment, known as BrECADD, was 94.3% vs. 90.9% for BEACOPP (hazard ratio, 0.66, 95% CI, P = .035), researchers led by Peter Borchmann, MD, assistant medical director of hematology and oncology at the University Hospital of Cologne, Germany, reported at the annual meeting of the American Society of Clinical Oncology (ASCO).

“These results are really striking,” said hematologist-oncologist Oreofe O. Odejide, MD, MPH, of the Dana-Farber Cancer Institute and Harvard Medical School, Boston, who was not involved in the study and commented on it during an ASCO news briefing. “This is really poised to impact the standard-of-care treatment for patients with advanced-stage classical Hodgkin lymphoma.”

As Dr. Borchmann explained at the briefing, Hodgkin lymphoma is the most common cancer among young adults. “The median age at onset is around 30 years, and it can be primarily cured with chemotherapy. Intensified chemotherapy probably is better primary lymphoma control than less intensive treatment, but this comes at the cost of treatment-related adverse events.”

Dr. Borchmann and colleagues developed the existing treatment known as BEACOPP, a combination of bleomycin, etoposide, doxorubicin, cyclophosphamide, vincristine, procarbazine, and prednisone. “It’s our standard of care due to its high primary cure rate, which is reflected by compelling progression-free survival,” he said.

However, he said, “it’s a high burden of treatment.” The investigational treatment, BrECADD, includes six drugs instead of seven: brentuximab vedotin, etoposide, cyclophosphamide, doxorubicin, dacarbazine, and dexamethasone. Two of the additions — brentuximab vedotin and dacarbazine — are cancer drugs, and dexamethasone is a steroid. There is one fewer cancer drug in the new formulation.

In the international HD21 trial (9 countries, 233 sites), researchers recruited patients aged 18-60 who received four or six cycles of either BEACOPP or BrECADD. The doses were guided by PET2 findings.

In the intention-to-treat cohort of 1,482 subjects (median age 31.1, 44% female), 742 were assigned to BrECADD and 740 to BEACOPP.

There were few early treatment failures in the BrECADD group vs. BEACOPP. The numbers who had primary progression within the first 3 months were 5 vs. 15, respectively, and the numbers reaching early relapse between months 3 and 12 were 11 vs. 23, respectively.

Four-year overall survival rates in the groups were nearly identical at 98.5% for BrECADD and 98.2% for BEACOPP. In regard to fertility, follicle-stimulating hormone recovery rates after 1 year were higher in the BrECADD group in both men (67% vs. 24%, respectively) and women (89% vs. 68%, respectively). Birth rates were also higher in the BrECADD group (n = 60 vs. n = 43 in the BEACOPP group).

Nearly two-thirds of those in BrECADD group (64%) required 12 weeks of therapy — four cycles. As for treatment-related morbidity toxicities, they were less common in the BrECADD group vs. the BEACOPP group (42% vs. 59%, respectively, P < .0001), and 1% of BrECADD-treated had them at 1 year.

Oncologist Julie R. Gralow, MD, chief medical officer and executive vice president of ASCO, welcomed the findings at the ACO news briefing. “By replacing some pretty toxic chemo with an antibody-drug conjugate [brentuximab vedotin], and changing the regimen a bit, and using PET scan to determine the number of cycles received, the long-term outcomes were maintained, if not even improved upon,” said Dr. Dr. Gralow, who was not involved in the study.

In addition, she said, the findings about fertility are good news because “these are young people who probably haven’t started a family yet, and we’re increasing the odds that they will be able to do so after survival.”

Moving forward, she said, “we will need to have some discussion on how this relates to ABVD, which is a more commonly used regimen in the United States right now.” ABVD refers to a combination of doxorubicin hydrochloride, bleomycin sulfate, vinblastine sulfate, and dacarbazine.

Takeda funded the study. Dr. Borchmann reported ties with BMS, GmbH & Co, Incyte, MSD/Merck, Roche, Takeda/Millennium, Miltenyi, Amgen, and Novartis. Some of the other study authors reported various disclosures. Dr. Odejide and Dr. Gralow have no disclosures.