Neil Osterweil

AURORA, COLO. – Only sparse evidence supports the use of dual-targeted therapy for patients with severe, refractory inflammatory bowel disease (IBD) -- and additional evidence will be hard to come by, according to a leading IBD researcher.

Dual-targeted therapy consists of either sequential or concomitant treatment with drugs from different classes of agents with distinct, specific mechanisms of action such as the use of a drug targeted against tumor necrosis factor (anti-TNFs) with an interleukin-12/23 inhibitor.

There have been only a handful of randomized clinical trials exploring such combinations, however. In addition, there are barriers to new trials, including the costs and risks of randomized trials, the need for cooperation rather than competition between pharmaceutical companies, and identifying patients who might optimally benefit from dual-targeted therapy, Laura Targownik, MD, said in a presentation at the annual Crohn’s & Colitis Congress®, a partnership of the Crohn’s & Colitis Foundation and the American Gastroenterological Association.

“In Canada we have absolutely no chance of getting coverage for this, and I imagine in hearing about the fights you have with insurers here in the [United] States, that you’re anticipating similar problems. So what do we do with this information? I think if we’re going to get answers on this question, it’s probably going to come from real-world evidence, from all of our experiences,” said Dr. Targownik of the Zane Cohen Centre for Digestive Diseases at Mount Sinai Hospital in Toronto.

Who might benefit?

Dual-targeted therapy has the potential to benefit patients with severe disease who may need intensive therapy upfront to prevent complications such as fistulas, strictures, or chronic abdominal pain. It may also benefit those who may require only short-term acute disease control; patients with meaningful yet incomplete responses to single-agent therapy who might have better outcomes with the addition of a second agent; and, patients with a unique phenotype that might be responsive to dual-targeted agents, Dr. Targownik said.

Another reason to consider dual-targeted therapy in IBD comes from applying data from recent clinical trials of upadacitinib (Rinvoq, Abbvie) for ulcerative colitis (UC) and risankizumab-rzaa (Skyrizi, Abbvie) for Crohn’s disease to hypothetical cohorts.

For example, of 1,000 persons with moderate to severe UC treated with upadacitinib, 736 would have a clinical response at the end of the induction, and at the end of the maintenance phase 191 would have endoscopic remissions, and 382 would remain in clinical remission.

Similarly, of 1,000 persons with moderate to severe Crohn’s disease treated with risankizumab, 434 would have a clinical response at the end of induction, and at the end of the maintenance phase, 172 would have endoscopic remissions, and 234 would remain in clinical remission.

“So, the vast majority of our patients are not achieving the targets that we want to hit,” she said.
 

Evidence from research clinical trials

Data from one of the few trials that have explored dual targeted therapy in IBD were presented at United European Gastroenterology Week in 2022.

The randomized double-blind phase 2a VEGA study looked at induction therapy with either a combination of the IL-23 inhibitor guselkumab (Tremfya, Janssen) and the anti-TNF monoclonal antibody golimumab (Simponi Aria, Janssen) followed by maintenance guselkumab, or each agent alone as induction monotherapy and maintenance.

The study population included 214 patients with moderate to severe UC with a modified Mayo Disease Activity Index scores of 6 or greater and endoscopy scores of 2 or 3 who had not received either anti-TNF or anti IL-23 agents.

At 12 weeks of follow-up, 36.6% of patients who started on combination therapy had clinical remissions, compared with 22.2% of patients on golimumab monotherapy and 22.1% of those on guselkumab alone, a clinically significant difference, Dr. Targownik said.

The combination also resulted in better endoscopic improvement over baseline (49.3% vs. 25% and 29.6%, respectively), although the study was not powered for this outcome.

At 38 weeks, 22.2% of patients who started on golimumab alone were in clinical remission, compared with 31% of those assigned to guselkumab monotherapy and 43.7% of those who started on the combination.

Endoscopic normalization at 38 weeks was seen in 6.9%, 15.5%, and 25.4% of patients, respectively.

“Even in the patients who went back on guselkumab monotherapy that were induced with dual therapy, there were statistically higher rates of clinical remission and endoscopic normalization at the end of the study,” Dr. Targownik said, although she noted that it’s unknown whether the benefit of the combination would be sustained over longer follow-up.

In the open-label EXPLORER Crohn’s disease trial, among 55 patients with high risk Crohn’s disease, within 24 months of diagnosis investigators looked at the triple combination therapy of the anti-integrin agent vedolizumab (Entyvio, Takeda), the anti-TNF agent adalimumab (Humira, Abbvie) and methotrexate. An interim analysis at week 26 of the 34-week trial showed clinical remissions in 54.5% of patients and endoscopic remissions in 34.5%, “which I would argue for an open-label study are not terribly high results,” she said.
 

Real-world experience

Dr. Targownik pointed to a systematic review and meta-analysis of the safety and effectiveness of combining biologic agents and small molecules in patients with IBD as evidence for how combinations work in the real world.

The analysis included data from 1 clinical trial and 12 observational studies on a total of 266 patients treated with one of seven different combinations. It showed estimates of clinical efficacy ranging from about 40% to 80%, albeit with wide and overlapping confidence intervals, making it difficult to come to any conclusions about the relatively superiority of one combination over another, Dr. Targownik said.

The authors of the meta-analysis did note, however, that the incidence of serious adverse events was relatively low, ranging from 9.6% for the combination of vedolizumab and anti-TNF, to just 1% for the JAK inhibitor tofacitinib (Xeljanz, Pfizer) plus vedolizumab.
 

Registry data may help

The use of registry data will shed more light on the potential benefits and drawbacks of dual-targeted therapy.

“If we can identify...the patient phenotypes that we want to evaluate dual therapy in, and try to catalog their experiences in a regimented way with defined outcomes and periods of follow-up, we may be able to get more meaningful information,” Dr. Targownik said.

Dr. Targownik disclosed fees, grant support, and/or scientific advisory board participation with multiple companies.

This article was updated 1/25/23.

AURORA, COLO. – Only sparse evidence supports the use of dual-targeted therapy for patients with severe, refractory inflammatory bowel disease (IBD) -- and additional evidence will be hard to come by, according to a leading IBD researcher.

Dual-targeted therapy consists of either sequential or concomitant treatment with drugs from different classes of agents with distinct, specific mechanisms of action such as the use of a drug targeted against tumor necrosis factor (anti-TNFs) with an interleukin-12/23 inhibitor.

There have been only a handful of randomized clinical trials exploring such combinations, however. In addition, there are barriers to new trials, including the costs and risks of randomized trials, the need for cooperation rather than competition between pharmaceutical companies, and identifying patients who might optimally benefit from dual-targeted therapy, Laura Targownik, MD, said in a presentation at the annual Crohn’s & Colitis Congress®, a partnership of the Crohn’s & Colitis Foundation and the American Gastroenterological Association.

“In Canada we have absolutely no chance of getting coverage for this, and I imagine in hearing about the fights you have with insurers here in the [United] States, that you’re anticipating similar problems. So what do we do with this information? I think if we’re going to get answers on this question, it’s probably going to come from real-world evidence, from all of our experiences,” said Dr. Targownik of the Zane Cohen Centre for Digestive Diseases at Mount Sinai Hospital in Toronto.

Who might benefit?

Dual-targeted therapy has the potential to benefit patients with severe disease who may need intensive therapy upfront to prevent complications such as fistulas, strictures, or chronic abdominal pain. It may also benefit those who may require only short-term acute disease control; patients with meaningful yet incomplete responses to single-agent therapy who might have better outcomes with the addition of a second agent; and, patients with a unique phenotype that might be responsive to dual-targeted agents, Dr. Targownik said.

Another reason to consider dual-targeted therapy in IBD comes from applying data from recent clinical trials of upadacitinib (Rinvoq, Abbvie) for ulcerative colitis (UC) and risankizumab-rzaa (Skyrizi, Abbvie) for Crohn’s disease to hypothetical cohorts.

For example, of 1,000 persons with moderate to severe UC treated with upadacitinib, 736 would have a clinical response at the end of the induction, and at the end of the maintenance phase 191 would have endoscopic remissions, and 382 would remain in clinical remission.

Similarly, of 1,000 persons with moderate to severe Crohn’s disease treated with risankizumab, 434 would have a clinical response at the end of induction, and at the end of the maintenance phase, 172 would have endoscopic remissions, and 234 would remain in clinical remission.

“So, the vast majority of our patients are not achieving the targets that we want to hit,” she said.
 

Evidence from research clinical trials

Data from one of the few trials that have explored dual targeted therapy in IBD were presented at United European Gastroenterology Week in 2022.

The randomized double-blind phase 2a VEGA study looked at induction therapy with either a combination of the IL-23 inhibitor guselkumab (Tremfya, Janssen) and the anti-TNF monoclonal antibody golimumab (Simponi Aria, Janssen) followed by maintenance guselkumab, or each agent alone as induction monotherapy and maintenance.

The study population included 214 patients with moderate to severe UC with a modified Mayo Disease Activity Index scores of 6 or greater and endoscopy scores of 2 or 3 who had not received either anti-TNF or anti IL-23 agents.

At 12 weeks of follow-up, 36.6% of patients who started on combination therapy had clinical remissions, compared with 22.2% of patients on golimumab monotherapy and 22.1% of those on guselkumab alone, a clinically significant difference, Dr. Targownik said.

The combination also resulted in better endoscopic improvement over baseline (49.3% vs. 25% and 29.6%, respectively), although the study was not powered for this outcome.

At 38 weeks, 22.2% of patients who started on golimumab alone were in clinical remission, compared with 31% of those assigned to guselkumab monotherapy and 43.7% of those who started on the combination.

Endoscopic normalization at 38 weeks was seen in 6.9%, 15.5%, and 25.4% of patients, respectively.

“Even in the patients who went back on guselkumab monotherapy that were induced with dual therapy, there were statistically higher rates of clinical remission and endoscopic normalization at the end of the study,” Dr. Targownik said, although she noted that it’s unknown whether the benefit of the combination would be sustained over longer follow-up.

In the open-label EXPLORER Crohn’s disease trial, among 55 patients with high risk Crohn’s disease, within 24 months of diagnosis investigators looked at the triple combination therapy of the anti-integrin agent vedolizumab (Entyvio, Takeda), the anti-TNF agent adalimumab (Humira, Abbvie) and methotrexate. An interim analysis at week 26 of the 34-week trial showed clinical remissions in 54.5% of patients and endoscopic remissions in 34.5%, “which I would argue for an open-label study are not terribly high results,” she said.
 

Real-world experience

Dr. Targownik pointed to a systematic review and meta-analysis of the safety and effectiveness of combining biologic agents and small molecules in patients with IBD as evidence for how combinations work in the real world.

The analysis included data from 1 clinical trial and 12 observational studies on a total of 266 patients treated with one of seven different combinations. It showed estimates of clinical efficacy ranging from about 40% to 80%, albeit with wide and overlapping confidence intervals, making it difficult to come to any conclusions about the relatively superiority of one combination over another, Dr. Targownik said.

The authors of the meta-analysis did note, however, that the incidence of serious adverse events was relatively low, ranging from 9.6% for the combination of vedolizumab and anti-TNF, to just 1% for the JAK inhibitor tofacitinib (Xeljanz, Pfizer) plus vedolizumab.
 

Registry data may help

The use of registry data will shed more light on the potential benefits and drawbacks of dual-targeted therapy.

“If we can identify...the patient phenotypes that we want to evaluate dual therapy in, and try to catalog their experiences in a regimented way with defined outcomes and periods of follow-up, we may be able to get more meaningful information,” Dr. Targownik said.

Dr. Targownik disclosed fees, grant support, and/or scientific advisory board participation with multiple companies.

This article was updated 1/25/23.

AURORA, COLO. – Only sparse evidence supports the use of dual-targeted therapy for patients with severe, refractory inflammatory bowel disease (IBD) -- and additional evidence will be hard to come by, according to a leading IBD researcher.

Dual-targeted therapy consists of either sequential or concomitant treatment with drugs from different classes of agents with distinct, specific mechanisms of action such as the use of a drug targeted against tumor necrosis factor (anti-TNFs) with an interleukin-12/23 inhibitor.

There have been only a handful of randomized clinical trials exploring such combinations, however. In addition, there are barriers to new trials, including the costs and risks of randomized trials, the need for cooperation rather than competition between pharmaceutical companies, and identifying patients who might optimally benefit from dual-targeted therapy, Laura Targownik, MD, said in a presentation at the annual Crohn’s & Colitis Congress®, a partnership of the Crohn’s & Colitis Foundation and the American Gastroenterological Association.

“In Canada we have absolutely no chance of getting coverage for this, and I imagine in hearing about the fights you have with insurers here in the [United] States, that you’re anticipating similar problems. So what do we do with this information? I think if we’re going to get answers on this question, it’s probably going to come from real-world evidence, from all of our experiences,” said Dr. Targownik of the Zane Cohen Centre for Digestive Diseases at Mount Sinai Hospital in Toronto.

Who might benefit?

Dual-targeted therapy has the potential to benefit patients with severe disease who may need intensive therapy upfront to prevent complications such as fistulas, strictures, or chronic abdominal pain. It may also benefit those who may require only short-term acute disease control; patients with meaningful yet incomplete responses to single-agent therapy who might have better outcomes with the addition of a second agent; and, patients with a unique phenotype that might be responsive to dual-targeted agents, Dr. Targownik said.

Another reason to consider dual-targeted therapy in IBD comes from applying data from recent clinical trials of upadacitinib (Rinvoq, Abbvie) for ulcerative colitis (UC) and risankizumab-rzaa (Skyrizi, Abbvie) for Crohn’s disease to hypothetical cohorts.

For example, of 1,000 persons with moderate to severe UC treated with upadacitinib, 736 would have a clinical response at the end of the induction, and at the end of the maintenance phase 191 would have endoscopic remissions, and 382 would remain in clinical remission.

Similarly, of 1,000 persons with moderate to severe Crohn’s disease treated with risankizumab, 434 would have a clinical response at the end of induction, and at the end of the maintenance phase, 172 would have endoscopic remissions, and 234 would remain in clinical remission.

“So, the vast majority of our patients are not achieving the targets that we want to hit,” she said.
 

Evidence from research clinical trials

Data from one of the few trials that have explored dual targeted therapy in IBD were presented at United European Gastroenterology Week in 2022.

The randomized double-blind phase 2a VEGA study looked at induction therapy with either a combination of the IL-23 inhibitor guselkumab (Tremfya, Janssen) and the anti-TNF monoclonal antibody golimumab (Simponi Aria, Janssen) followed by maintenance guselkumab, or each agent alone as induction monotherapy and maintenance.

The study population included 214 patients with moderate to severe UC with a modified Mayo Disease Activity Index scores of 6 or greater and endoscopy scores of 2 or 3 who had not received either anti-TNF or anti IL-23 agents.

At 12 weeks of follow-up, 36.6% of patients who started on combination therapy had clinical remissions, compared with 22.2% of patients on golimumab monotherapy and 22.1% of those on guselkumab alone, a clinically significant difference, Dr. Targownik said.

The combination also resulted in better endoscopic improvement over baseline (49.3% vs. 25% and 29.6%, respectively), although the study was not powered for this outcome.

At 38 weeks, 22.2% of patients who started on golimumab alone were in clinical remission, compared with 31% of those assigned to guselkumab monotherapy and 43.7% of those who started on the combination.

Endoscopic normalization at 38 weeks was seen in 6.9%, 15.5%, and 25.4% of patients, respectively.

“Even in the patients who went back on guselkumab monotherapy that were induced with dual therapy, there were statistically higher rates of clinical remission and endoscopic normalization at the end of the study,” Dr. Targownik said, although she noted that it’s unknown whether the benefit of the combination would be sustained over longer follow-up.

In the open-label EXPLORER Crohn’s disease trial, among 55 patients with high risk Crohn’s disease, within 24 months of diagnosis investigators looked at the triple combination therapy of the anti-integrin agent vedolizumab (Entyvio, Takeda), the anti-TNF agent adalimumab (Humira, Abbvie) and methotrexate. An interim analysis at week 26 of the 34-week trial showed clinical remissions in 54.5% of patients and endoscopic remissions in 34.5%, “which I would argue for an open-label study are not terribly high results,” she said.
 

Real-world experience

Dr. Targownik pointed to a systematic review and meta-analysis of the safety and effectiveness of combining biologic agents and small molecules in patients with IBD as evidence for how combinations work in the real world.

The analysis included data from 1 clinical trial and 12 observational studies on a total of 266 patients treated with one of seven different combinations. It showed estimates of clinical efficacy ranging from about 40% to 80%, albeit with wide and overlapping confidence intervals, making it difficult to come to any conclusions about the relatively superiority of one combination over another, Dr. Targownik said.

The authors of the meta-analysis did note, however, that the incidence of serious adverse events was relatively low, ranging from 9.6% for the combination of vedolizumab and anti-TNF, to just 1% for the JAK inhibitor tofacitinib (Xeljanz, Pfizer) plus vedolizumab.
 

Registry data may help

The use of registry data will shed more light on the potential benefits and drawbacks of dual-targeted therapy.

“If we can identify...the patient phenotypes that we want to evaluate dual therapy in, and try to catalog their experiences in a regimented way with defined outcomes and periods of follow-up, we may be able to get more meaningful information,” Dr. Targownik said.

Dr. Targownik disclosed fees, grant support, and/or scientific advisory board participation with multiple companies.

This article was updated 1/25/23.

Any of four variants of genes associated with immunity can significantly increase a carrier’s risk for developing progressive multifocal leukoencephalopathy (PML) after exposure to immunosuppressing drugs, a team of European and U.S. investigators reported.

The four-gene signature could be used to screen patients who are currently taking or are candidates for drugs know to increase risk for PML, a rare but frequently lethal demyelinating disorder of the central nervous system, according to Eli Hatchwell, MD, PhD, from Population BIO UK in Oxfordshire, England, and colleagues.

“Due to the seriousness of a PML diagnosis – particularly because it often leads to life-threatening outcomes and the lack of treatment options once it develops – it would seem unethical not to test individuals considering immunosuppressive therapies with PML risk for our top four variants, and advising those with a positive result to consider an alternative therapy or treatment strategy,” they wrote in a study published in Frontiers in Neurology.
 

Benign virus, bad disease

PML is caused by reactivation of the otherwise benign JC virus (JCV), also known as human polyomavirus 2. (The “J” and “C” in the virus’ common name stand for John Cunningham, a man with Hodgkin lymphoma from whose brain the virus was first isolated, in 1971.)

The estimated prevalence of JCV infection ranges from 40% to 70% of the population worldwide, although PML itself is rare, with an incidence of approximately 1 in 200,000.

PML is a complication of treatment with targeted monoclonal antibodies, such as natalizumab (Tysabri), rituximab (Rituxan), alemtuzumab (Campath; Lemtrada), and other agents with immunosuppressive properties, such as dimethyl fumarate and mycophenolate mofetil.

In addition, PML can occur among patients with diseases that disrupt or inhibit natural immunity, such as HIV/AIDS, hematologic cancers, and autoimmune diseases.
 

Predisposing variants suspected

Dr. Hatchwell and colleagues hypothesized that some patients may have rare genetic variants in immune-system genes that predispose them to increased risk for PML. The researchers had previously shown an association between PML and 19 genetic risk variants among 184 patients with PML.

In the current study, they looked at variants in an additional 152 patients with PML who served as a validation sample. Of the 19 risk variants they had previously identified, the investigators narrowed the field down to 4 variants in both population controls and in a matched control set consisting of patients with multiple sclerosis (MS) who were positive for JCV and who were on therapy with a PML-linked drug for at least 2 years.

The four variants they identified, all linked to immune viral defense, were C8B, 1-57409459-C-A, rs139498867; LY9 (a checkpoint regulator also known as SLAMF3), 1-160769595-AG-A, rs763811636; FCN2, 9-137779251-G-A, rs76267164; and STXBP2, 19-7712287-G-C, rs35490401.

In all, 10.9% of patients with PML carried at least one of the variants.

The investigators reported that carriers of any one of the variants has a nearly ninefold risk for developing PML after exposure to a PML-linked drug compared with non-carriers with similar drug exposures (odds ratio, 8.7; P < .001).

“Measures of clinical validity and utility compare favorably to other genetic risk tests, such as BRCA1 and BRCA2 screening for breast cancer risk and HLA-B_15:02 pharmacogenetic screening for pharmacovigilance of carbamazepine to prevent Stevens-Johnson syndrome and toxic epidermal necrolysis,” the authors noted.
 

Screening? Maybe

In a press release, Lawrence Steinman, MD, from Stanford (Calif.) University, who was not involved in the study, stated that “preventative screening for these variants should become part of the standard of care. I wish we had more powerful tools like this for other therapies.”

But another neurologist who was not involved in the study commented that the finding, while “exciting” as a confirmation study, is not as yet practice changing.

“It does give us very good confidence that these four genes are indeed risk factors that increase the risk of this brain infection by quite a bit, so that makes it very exciting,” said Robert Fox, MD, from the Neurological Institute at the Cleveland Clinic.

“Indeed, we are trying to risk-stratify patients to try to reduce the risk of PML in the patients treated with our MS drugs. So for natalizumab we risk stratify by testing them for JC virus serology. Half of people don’t have it and we say ‘OK, you’re good to go.’ With other drugs like Tecfidera – dimethyl fumarate – we follow their lymphocyte counts, so when their lymphocyte counts drop too low we say ‘OK, you need to come off the drug because of the risk of PML,’ ” he said in an interview.

The four-gene signature, however, only identifies about 11% of patients with PML, which is not a sufficiently large enough effect to be clinically useful. For example, the risk for PML in patients treated with natalizumab is about 1%, and if the test can only detect enhanced risk in about 11% of those patients, the risk would drop from 1% to 0.9%, which “doesn’t really the move needle much,” he pointed out.

Dr. Fox also noted that neurologists now have a large formulary of drugs to offer their patients, including agents (such as interferon-beta and corticosteroids that are not associated with increased risk for PML).

The study was funded by Emerald Lake Safety and Population Bio. Dr. Hatchwell and several coauthors are employees of the respective companies, and several are inventors of genetic screening methods for PML. Dr. Steiman has disclosed consulting for TG Therapeutics. Dr. Fox reported consulting for manufacturers of MS therapies.

Any of four variants of genes associated with immunity can significantly increase a carrier’s risk for developing progressive multifocal leukoencephalopathy (PML) after exposure to immunosuppressing drugs, a team of European and U.S. investigators reported.

The four-gene signature could be used to screen patients who are currently taking or are candidates for drugs know to increase risk for PML, a rare but frequently lethal demyelinating disorder of the central nervous system, according to Eli Hatchwell, MD, PhD, from Population BIO UK in Oxfordshire, England, and colleagues.

“Due to the seriousness of a PML diagnosis – particularly because it often leads to life-threatening outcomes and the lack of treatment options once it develops – it would seem unethical not to test individuals considering immunosuppressive therapies with PML risk for our top four variants, and advising those with a positive result to consider an alternative therapy or treatment strategy,” they wrote in a study published in Frontiers in Neurology.
 

Benign virus, bad disease

PML is caused by reactivation of the otherwise benign JC virus (JCV), also known as human polyomavirus 2. (The “J” and “C” in the virus’ common name stand for John Cunningham, a man with Hodgkin lymphoma from whose brain the virus was first isolated, in 1971.)

The estimated prevalence of JCV infection ranges from 40% to 70% of the population worldwide, although PML itself is rare, with an incidence of approximately 1 in 200,000.

PML is a complication of treatment with targeted monoclonal antibodies, such as natalizumab (Tysabri), rituximab (Rituxan), alemtuzumab (Campath; Lemtrada), and other agents with immunosuppressive properties, such as dimethyl fumarate and mycophenolate mofetil.

In addition, PML can occur among patients with diseases that disrupt or inhibit natural immunity, such as HIV/AIDS, hematologic cancers, and autoimmune diseases.
 

Predisposing variants suspected

Dr. Hatchwell and colleagues hypothesized that some patients may have rare genetic variants in immune-system genes that predispose them to increased risk for PML. The researchers had previously shown an association between PML and 19 genetic risk variants among 184 patients with PML.

In the current study, they looked at variants in an additional 152 patients with PML who served as a validation sample. Of the 19 risk variants they had previously identified, the investigators narrowed the field down to 4 variants in both population controls and in a matched control set consisting of patients with multiple sclerosis (MS) who were positive for JCV and who were on therapy with a PML-linked drug for at least 2 years.

The four variants they identified, all linked to immune viral defense, were C8B, 1-57409459-C-A, rs139498867; LY9 (a checkpoint regulator also known as SLAMF3), 1-160769595-AG-A, rs763811636; FCN2, 9-137779251-G-A, rs76267164; and STXBP2, 19-7712287-G-C, rs35490401.

In all, 10.9% of patients with PML carried at least one of the variants.

The investigators reported that carriers of any one of the variants has a nearly ninefold risk for developing PML after exposure to a PML-linked drug compared with non-carriers with similar drug exposures (odds ratio, 8.7; P < .001).

“Measures of clinical validity and utility compare favorably to other genetic risk tests, such as BRCA1 and BRCA2 screening for breast cancer risk and HLA-B_15:02 pharmacogenetic screening for pharmacovigilance of carbamazepine to prevent Stevens-Johnson syndrome and toxic epidermal necrolysis,” the authors noted.
 

Screening? Maybe

In a press release, Lawrence Steinman, MD, from Stanford (Calif.) University, who was not involved in the study, stated that “preventative screening for these variants should become part of the standard of care. I wish we had more powerful tools like this for other therapies.”

But another neurologist who was not involved in the study commented that the finding, while “exciting” as a confirmation study, is not as yet practice changing.

“It does give us very good confidence that these four genes are indeed risk factors that increase the risk of this brain infection by quite a bit, so that makes it very exciting,” said Robert Fox, MD, from the Neurological Institute at the Cleveland Clinic.

“Indeed, we are trying to risk-stratify patients to try to reduce the risk of PML in the patients treated with our MS drugs. So for natalizumab we risk stratify by testing them for JC virus serology. Half of people don’t have it and we say ‘OK, you’re good to go.’ With other drugs like Tecfidera – dimethyl fumarate – we follow their lymphocyte counts, so when their lymphocyte counts drop too low we say ‘OK, you need to come off the drug because of the risk of PML,’ ” he said in an interview.

The four-gene signature, however, only identifies about 11% of patients with PML, which is not a sufficiently large enough effect to be clinically useful. For example, the risk for PML in patients treated with natalizumab is about 1%, and if the test can only detect enhanced risk in about 11% of those patients, the risk would drop from 1% to 0.9%, which “doesn’t really the move needle much,” he pointed out.

Dr. Fox also noted that neurologists now have a large formulary of drugs to offer their patients, including agents (such as interferon-beta and corticosteroids that are not associated with increased risk for PML).

The study was funded by Emerald Lake Safety and Population Bio. Dr. Hatchwell and several coauthors are employees of the respective companies, and several are inventors of genetic screening methods for PML. Dr. Steiman has disclosed consulting for TG Therapeutics. Dr. Fox reported consulting for manufacturers of MS therapies.

Any of four variants of genes associated with immunity can significantly increase a carrier’s risk for developing progressive multifocal leukoencephalopathy (PML) after exposure to immunosuppressing drugs, a team of European and U.S. investigators reported.

The four-gene signature could be used to screen patients who are currently taking or are candidates for drugs know to increase risk for PML, a rare but frequently lethal demyelinating disorder of the central nervous system, according to Eli Hatchwell, MD, PhD, from Population BIO UK in Oxfordshire, England, and colleagues.

“Due to the seriousness of a PML diagnosis – particularly because it often leads to life-threatening outcomes and the lack of treatment options once it develops – it would seem unethical not to test individuals considering immunosuppressive therapies with PML risk for our top four variants, and advising those with a positive result to consider an alternative therapy or treatment strategy,” they wrote in a study published in Frontiers in Neurology.
 

Benign virus, bad disease

PML is caused by reactivation of the otherwise benign JC virus (JCV), also known as human polyomavirus 2. (The “J” and “C” in the virus’ common name stand for John Cunningham, a man with Hodgkin lymphoma from whose brain the virus was first isolated, in 1971.)

The estimated prevalence of JCV infection ranges from 40% to 70% of the population worldwide, although PML itself is rare, with an incidence of approximately 1 in 200,000.

PML is a complication of treatment with targeted monoclonal antibodies, such as natalizumab (Tysabri), rituximab (Rituxan), alemtuzumab (Campath; Lemtrada), and other agents with immunosuppressive properties, such as dimethyl fumarate and mycophenolate mofetil.

In addition, PML can occur among patients with diseases that disrupt or inhibit natural immunity, such as HIV/AIDS, hematologic cancers, and autoimmune diseases.
 

Predisposing variants suspected

Dr. Hatchwell and colleagues hypothesized that some patients may have rare genetic variants in immune-system genes that predispose them to increased risk for PML. The researchers had previously shown an association between PML and 19 genetic risk variants among 184 patients with PML.

In the current study, they looked at variants in an additional 152 patients with PML who served as a validation sample. Of the 19 risk variants they had previously identified, the investigators narrowed the field down to 4 variants in both population controls and in a matched control set consisting of patients with multiple sclerosis (MS) who were positive for JCV and who were on therapy with a PML-linked drug for at least 2 years.

The four variants they identified, all linked to immune viral defense, were C8B, 1-57409459-C-A, rs139498867; LY9 (a checkpoint regulator also known as SLAMF3), 1-160769595-AG-A, rs763811636; FCN2, 9-137779251-G-A, rs76267164; and STXBP2, 19-7712287-G-C, rs35490401.

In all, 10.9% of patients with PML carried at least one of the variants.

The investigators reported that carriers of any one of the variants has a nearly ninefold risk for developing PML after exposure to a PML-linked drug compared with non-carriers with similar drug exposures (odds ratio, 8.7; P < .001).

“Measures of clinical validity and utility compare favorably to other genetic risk tests, such as BRCA1 and BRCA2 screening for breast cancer risk and HLA-B_15:02 pharmacogenetic screening for pharmacovigilance of carbamazepine to prevent Stevens-Johnson syndrome and toxic epidermal necrolysis,” the authors noted.
 

Screening? Maybe

In a press release, Lawrence Steinman, MD, from Stanford (Calif.) University, who was not involved in the study, stated that “preventative screening for these variants should become part of the standard of care. I wish we had more powerful tools like this for other therapies.”

But another neurologist who was not involved in the study commented that the finding, while “exciting” as a confirmation study, is not as yet practice changing.

“It does give us very good confidence that these four genes are indeed risk factors that increase the risk of this brain infection by quite a bit, so that makes it very exciting,” said Robert Fox, MD, from the Neurological Institute at the Cleveland Clinic.

“Indeed, we are trying to risk-stratify patients to try to reduce the risk of PML in the patients treated with our MS drugs. So for natalizumab we risk stratify by testing them for JC virus serology. Half of people don’t have it and we say ‘OK, you’re good to go.’ With other drugs like Tecfidera – dimethyl fumarate – we follow their lymphocyte counts, so when their lymphocyte counts drop too low we say ‘OK, you need to come off the drug because of the risk of PML,’ ” he said in an interview.

The four-gene signature, however, only identifies about 11% of patients with PML, which is not a sufficiently large enough effect to be clinically useful. For example, the risk for PML in patients treated with natalizumab is about 1%, and if the test can only detect enhanced risk in about 11% of those patients, the risk would drop from 1% to 0.9%, which “doesn’t really the move needle much,” he pointed out.

Dr. Fox also noted that neurologists now have a large formulary of drugs to offer their patients, including agents (such as interferon-beta and corticosteroids that are not associated with increased risk for PML).

The study was funded by Emerald Lake Safety and Population Bio. Dr. Hatchwell and several coauthors are employees of the respective companies, and several are inventors of genetic screening methods for PML. Dr. Steiman has disclosed consulting for TG Therapeutics. Dr. Fox reported consulting for manufacturers of MS therapies.

SAN ANTONIO – For patients with hormone receptor-positive/HER2-negative (HR+/HER2–) breast cancers resistant to aromatase inhibitors, the combination of the investigational AKT inhibitor capivasertib with the selective estrogen receptor degrader fulvestrant (Faslodex) was associated with significant improvement in progression-free survival compared with fulvestrant alone in the CAPItelllo-291 study recently presented at the San Antonio Breast Cancer Symposium.

The benefit of adding capivasertib to fulvestrant was also seen in patients with previous exposure to cyclin-dependent kinase 4/6 (CDK4/6) inhibitors and in patients with liver metastases, reported Nicholas Turner, MD, PhD, of the Institute of Cancer Research and Royal Marsden NHS Foundation Trust in London.

“Capivasertib plus fulvestrant has the potential to be a future treatment option for patients with hormone receptor–positive advanced breast cancer who have progressed on an endocrine-based regimen,” he said.
 

AKT alterations

Many HR+/HER2– advanced breast cancers have activation of the AKT pathway through alteration in PIK3CA, AKT1, and PTEN, but this activation can also occur in the absence of genetic alterations. AKT signaling is also a mechanism of resistance to endocrine therapy, Dr. Turner said.

Capivasertib, a select inhibitor of the AKT isoforms 1, 2, and 3, was combined with fulvestrant in the phase 2 FAKTION trial. The combination was associated with significant improvements in both progression-free survival (PFS) and overall survival (OS) compared with fulvestrant plus placebo in CDK4/6-naive postmenopausal women with aromatase inhibitor–resistant HR+/HER2– advanced breast cancer. The clinical benefit in this trial was more pronounced among patients with tumors bearing AKT pathway alterations, he said.

In the phase 3 CAPItello study, Dr. Turner and colleagues enrolled men and both pre- and postmenopausal women with HR+/HER2– advanced breast cancer who experienced recurrence either during therapy with adjuvant aromatase inhibitor or within 12 months of the end of therapy, or who had disease progression while on prior aromatase inhibitor therapy for advanced breast cancer.

The patients could have no more than two prior lines of endocrine therapy and no more than one prior line of chemotherapy for advanced breast cancer, and no prior selective estrogen receptor degrader (SERD), mTOR inhibitor, PI3K inhibitor, or AKT inhibitor. Patients with hemoglobin A1c below 8% and with diabetes not requiring insulin were eligible for the study. After stratification for liver metastases, prior CDK4/6 inhibitor therapy, and geographic region, 708 patients were randomized to either capivasertib 400 mg twice daily 4 days on and 3 days off plus fulvestrant 500 mg on days 1 and 15 of cycle 1 and then every 4 weeks, or to fulvestrant in the same dose and schedule plus placebo.
 

Results

The dual primary endpoint was investigator assessed PFS in both the overall population and in those with AKT pathway alterations. The median PFS in the overall population was 7.2 months with the combination, compared with 3.6 months for fulvestrant alone, translating into an adjusted hazard ratio for progression of 0.60 (P < .001).

In the pathway-altered population, the median PFS was 7.3 months with capivasertib/fulvestrant vs. 3.1 months with fulvestrant placebo, which translated into an adjusted hazard ratio for progression on the combination of 0.50 (P < .001).

An exploratory analysis of PFS among patients either without pathway alterations or unknown AKT status showed median PFS of 7.2 months and 3.7 months, respectively, with a hazard ratio of 0.70.

An analysis of benefit by subgroups in the overall population showed that the balance tipped in favor of the combination in nearly all categories, including among patients with or without liver metastases and with or without prior CDK4/6 inhibitor use.

Among patients with measurable disease at baseline the combination was associated with objective response rates (ORR) of 22.9% in the overall population and 28.8% in the pathway-altered population. The respective ORR for fulvestrant/placebo were 12.2% and 9.7%.

Overall survival data were not mature at the time of data cutoff, but showed trends favoring capivasertib plus fulvestrant in both the overall and AKT-pathway-altered population.

There were four fatal adverse events in the combination arm (acute myocardial infarction, cerebral hemorrhage, pneumonia aspiration, and sepsis), and one in the fulvestrant alone arm (COVID-19).

The most common grade 3 or greater adverse events among patients treated with the combination were rash (12.1%), diarrhea (9.3 %), and hyperglycemia (2.3%). In all, 13% of patients randomized to capivasertib/fulvestrant discontinued therapy due to adverse events, compared with 2.3% of patients assigned to fulvestrant/placebo.

Dr. Turner said that the overall adverse event profile with the combination was manageable and consistent with data from previous studies.
 

‘Clinically relevant benefit’

Invited discussant Fabrice André, MD, PhD, of Gustave Roussy Cancer Center in Villejuif, France, noted that the CAPItello-291 study is one of the first randomized trials enriched with patients whose tumors are resistant to CDK4/6 inhibitors.

“What are the take-home messages? First, there is a clinically relevant benefit in the overall population and in the PIK3CA mutant/AKT/PTEN altered population,” he said.

He noted that the exploratory analysis showed a small clinical benefit with an impressive hazard ratio but broad confidence interval in patients with biomarker-negative tumors, and noted that the study lacked either circulating tumor DNA analysis or exploration of other mechanisms of AKT pathway alteration.

The study was funded by AstraZeneca. Dr. Turner has served on the advisory board for AstraZeneca, and his institution has received research funding from the company. Dr. Andre disclosed fees to his hospital on his behalf from AstraZeneca, Daiichi Sankyo, Sanofi, Pfizer, Lilly, and Roche.

SAN ANTONIO – For patients with hormone receptor-positive/HER2-negative (HR+/HER2–) breast cancers resistant to aromatase inhibitors, the combination of the investigational AKT inhibitor capivasertib with the selective estrogen receptor degrader fulvestrant (Faslodex) was associated with significant improvement in progression-free survival compared with fulvestrant alone in the CAPItelllo-291 study recently presented at the San Antonio Breast Cancer Symposium.

The benefit of adding capivasertib to fulvestrant was also seen in patients with previous exposure to cyclin-dependent kinase 4/6 (CDK4/6) inhibitors and in patients with liver metastases, reported Nicholas Turner, MD, PhD, of the Institute of Cancer Research and Royal Marsden NHS Foundation Trust in London.

“Capivasertib plus fulvestrant has the potential to be a future treatment option for patients with hormone receptor–positive advanced breast cancer who have progressed on an endocrine-based regimen,” he said.
 

AKT alterations

Many HR+/HER2– advanced breast cancers have activation of the AKT pathway through alteration in PIK3CA, AKT1, and PTEN, but this activation can also occur in the absence of genetic alterations. AKT signaling is also a mechanism of resistance to endocrine therapy, Dr. Turner said.

Capivasertib, a select inhibitor of the AKT isoforms 1, 2, and 3, was combined with fulvestrant in the phase 2 FAKTION trial. The combination was associated with significant improvements in both progression-free survival (PFS) and overall survival (OS) compared with fulvestrant plus placebo in CDK4/6-naive postmenopausal women with aromatase inhibitor–resistant HR+/HER2– advanced breast cancer. The clinical benefit in this trial was more pronounced among patients with tumors bearing AKT pathway alterations, he said.

In the phase 3 CAPItello study, Dr. Turner and colleagues enrolled men and both pre- and postmenopausal women with HR+/HER2– advanced breast cancer who experienced recurrence either during therapy with adjuvant aromatase inhibitor or within 12 months of the end of therapy, or who had disease progression while on prior aromatase inhibitor therapy for advanced breast cancer.

The patients could have no more than two prior lines of endocrine therapy and no more than one prior line of chemotherapy for advanced breast cancer, and no prior selective estrogen receptor degrader (SERD), mTOR inhibitor, PI3K inhibitor, or AKT inhibitor. Patients with hemoglobin A1c below 8% and with diabetes not requiring insulin were eligible for the study. After stratification for liver metastases, prior CDK4/6 inhibitor therapy, and geographic region, 708 patients were randomized to either capivasertib 400 mg twice daily 4 days on and 3 days off plus fulvestrant 500 mg on days 1 and 15 of cycle 1 and then every 4 weeks, or to fulvestrant in the same dose and schedule plus placebo.
 

Results

The dual primary endpoint was investigator assessed PFS in both the overall population and in those with AKT pathway alterations. The median PFS in the overall population was 7.2 months with the combination, compared with 3.6 months for fulvestrant alone, translating into an adjusted hazard ratio for progression of 0.60 (P < .001).

In the pathway-altered population, the median PFS was 7.3 months with capivasertib/fulvestrant vs. 3.1 months with fulvestrant placebo, which translated into an adjusted hazard ratio for progression on the combination of 0.50 (P < .001).

An exploratory analysis of PFS among patients either without pathway alterations or unknown AKT status showed median PFS of 7.2 months and 3.7 months, respectively, with a hazard ratio of 0.70.

An analysis of benefit by subgroups in the overall population showed that the balance tipped in favor of the combination in nearly all categories, including among patients with or without liver metastases and with or without prior CDK4/6 inhibitor use.

Among patients with measurable disease at baseline the combination was associated with objective response rates (ORR) of 22.9% in the overall population and 28.8% in the pathway-altered population. The respective ORR for fulvestrant/placebo were 12.2% and 9.7%.

Overall survival data were not mature at the time of data cutoff, but showed trends favoring capivasertib plus fulvestrant in both the overall and AKT-pathway-altered population.

There were four fatal adverse events in the combination arm (acute myocardial infarction, cerebral hemorrhage, pneumonia aspiration, and sepsis), and one in the fulvestrant alone arm (COVID-19).

The most common grade 3 or greater adverse events among patients treated with the combination were rash (12.1%), diarrhea (9.3 %), and hyperglycemia (2.3%). In all, 13% of patients randomized to capivasertib/fulvestrant discontinued therapy due to adverse events, compared with 2.3% of patients assigned to fulvestrant/placebo.

Dr. Turner said that the overall adverse event profile with the combination was manageable and consistent with data from previous studies.
 

‘Clinically relevant benefit’

Invited discussant Fabrice André, MD, PhD, of Gustave Roussy Cancer Center in Villejuif, France, noted that the CAPItello-291 study is one of the first randomized trials enriched with patients whose tumors are resistant to CDK4/6 inhibitors.

“What are the take-home messages? First, there is a clinically relevant benefit in the overall population and in the PIK3CA mutant/AKT/PTEN altered population,” he said.

He noted that the exploratory analysis showed a small clinical benefit with an impressive hazard ratio but broad confidence interval in patients with biomarker-negative tumors, and noted that the study lacked either circulating tumor DNA analysis or exploration of other mechanisms of AKT pathway alteration.

The study was funded by AstraZeneca. Dr. Turner has served on the advisory board for AstraZeneca, and his institution has received research funding from the company. Dr. Andre disclosed fees to his hospital on his behalf from AstraZeneca, Daiichi Sankyo, Sanofi, Pfizer, Lilly, and Roche.

SAN ANTONIO – For patients with hormone receptor-positive/HER2-negative (HR+/HER2–) breast cancers resistant to aromatase inhibitors, the combination of the investigational AKT inhibitor capivasertib with the selective estrogen receptor degrader fulvestrant (Faslodex) was associated with significant improvement in progression-free survival compared with fulvestrant alone in the CAPItelllo-291 study recently presented at the San Antonio Breast Cancer Symposium.

The benefit of adding capivasertib to fulvestrant was also seen in patients with previous exposure to cyclin-dependent kinase 4/6 (CDK4/6) inhibitors and in patients with liver metastases, reported Nicholas Turner, MD, PhD, of the Institute of Cancer Research and Royal Marsden NHS Foundation Trust in London.

“Capivasertib plus fulvestrant has the potential to be a future treatment option for patients with hormone receptor–positive advanced breast cancer who have progressed on an endocrine-based regimen,” he said.
 

AKT alterations

Many HR+/HER2– advanced breast cancers have activation of the AKT pathway through alteration in PIK3CA, AKT1, and PTEN, but this activation can also occur in the absence of genetic alterations. AKT signaling is also a mechanism of resistance to endocrine therapy, Dr. Turner said.

Capivasertib, a select inhibitor of the AKT isoforms 1, 2, and 3, was combined with fulvestrant in the phase 2 FAKTION trial. The combination was associated with significant improvements in both progression-free survival (PFS) and overall survival (OS) compared with fulvestrant plus placebo in CDK4/6-naive postmenopausal women with aromatase inhibitor–resistant HR+/HER2– advanced breast cancer. The clinical benefit in this trial was more pronounced among patients with tumors bearing AKT pathway alterations, he said.

In the phase 3 CAPItello study, Dr. Turner and colleagues enrolled men and both pre- and postmenopausal women with HR+/HER2– advanced breast cancer who experienced recurrence either during therapy with adjuvant aromatase inhibitor or within 12 months of the end of therapy, or who had disease progression while on prior aromatase inhibitor therapy for advanced breast cancer.

The patients could have no more than two prior lines of endocrine therapy and no more than one prior line of chemotherapy for advanced breast cancer, and no prior selective estrogen receptor degrader (SERD), mTOR inhibitor, PI3K inhibitor, or AKT inhibitor. Patients with hemoglobin A1c below 8% and with diabetes not requiring insulin were eligible for the study. After stratification for liver metastases, prior CDK4/6 inhibitor therapy, and geographic region, 708 patients were randomized to either capivasertib 400 mg twice daily 4 days on and 3 days off plus fulvestrant 500 mg on days 1 and 15 of cycle 1 and then every 4 weeks, or to fulvestrant in the same dose and schedule plus placebo.
 

Results

The dual primary endpoint was investigator assessed PFS in both the overall population and in those with AKT pathway alterations. The median PFS in the overall population was 7.2 months with the combination, compared with 3.6 months for fulvestrant alone, translating into an adjusted hazard ratio for progression of 0.60 (P < .001).

In the pathway-altered population, the median PFS was 7.3 months with capivasertib/fulvestrant vs. 3.1 months with fulvestrant placebo, which translated into an adjusted hazard ratio for progression on the combination of 0.50 (P < .001).

An exploratory analysis of PFS among patients either without pathway alterations or unknown AKT status showed median PFS of 7.2 months and 3.7 months, respectively, with a hazard ratio of 0.70.

An analysis of benefit by subgroups in the overall population showed that the balance tipped in favor of the combination in nearly all categories, including among patients with or without liver metastases and with or without prior CDK4/6 inhibitor use.

Among patients with measurable disease at baseline the combination was associated with objective response rates (ORR) of 22.9% in the overall population and 28.8% in the pathway-altered population. The respective ORR for fulvestrant/placebo were 12.2% and 9.7%.

Overall survival data were not mature at the time of data cutoff, but showed trends favoring capivasertib plus fulvestrant in both the overall and AKT-pathway-altered population.

There were four fatal adverse events in the combination arm (acute myocardial infarction, cerebral hemorrhage, pneumonia aspiration, and sepsis), and one in the fulvestrant alone arm (COVID-19).

The most common grade 3 or greater adverse events among patients treated with the combination were rash (12.1%), diarrhea (9.3 %), and hyperglycemia (2.3%). In all, 13% of patients randomized to capivasertib/fulvestrant discontinued therapy due to adverse events, compared with 2.3% of patients assigned to fulvestrant/placebo.

Dr. Turner said that the overall adverse event profile with the combination was manageable and consistent with data from previous studies.
 

‘Clinically relevant benefit’

Invited discussant Fabrice André, MD, PhD, of Gustave Roussy Cancer Center in Villejuif, France, noted that the CAPItello-291 study is one of the first randomized trials enriched with patients whose tumors are resistant to CDK4/6 inhibitors.

“What are the take-home messages? First, there is a clinically relevant benefit in the overall population and in the PIK3CA mutant/AKT/PTEN altered population,” he said.

He noted that the exploratory analysis showed a small clinical benefit with an impressive hazard ratio but broad confidence interval in patients with biomarker-negative tumors, and noted that the study lacked either circulating tumor DNA analysis or exploration of other mechanisms of AKT pathway alteration.

The study was funded by AstraZeneca. Dr. Turner has served on the advisory board for AstraZeneca, and his institution has received research funding from the company. Dr. Andre disclosed fees to his hospital on his behalf from AstraZeneca, Daiichi Sankyo, Sanofi, Pfizer, Lilly, and Roche.

AT ASH 2022 NEW ORLEANS – Children with Hodgkin lymphoma can be cured with intensive chemotherapy, radiation, and other modalities, but a large majority of those who survive into adulthood then pay a high price in terms of accelerated aging and neurocognitive impairment.

The research findings emerged from a study of nearly 500 individuals in their late 30s, of whom 215 were adult survivors of pediatric Hodgkin lymphoma (HL) and 282 were community controls.

The results showed that HL survivors had a higher epigenetic age relative to their chronological age, compared with controls, translating into epigenetic age acceleration over chronological age equivalent to a mean of 7.7 years.

In addition, this accelerated epigenetic aging in HL survivors was accompanied by neurocognitive deficits, including declines in visual-motor processing, short-term memory, verbal learning and recall, and executive function.

“We found that biologic aging is associated with long-term neurocognitive impairment in Hodgkin lymphoma survivors,” commented lead author AnnaLynn M. Williams, PhD, of the Wilmot Cancer Institute at the University of Rochester (N.Y.) “Specifically, we see strong and consistent associations with memory impairment, which suggests that biologic aging is likely related to cognitive aging.”

Dr. Williams presented the findings at the annual meeting of the American Society of Hematology.

“Our hope is that this biomarker may help us identify those survivors most at risk for early-onset cognitive aging and might actually help us gauge a preclinical response to interventions, so that we can see efficacy sooner than some other endpoints,” she said in a media briefing prior to presenting the data.

“This is an area that is very near and dear to my heart,” commented ASH President Jane N. Winter, MD, from Northwestern University, Chicago.

“Pediatricians have been very much wedded to very intensive therapies and intend to incorporate radiation more frequently in their treatment strategies for children than we do in adults,” she said. In addition, “we are very much focused on the long-term consequences of mediastinal radiation causing breast cancer in adults who were treated as young adults or children for Hodgkin lymphoma, but now we’re shedding a light on the neurocognitive deficits, which I think are underappreciated.”

Such HL therapies may exert a significant long-term impact on a patient population “that we otherwise cure,” Dr. Winter commented, pointing to a study by investigators in Germany that showed high unemployment levels among adult survivors of childhood HL, compared with the general population.

Also reacting to Dr. Williams’ findings, Catherine Bollard, MD, of the Center for Cancer and Immunology Research at Children’s National Research Institute in Washington, D.C., said: “My concern actually is that even today, in pediatrics, we’re still giving combined chemotherapy and radiation to the majority of the children with the more advanced disease, and that is not what is happening for the treatment of adult Hodgkin disease.”

She noted that there are now many immune-based therapies available for Hodgkin lymphoma that could soon obviate the need for chemotherapy.
 

Long-term complications

Dr. Williams and colleagues had previously reported that, compared with their healthy siblings, long-term survivors of HL had significantly higher risk (P < .05 for all comparisons) of neurocognitive impairment, anxiety, depression, unemployment, and impaired physical/mental quality of life.

In the current study, they looked specifically at epigenetic aging, and asked all participants to complete a comprehensive neuropsychological battery of tests.

The 215 trial participants who were survivors of pediatric HL came from the St Jude Lifetime Cohort. The mean patient age was 39, and the survivors were an average of 25 years out from their initial diagnosis.

The mean age of the 282 community controls was 36 years. Both the cohort and the controls were all European ancestry.

All participants provided a blood sample. The investigators performed genome-wide methylation studies on DNA derived from peripheral blood mononuclear cells (PBMC), and used the data to calculate epigenetic age according to a biomarker called DNAm PhenoAge. Also known as “Levine’s Clock,” this epigenetic biomarker of aging for life span and health span was developed by Morgan E. Levine, PhD, and colleagues at the University of California, Los Angeles, and other centers.

Dr. Williams and her team determined epigenetic age acceleration by calculating the difference between epigenetic and chronological age, with a higher epigenetic accelerated age suggesting an older biological age relative to the patient’s actual age.

As noted above, they found that HL survivors had a significantly higher epigenetic accelerated age, compared with controls, equivalent to a mean difference of 7.7 years (P < .001).

More than 80% of the survivors had some degree of accelerated aging, compared with only 23% of controls.

HL survivors with higher degrees (second and third tertiles) of accelerated aging had significantly worse visual-motor processing speed compared with survivors in the first (lowest) tertile, with survivors in the second tertile performing on average 0.42 standard deviations worse (P = .005) and those in the third tertile performing 0.55 SD worse (P < .001).

In addition, relative to first tertile survivors, those in the second and third tertiles performed worse on short-term memory, with a decrease of –0.42 SD (P = .011) and 0.59 SD (P < .001), respectively.

HL survivors in the third tertile performed worse than those in the other tertiles on measures of verbal learning (P =.007) and long-term verbal recall (P = .005), and those in the second or third tertiles had an average decline of 0.4 SD, compared with those in first tertile on verbal fluency, a measure of executive function.

The declines in neurocognitive measures among survivors were relatively small but clinically significant, Dr. Williams said, and were likely to prove troublesome for patients.

Dr. Williams added that she and her colleagues are currently compiling data on a comparison of neurocognitive scores between cohort members and control, for future publication, “but I can say that, in the majority of measures that are reported on, survivors do worse.”

The investigators are planning expansion of DNA methylation profiling in the St. Jude Lifetime Cohort and will follow survivors prospectively to look for changes in epigenetic acceleration and how those changes might predict who is most at risk for neurocognitive decline.

The study was supported by grants from the National Cancer Institute. Dr. Williams, Dr. Winter, and Dr. Bollard all reported no relevant financial relationships.

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

AT ASH 2022 NEW ORLEANS – Children with Hodgkin lymphoma can be cured with intensive chemotherapy, radiation, and other modalities, but a large majority of those who survive into adulthood then pay a high price in terms of accelerated aging and neurocognitive impairment.

The research findings emerged from a study of nearly 500 individuals in their late 30s, of whom 215 were adult survivors of pediatric Hodgkin lymphoma (HL) and 282 were community controls.

The results showed that HL survivors had a higher epigenetic age relative to their chronological age, compared with controls, translating into epigenetic age acceleration over chronological age equivalent to a mean of 7.7 years.

In addition, this accelerated epigenetic aging in HL survivors was accompanied by neurocognitive deficits, including declines in visual-motor processing, short-term memory, verbal learning and recall, and executive function.

“We found that biologic aging is associated with long-term neurocognitive impairment in Hodgkin lymphoma survivors,” commented lead author AnnaLynn M. Williams, PhD, of the Wilmot Cancer Institute at the University of Rochester (N.Y.) “Specifically, we see strong and consistent associations with memory impairment, which suggests that biologic aging is likely related to cognitive aging.”

Dr. Williams presented the findings at the annual meeting of the American Society of Hematology.

“Our hope is that this biomarker may help us identify those survivors most at risk for early-onset cognitive aging and might actually help us gauge a preclinical response to interventions, so that we can see efficacy sooner than some other endpoints,” she said in a media briefing prior to presenting the data.

“This is an area that is very near and dear to my heart,” commented ASH President Jane N. Winter, MD, from Northwestern University, Chicago.

“Pediatricians have been very much wedded to very intensive therapies and intend to incorporate radiation more frequently in their treatment strategies for children than we do in adults,” she said. In addition, “we are very much focused on the long-term consequences of mediastinal radiation causing breast cancer in adults who were treated as young adults or children for Hodgkin lymphoma, but now we’re shedding a light on the neurocognitive deficits, which I think are underappreciated.”

Such HL therapies may exert a significant long-term impact on a patient population “that we otherwise cure,” Dr. Winter commented, pointing to a study by investigators in Germany that showed high unemployment levels among adult survivors of childhood HL, compared with the general population.

Also reacting to Dr. Williams’ findings, Catherine Bollard, MD, of the Center for Cancer and Immunology Research at Children’s National Research Institute in Washington, D.C., said: “My concern actually is that even today, in pediatrics, we’re still giving combined chemotherapy and radiation to the majority of the children with the more advanced disease, and that is not what is happening for the treatment of adult Hodgkin disease.”

She noted that there are now many immune-based therapies available for Hodgkin lymphoma that could soon obviate the need for chemotherapy.
 

Long-term complications

Dr. Williams and colleagues had previously reported that, compared with their healthy siblings, long-term survivors of HL had significantly higher risk (P < .05 for all comparisons) of neurocognitive impairment, anxiety, depression, unemployment, and impaired physical/mental quality of life.

In the current study, they looked specifically at epigenetic aging, and asked all participants to complete a comprehensive neuropsychological battery of tests.

The 215 trial participants who were survivors of pediatric HL came from the St Jude Lifetime Cohort. The mean patient age was 39, and the survivors were an average of 25 years out from their initial diagnosis.

The mean age of the 282 community controls was 36 years. Both the cohort and the controls were all European ancestry.

All participants provided a blood sample. The investigators performed genome-wide methylation studies on DNA derived from peripheral blood mononuclear cells (PBMC), and used the data to calculate epigenetic age according to a biomarker called DNAm PhenoAge. Also known as “Levine’s Clock,” this epigenetic biomarker of aging for life span and health span was developed by Morgan E. Levine, PhD, and colleagues at the University of California, Los Angeles, and other centers.

Dr. Williams and her team determined epigenetic age acceleration by calculating the difference between epigenetic and chronological age, with a higher epigenetic accelerated age suggesting an older biological age relative to the patient’s actual age.

As noted above, they found that HL survivors had a significantly higher epigenetic accelerated age, compared with controls, equivalent to a mean difference of 7.7 years (P < .001).

More than 80% of the survivors had some degree of accelerated aging, compared with only 23% of controls.

HL survivors with higher degrees (second and third tertiles) of accelerated aging had significantly worse visual-motor processing speed compared with survivors in the first (lowest) tertile, with survivors in the second tertile performing on average 0.42 standard deviations worse (P = .005) and those in the third tertile performing 0.55 SD worse (P < .001).

In addition, relative to first tertile survivors, those in the second and third tertiles performed worse on short-term memory, with a decrease of –0.42 SD (P = .011) and 0.59 SD (P < .001), respectively.

HL survivors in the third tertile performed worse than those in the other tertiles on measures of verbal learning (P =.007) and long-term verbal recall (P = .005), and those in the second or third tertiles had an average decline of 0.4 SD, compared with those in first tertile on verbal fluency, a measure of executive function.

The declines in neurocognitive measures among survivors were relatively small but clinically significant, Dr. Williams said, and were likely to prove troublesome for patients.

Dr. Williams added that she and her colleagues are currently compiling data on a comparison of neurocognitive scores between cohort members and control, for future publication, “but I can say that, in the majority of measures that are reported on, survivors do worse.”

The investigators are planning expansion of DNA methylation profiling in the St. Jude Lifetime Cohort and will follow survivors prospectively to look for changes in epigenetic acceleration and how those changes might predict who is most at risk for neurocognitive decline.

The study was supported by grants from the National Cancer Institute. Dr. Williams, Dr. Winter, and Dr. Bollard all reported no relevant financial relationships.

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

AT ASH 2022 NEW ORLEANS – Children with Hodgkin lymphoma can be cured with intensive chemotherapy, radiation, and other modalities, but a large majority of those who survive into adulthood then pay a high price in terms of accelerated aging and neurocognitive impairment.

The research findings emerged from a study of nearly 500 individuals in their late 30s, of whom 215 were adult survivors of pediatric Hodgkin lymphoma (HL) and 282 were community controls.

The results showed that HL survivors had a higher epigenetic age relative to their chronological age, compared with controls, translating into epigenetic age acceleration over chronological age equivalent to a mean of 7.7 years.

In addition, this accelerated epigenetic aging in HL survivors was accompanied by neurocognitive deficits, including declines in visual-motor processing, short-term memory, verbal learning and recall, and executive function.

“We found that biologic aging is associated with long-term neurocognitive impairment in Hodgkin lymphoma survivors,” commented lead author AnnaLynn M. Williams, PhD, of the Wilmot Cancer Institute at the University of Rochester (N.Y.) “Specifically, we see strong and consistent associations with memory impairment, which suggests that biologic aging is likely related to cognitive aging.”

Dr. Williams presented the findings at the annual meeting of the American Society of Hematology.

“Our hope is that this biomarker may help us identify those survivors most at risk for early-onset cognitive aging and might actually help us gauge a preclinical response to interventions, so that we can see efficacy sooner than some other endpoints,” she said in a media briefing prior to presenting the data.

“This is an area that is very near and dear to my heart,” commented ASH President Jane N. Winter, MD, from Northwestern University, Chicago.

“Pediatricians have been very much wedded to very intensive therapies and intend to incorporate radiation more frequently in their treatment strategies for children than we do in adults,” she said. In addition, “we are very much focused on the long-term consequences of mediastinal radiation causing breast cancer in adults who were treated as young adults or children for Hodgkin lymphoma, but now we’re shedding a light on the neurocognitive deficits, which I think are underappreciated.”

Such HL therapies may exert a significant long-term impact on a patient population “that we otherwise cure,” Dr. Winter commented, pointing to a study by investigators in Germany that showed high unemployment levels among adult survivors of childhood HL, compared with the general population.

Also reacting to Dr. Williams’ findings, Catherine Bollard, MD, of the Center for Cancer and Immunology Research at Children’s National Research Institute in Washington, D.C., said: “My concern actually is that even today, in pediatrics, we’re still giving combined chemotherapy and radiation to the majority of the children with the more advanced disease, and that is not what is happening for the treatment of adult Hodgkin disease.”

She noted that there are now many immune-based therapies available for Hodgkin lymphoma that could soon obviate the need for chemotherapy.
 

Long-term complications

Dr. Williams and colleagues had previously reported that, compared with their healthy siblings, long-term survivors of HL had significantly higher risk (P < .05 for all comparisons) of neurocognitive impairment, anxiety, depression, unemployment, and impaired physical/mental quality of life.

In the current study, they looked specifically at epigenetic aging, and asked all participants to complete a comprehensive neuropsychological battery of tests.

The 215 trial participants who were survivors of pediatric HL came from the St Jude Lifetime Cohort. The mean patient age was 39, and the survivors were an average of 25 years out from their initial diagnosis.

The mean age of the 282 community controls was 36 years. Both the cohort and the controls were all European ancestry.

All participants provided a blood sample. The investigators performed genome-wide methylation studies on DNA derived from peripheral blood mononuclear cells (PBMC), and used the data to calculate epigenetic age according to a biomarker called DNAm PhenoAge. Also known as “Levine’s Clock,” this epigenetic biomarker of aging for life span and health span was developed by Morgan E. Levine, PhD, and colleagues at the University of California, Los Angeles, and other centers.

Dr. Williams and her team determined epigenetic age acceleration by calculating the difference between epigenetic and chronological age, with a higher epigenetic accelerated age suggesting an older biological age relative to the patient’s actual age.

As noted above, they found that HL survivors had a significantly higher epigenetic accelerated age, compared with controls, equivalent to a mean difference of 7.7 years (P < .001).

More than 80% of the survivors had some degree of accelerated aging, compared with only 23% of controls.

HL survivors with higher degrees (second and third tertiles) of accelerated aging had significantly worse visual-motor processing speed compared with survivors in the first (lowest) tertile, with survivors in the second tertile performing on average 0.42 standard deviations worse (P = .005) and those in the third tertile performing 0.55 SD worse (P < .001).

In addition, relative to first tertile survivors, those in the second and third tertiles performed worse on short-term memory, with a decrease of –0.42 SD (P = .011) and 0.59 SD (P < .001), respectively.

HL survivors in the third tertile performed worse than those in the other tertiles on measures of verbal learning (P =.007) and long-term verbal recall (P = .005), and those in the second or third tertiles had an average decline of 0.4 SD, compared with those in first tertile on verbal fluency, a measure of executive function.

The declines in neurocognitive measures among survivors were relatively small but clinically significant, Dr. Williams said, and were likely to prove troublesome for patients.

Dr. Williams added that she and her colleagues are currently compiling data on a comparison of neurocognitive scores between cohort members and control, for future publication, “but I can say that, in the majority of measures that are reported on, survivors do worse.”

The investigators are planning expansion of DNA methylation profiling in the St. Jude Lifetime Cohort and will follow survivors prospectively to look for changes in epigenetic acceleration and how those changes might predict who is most at risk for neurocognitive decline.

The study was supported by grants from the National Cancer Institute. Dr. Williams, Dr. Winter, and Dr. Bollard all reported no relevant financial relationships.

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

NEW ORLEANS – Save lives; save money. What’s not to love? That’s the claim made for a proposed nationwide data bank on alloantibodies, which develop in response to foreign red blood cells in individuals who undergo repeated blood transfusions. They can occur after pregnancy or transplants, as well as in patients with sickle cell disease.

A central repository of data on alloantibodies would save lives by preventing serious immune reactions among patients with sickle cell disease and other maladies, and would save costs associated with hospitalization for serious and potentially fatal infusion reactions, say the creators of a mathematical model demonstrating the clear value of such a databank.

“The findings from our model are pretty definitive,” said George Goshua, MD, MSc, of Yale University, New Haven, Conn. “Despite very conservative assumptions, our results still show a huge financial benefit to having a system in place to serve as a preventive net that catches patients before they have to go through a delayed hemolytic transfusion reaction (DHTR).”

Dr. Goshua presented the study at the American Society of Hematology annual meeting. The proposed registry would significantly reduce the risk that transfusion-dependent patients, and others who require occasional transfusions, would develop complications requiring hospitalization, he said.

A similar registry has been up and running in the Netherlands for 15 years, he said at a press briefing.

Briefing moderator Catherine Bollard, MD, of the Center for Cancer and Immunology at Children’s National Research Institute in Washington, asked Dr. Goshua why such an exchange hasn’t been started in the United States already.

“I will say first that our European colleagues are far ahead in terms of preventative care,” he replied.

“On top of that, there’s a unique environment in the United States – and this dates back about 15 years now – where we are almost allergic to putting costs on benefits, that is, attaching a cost value to a benefit that a population can gain,” Dr. Goshua said. “So in this context, there hasn’t been an analysis that shows that this [exchange] actually makes sense, but I think it’s one of those analyses kind of showing people that the sky is blue but proving it quantitatively.”

Dr. Bollard said that the potential beneficial impact of such an exchange “is huge,” but it would “require upfront expenditure to actually realize these massive gains you will get down the road for these patients.”
 

Would be cost-effective

Although hospitals and transfusion centers check donated blood against an individual patient’s alloantibody profile, that information is usually kept in localized records and is not typically shared across health systems nationwide.

It’s different in the Netherlands, where the Transfusion Register of Irregular Antibodies and Cross-match Problems (TRIX) was launched in 2007. Under this system, transfusion laboratories register the presence of irregular red blood cell alloantibodies for their patients and can consult the database for information that is relevant for pretransfusion testing.

To see whether such a system, if implemented in the United States, would satisfy even the most parsimonious administrator or insurer, Dr. Goshua and colleagues created a computer simulation.

They estimated age- and gender-adjusted quality-adjusted life years (QALYs) for patients living with sickle cell disease, who typically require frequent transfusions and are thus especially at risk for developing alloantibodies and immune reactions from repeat exposures to the blood of others.

The model included age- and gender-adjusted costs based on 10 years of claims data, with the assumption that equal numbers of male and females would be in the sample.

The model estimated that by reducing DHTR incidence and DHTR-specific mortality in 20% to 44% of alloimmunized patients (a very conservative estimate, according to Dr. Goshua), the existence of a U.S. exchange would result in a gain of between 7,140 and 15,710 QALYs.

Assuming a willingness to pay up to $100,000 per QALY, a commonly used threshold in economic analyses in the United States, the exchange (vs. no exchange) would be preferred in 100% of 10,000 different iterations of a cost-effectiveness acceptability curve, Dr. Goshua said.

Even if the lifetime operational costs of such an exchange exceeded $600 million, it would still be cost-effective, and the net monetary benefit to the U.S. economy would be $0.7 billion, the authors found.

And although the model was limited to patients with sickle cell anemia, many other alloimmunized patients would be likely to benefit from such an exchange, including women with a prior pregnancy, and patients with autoimmunity, myelodysplastic syndrome, or beta-thalassemia, Dr. Goshua said.

The study was supported by the American Society of Hematology, the Yale School of Medicine, and Yale Center. Dr. Goshua and Dr. Bollard reported no relevant financial relationships.

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

NEW ORLEANS – Save lives; save money. What’s not to love? That’s the claim made for a proposed nationwide data bank on alloantibodies, which develop in response to foreign red blood cells in individuals who undergo repeated blood transfusions. They can occur after pregnancy or transplants, as well as in patients with sickle cell disease.

A central repository of data on alloantibodies would save lives by preventing serious immune reactions among patients with sickle cell disease and other maladies, and would save costs associated with hospitalization for serious and potentially fatal infusion reactions, say the creators of a mathematical model demonstrating the clear value of such a databank.

“The findings from our model are pretty definitive,” said George Goshua, MD, MSc, of Yale University, New Haven, Conn. “Despite very conservative assumptions, our results still show a huge financial benefit to having a system in place to serve as a preventive net that catches patients before they have to go through a delayed hemolytic transfusion reaction (DHTR).”

Dr. Goshua presented the study at the American Society of Hematology annual meeting. The proposed registry would significantly reduce the risk that transfusion-dependent patients, and others who require occasional transfusions, would develop complications requiring hospitalization, he said.

A similar registry has been up and running in the Netherlands for 15 years, he said at a press briefing.

Briefing moderator Catherine Bollard, MD, of the Center for Cancer and Immunology at Children’s National Research Institute in Washington, asked Dr. Goshua why such an exchange hasn’t been started in the United States already.

“I will say first that our European colleagues are far ahead in terms of preventative care,” he replied.

“On top of that, there’s a unique environment in the United States – and this dates back about 15 years now – where we are almost allergic to putting costs on benefits, that is, attaching a cost value to a benefit that a population can gain,” Dr. Goshua said. “So in this context, there hasn’t been an analysis that shows that this [exchange] actually makes sense, but I think it’s one of those analyses kind of showing people that the sky is blue but proving it quantitatively.”

Dr. Bollard said that the potential beneficial impact of such an exchange “is huge,” but it would “require upfront expenditure to actually realize these massive gains you will get down the road for these patients.”
 

Would be cost-effective

Although hospitals and transfusion centers check donated blood against an individual patient’s alloantibody profile, that information is usually kept in localized records and is not typically shared across health systems nationwide.

It’s different in the Netherlands, where the Transfusion Register of Irregular Antibodies and Cross-match Problems (TRIX) was launched in 2007. Under this system, transfusion laboratories register the presence of irregular red blood cell alloantibodies for their patients and can consult the database for information that is relevant for pretransfusion testing.

To see whether such a system, if implemented in the United States, would satisfy even the most parsimonious administrator or insurer, Dr. Goshua and colleagues created a computer simulation.

They estimated age- and gender-adjusted quality-adjusted life years (QALYs) for patients living with sickle cell disease, who typically require frequent transfusions and are thus especially at risk for developing alloantibodies and immune reactions from repeat exposures to the blood of others.

The model included age- and gender-adjusted costs based on 10 years of claims data, with the assumption that equal numbers of male and females would be in the sample.

The model estimated that by reducing DHTR incidence and DHTR-specific mortality in 20% to 44% of alloimmunized patients (a very conservative estimate, according to Dr. Goshua), the existence of a U.S. exchange would result in a gain of between 7,140 and 15,710 QALYs.

Assuming a willingness to pay up to $100,000 per QALY, a commonly used threshold in economic analyses in the United States, the exchange (vs. no exchange) would be preferred in 100% of 10,000 different iterations of a cost-effectiveness acceptability curve, Dr. Goshua said.

Even if the lifetime operational costs of such an exchange exceeded $600 million, it would still be cost-effective, and the net monetary benefit to the U.S. economy would be $0.7 billion, the authors found.

And although the model was limited to patients with sickle cell anemia, many other alloimmunized patients would be likely to benefit from such an exchange, including women with a prior pregnancy, and patients with autoimmunity, myelodysplastic syndrome, or beta-thalassemia, Dr. Goshua said.

The study was supported by the American Society of Hematology, the Yale School of Medicine, and Yale Center. Dr. Goshua and Dr. Bollard reported no relevant financial relationships.

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

NEW ORLEANS – Save lives; save money. What’s not to love? That’s the claim made for a proposed nationwide data bank on alloantibodies, which develop in response to foreign red blood cells in individuals who undergo repeated blood transfusions. They can occur after pregnancy or transplants, as well as in patients with sickle cell disease.

A central repository of data on alloantibodies would save lives by preventing serious immune reactions among patients with sickle cell disease and other maladies, and would save costs associated with hospitalization for serious and potentially fatal infusion reactions, say the creators of a mathematical model demonstrating the clear value of such a databank.

“The findings from our model are pretty definitive,” said George Goshua, MD, MSc, of Yale University, New Haven, Conn. “Despite very conservative assumptions, our results still show a huge financial benefit to having a system in place to serve as a preventive net that catches patients before they have to go through a delayed hemolytic transfusion reaction (DHTR).”

Dr. Goshua presented the study at the American Society of Hematology annual meeting. The proposed registry would significantly reduce the risk that transfusion-dependent patients, and others who require occasional transfusions, would develop complications requiring hospitalization, he said.

A similar registry has been up and running in the Netherlands for 15 years, he said at a press briefing.

Briefing moderator Catherine Bollard, MD, of the Center for Cancer and Immunology at Children’s National Research Institute in Washington, asked Dr. Goshua why such an exchange hasn’t been started in the United States already.

“I will say first that our European colleagues are far ahead in terms of preventative care,” he replied.

“On top of that, there’s a unique environment in the United States – and this dates back about 15 years now – where we are almost allergic to putting costs on benefits, that is, attaching a cost value to a benefit that a population can gain,” Dr. Goshua said. “So in this context, there hasn’t been an analysis that shows that this [exchange] actually makes sense, but I think it’s one of those analyses kind of showing people that the sky is blue but proving it quantitatively.”

Dr. Bollard said that the potential beneficial impact of such an exchange “is huge,” but it would “require upfront expenditure to actually realize these massive gains you will get down the road for these patients.”
 

Would be cost-effective

Although hospitals and transfusion centers check donated blood against an individual patient’s alloantibody profile, that information is usually kept in localized records and is not typically shared across health systems nationwide.

It’s different in the Netherlands, where the Transfusion Register of Irregular Antibodies and Cross-match Problems (TRIX) was launched in 2007. Under this system, transfusion laboratories register the presence of irregular red blood cell alloantibodies for their patients and can consult the database for information that is relevant for pretransfusion testing.

To see whether such a system, if implemented in the United States, would satisfy even the most parsimonious administrator or insurer, Dr. Goshua and colleagues created a computer simulation.

They estimated age- and gender-adjusted quality-adjusted life years (QALYs) for patients living with sickle cell disease, who typically require frequent transfusions and are thus especially at risk for developing alloantibodies and immune reactions from repeat exposures to the blood of others.

The model included age- and gender-adjusted costs based on 10 years of claims data, with the assumption that equal numbers of male and females would be in the sample.

The model estimated that by reducing DHTR incidence and DHTR-specific mortality in 20% to 44% of alloimmunized patients (a very conservative estimate, according to Dr. Goshua), the existence of a U.S. exchange would result in a gain of between 7,140 and 15,710 QALYs.

Assuming a willingness to pay up to $100,000 per QALY, a commonly used threshold in economic analyses in the United States, the exchange (vs. no exchange) would be preferred in 100% of 10,000 different iterations of a cost-effectiveness acceptability curve, Dr. Goshua said.

Even if the lifetime operational costs of such an exchange exceeded $600 million, it would still be cost-effective, and the net monetary benefit to the U.S. economy would be $0.7 billion, the authors found.

And although the model was limited to patients with sickle cell anemia, many other alloimmunized patients would be likely to benefit from such an exchange, including women with a prior pregnancy, and patients with autoimmunity, myelodysplastic syndrome, or beta-thalassemia, Dr. Goshua said.

The study was supported by the American Society of Hematology, the Yale School of Medicine, and Yale Center. Dr. Goshua and Dr. Bollard reported no relevant financial relationships.

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

San Antonio – A 16-gene molecular signature may identify patients with breast cancer who are at risk for locoregional recurrence, as well as those who can be safely spared from breast radiation following breast-conserving surgery, an international team of investigators said.

In combined data from three independent randomized trials grouped into a meta-analysis, patients who had low scores on the messenger RNA–based signature, dubbed “Profile for the Omission of Local Adjuvant Radiotherapy” (POLAR), derived only minimal benefit from radiotherapy following breast-conserving surgery. In contrast, patients with high POLAR scores had significant clinical benefit from adjuvant radiotherapy, reported Per Karlsson, MD, chief physician with the Sahlgrenska Comprehensive Cancer Center and the University of Gothenburg (Sweden). Dr. Karlsson reported his findings at the San Antonio Breast Cancer Symposium.

“To our knowledge, POLAR is the first genomic classifier that is not only prognostic but also predictive of radiotherapy benefit, showing a significant interaction between radiotherapy and the classifier,” he said. “These important retrospective findings warrant further investigation, including in contemporary clinical studies.”

Investigators with the Swedish SweBCG91RT trial (Swedish Breast Cancer Group 91 Radiotherapy), the Scottish Conservation (radiotherapy) Trial (SCT), and a trial from the Princess Margaret Cancer Hospital in Toronto, collaborated on improving and validating the POLAR signature, which was originally developed for use in the SweBCG91RT trial in patients with lymph node–negative breast cancer who underwent breast-conserving surgery. The patients were randomized to whole breast irradiation or no radiotherapy.

To develop the signature, researchers collected tumor blocks from 1,004 patients, and extracted RNA from the samples. Gene expression data were obtained from primary tumors of 764 patients. The subset of 597 patients with estrogen receptor–positive, HER2-negative tumors (ER+/HER2–) who did not receive systemic therapy were divided into a training set with 243 patients, and a validation cohort with 354 patients.

They identified a total of 16 genes involved in cellular proliferation and immune response, and then validated the signature using retrospective data from three clinical trials of patients randomized to radiotherapy or no radiation following breast-conserving surgery.

Of 623 patients with node-negative ER+/HER2– tumors who were included in the meta-analysis, 429 patients were found to have high POLAR scores. These patients benefited from adjuvant radiation therapy after breast-conserving surgery with a 10-year cumulative incidence of low risk of locoregional recurrence ranging from 15% to 26% for those who were not treated with radiation therapy, compared with only 4%-11% percent for those who received radiation therapy (hazard ratio, 0.37; P < .001).

In contrast, among the 194 patients whose tumors had POLAR low scores, there was no apparent benefit from radiation therapy with a nonsignificant HR of 0.92 (P = .832).

In Cox proportional hazard models for time to locoregional recurrences for 309 patients who did not undergo radiation, POLAR scores were significantly prognostic for recurrence, with a HR of 1.53 (P < .001) in univariable analysis, and 1.43 (P = .005) in multivariable analysis controlling for age, tumor size, tumor grade and molecular groupings.
 

New modalities may make findings less relevant

Alphonse Taghian, MD, PhD, a breast radiation oncologist with Mass General Cancer Center, Boston, who was not involved in the study, said there have been major changes in radiation therapy since the studies used for development of the POLAR signature were performed. For example, the Scottish Conservation Trial ran from 1985 to 1991, while the SweBCGR91RT trial and Princess Margaret trial were both conducted in the 1990s.

He noted that patients in those studies would likely experience more morbidities from radiation than patients treated with more recent modalities such as intensity modulated radiation therapy, and that patients treated 30 years ago would have to put up with lengthy fractionation schedules that required daily trips to the hospital over as long as 6 weeks, whereas a majority of patients can now be treated with hypofractionated radiation that can be performed in a much shorter time and with minimal comorbidities.

He acknowledged, however, that “it will help to have a signature proved, confirmed, or validated retrospectively with a different set of data.”

Dr. Taghian also said that it would be helpful to have more data about the age of patients, because omitting radiation is more common for elderly patients than it is for younger patients.

“It will maybe be beneficial to look at this signature in patients that we think might not need radiation,” he said.

The study was supported by the Swedish Cancer Society, Swedish Research Council, King Gustav 5 Jubilee Clinic Foundation, the ALF Agreement of the Swedish government, PFS Genomics, and Exact Sciences. Dr. Karlsson has pending patents with and receives royalties from Exact Sciences and PreludeDX. Dr. Taghian reported having no relevant disclosures.

San Antonio – A 16-gene molecular signature may identify patients with breast cancer who are at risk for locoregional recurrence, as well as those who can be safely spared from breast radiation following breast-conserving surgery, an international team of investigators said.

In combined data from three independent randomized trials grouped into a meta-analysis, patients who had low scores on the messenger RNA–based signature, dubbed “Profile for the Omission of Local Adjuvant Radiotherapy” (POLAR), derived only minimal benefit from radiotherapy following breast-conserving surgery. In contrast, patients with high POLAR scores had significant clinical benefit from adjuvant radiotherapy, reported Per Karlsson, MD, chief physician with the Sahlgrenska Comprehensive Cancer Center and the University of Gothenburg (Sweden). Dr. Karlsson reported his findings at the San Antonio Breast Cancer Symposium.

“To our knowledge, POLAR is the first genomic classifier that is not only prognostic but also predictive of radiotherapy benefit, showing a significant interaction between radiotherapy and the classifier,” he said. “These important retrospective findings warrant further investigation, including in contemporary clinical studies.”

Investigators with the Swedish SweBCG91RT trial (Swedish Breast Cancer Group 91 Radiotherapy), the Scottish Conservation (radiotherapy) Trial (SCT), and a trial from the Princess Margaret Cancer Hospital in Toronto, collaborated on improving and validating the POLAR signature, which was originally developed for use in the SweBCG91RT trial in patients with lymph node–negative breast cancer who underwent breast-conserving surgery. The patients were randomized to whole breast irradiation or no radiotherapy.

To develop the signature, researchers collected tumor blocks from 1,004 patients, and extracted RNA from the samples. Gene expression data were obtained from primary tumors of 764 patients. The subset of 597 patients with estrogen receptor–positive, HER2-negative tumors (ER+/HER2–) who did not receive systemic therapy were divided into a training set with 243 patients, and a validation cohort with 354 patients.

They identified a total of 16 genes involved in cellular proliferation and immune response, and then validated the signature using retrospective data from three clinical trials of patients randomized to radiotherapy or no radiation following breast-conserving surgery.

Of 623 patients with node-negative ER+/HER2– tumors who were included in the meta-analysis, 429 patients were found to have high POLAR scores. These patients benefited from adjuvant radiation therapy after breast-conserving surgery with a 10-year cumulative incidence of low risk of locoregional recurrence ranging from 15% to 26% for those who were not treated with radiation therapy, compared with only 4%-11% percent for those who received radiation therapy (hazard ratio, 0.37; P < .001).

In contrast, among the 194 patients whose tumors had POLAR low scores, there was no apparent benefit from radiation therapy with a nonsignificant HR of 0.92 (P = .832).

In Cox proportional hazard models for time to locoregional recurrences for 309 patients who did not undergo radiation, POLAR scores were significantly prognostic for recurrence, with a HR of 1.53 (P < .001) in univariable analysis, and 1.43 (P = .005) in multivariable analysis controlling for age, tumor size, tumor grade and molecular groupings.
 

New modalities may make findings less relevant

Alphonse Taghian, MD, PhD, a breast radiation oncologist with Mass General Cancer Center, Boston, who was not involved in the study, said there have been major changes in radiation therapy since the studies used for development of the POLAR signature were performed. For example, the Scottish Conservation Trial ran from 1985 to 1991, while the SweBCGR91RT trial and Princess Margaret trial were both conducted in the 1990s.

He noted that patients in those studies would likely experience more morbidities from radiation than patients treated with more recent modalities such as intensity modulated radiation therapy, and that patients treated 30 years ago would have to put up with lengthy fractionation schedules that required daily trips to the hospital over as long as 6 weeks, whereas a majority of patients can now be treated with hypofractionated radiation that can be performed in a much shorter time and with minimal comorbidities.

He acknowledged, however, that “it will help to have a signature proved, confirmed, or validated retrospectively with a different set of data.”

Dr. Taghian also said that it would be helpful to have more data about the age of patients, because omitting radiation is more common for elderly patients than it is for younger patients.

“It will maybe be beneficial to look at this signature in patients that we think might not need radiation,” he said.

The study was supported by the Swedish Cancer Society, Swedish Research Council, King Gustav 5 Jubilee Clinic Foundation, the ALF Agreement of the Swedish government, PFS Genomics, and Exact Sciences. Dr. Karlsson has pending patents with and receives royalties from Exact Sciences and PreludeDX. Dr. Taghian reported having no relevant disclosures.

San Antonio – A 16-gene molecular signature may identify patients with breast cancer who are at risk for locoregional recurrence, as well as those who can be safely spared from breast radiation following breast-conserving surgery, an international team of investigators said.

In combined data from three independent randomized trials grouped into a meta-analysis, patients who had low scores on the messenger RNA–based signature, dubbed “Profile for the Omission of Local Adjuvant Radiotherapy” (POLAR), derived only minimal benefit from radiotherapy following breast-conserving surgery. In contrast, patients with high POLAR scores had significant clinical benefit from adjuvant radiotherapy, reported Per Karlsson, MD, chief physician with the Sahlgrenska Comprehensive Cancer Center and the University of Gothenburg (Sweden). Dr. Karlsson reported his findings at the San Antonio Breast Cancer Symposium.

“To our knowledge, POLAR is the first genomic classifier that is not only prognostic but also predictive of radiotherapy benefit, showing a significant interaction between radiotherapy and the classifier,” he said. “These important retrospective findings warrant further investigation, including in contemporary clinical studies.”

Investigators with the Swedish SweBCG91RT trial (Swedish Breast Cancer Group 91 Radiotherapy), the Scottish Conservation (radiotherapy) Trial (SCT), and a trial from the Princess Margaret Cancer Hospital in Toronto, collaborated on improving and validating the POLAR signature, which was originally developed for use in the SweBCG91RT trial in patients with lymph node–negative breast cancer who underwent breast-conserving surgery. The patients were randomized to whole breast irradiation or no radiotherapy.

To develop the signature, researchers collected tumor blocks from 1,004 patients, and extracted RNA from the samples. Gene expression data were obtained from primary tumors of 764 patients. The subset of 597 patients with estrogen receptor–positive, HER2-negative tumors (ER+/HER2–) who did not receive systemic therapy were divided into a training set with 243 patients, and a validation cohort with 354 patients.

They identified a total of 16 genes involved in cellular proliferation and immune response, and then validated the signature using retrospective data from three clinical trials of patients randomized to radiotherapy or no radiation following breast-conserving surgery.

Of 623 patients with node-negative ER+/HER2– tumors who were included in the meta-analysis, 429 patients were found to have high POLAR scores. These patients benefited from adjuvant radiation therapy after breast-conserving surgery with a 10-year cumulative incidence of low risk of locoregional recurrence ranging from 15% to 26% for those who were not treated with radiation therapy, compared with only 4%-11% percent for those who received radiation therapy (hazard ratio, 0.37; P < .001).

In contrast, among the 194 patients whose tumors had POLAR low scores, there was no apparent benefit from radiation therapy with a nonsignificant HR of 0.92 (P = .832).

In Cox proportional hazard models for time to locoregional recurrences for 309 patients who did not undergo radiation, POLAR scores were significantly prognostic for recurrence, with a HR of 1.53 (P < .001) in univariable analysis, and 1.43 (P = .005) in multivariable analysis controlling for age, tumor size, tumor grade and molecular groupings.
 

New modalities may make findings less relevant

Alphonse Taghian, MD, PhD, a breast radiation oncologist with Mass General Cancer Center, Boston, who was not involved in the study, said there have been major changes in radiation therapy since the studies used for development of the POLAR signature were performed. For example, the Scottish Conservation Trial ran from 1985 to 1991, while the SweBCGR91RT trial and Princess Margaret trial were both conducted in the 1990s.

He noted that patients in those studies would likely experience more morbidities from radiation than patients treated with more recent modalities such as intensity modulated radiation therapy, and that patients treated 30 years ago would have to put up with lengthy fractionation schedules that required daily trips to the hospital over as long as 6 weeks, whereas a majority of patients can now be treated with hypofractionated radiation that can be performed in a much shorter time and with minimal comorbidities.

He acknowledged, however, that “it will help to have a signature proved, confirmed, or validated retrospectively with a different set of data.”

Dr. Taghian also said that it would be helpful to have more data about the age of patients, because omitting radiation is more common for elderly patients than it is for younger patients.

“It will maybe be beneficial to look at this signature in patients that we think might not need radiation,” he said.

The study was supported by the Swedish Cancer Society, Swedish Research Council, King Gustav 5 Jubilee Clinic Foundation, the ALF Agreement of the Swedish government, PFS Genomics, and Exact Sciences. Dr. Karlsson has pending patents with and receives royalties from Exact Sciences and PreludeDX. Dr. Taghian reported having no relevant disclosures.

NEW ORLEANS – A novel, off-the-shelf antibody, talquetamab, has shown high response rates among patients with heavily pretreated multiple myeloma in both phase 1 and now phase 2 studies, which have been submitted for approval.

“Talquetamab is a novel agent directed against a new antigen target in myeloma,” explained lead investigator Ajai Chari, MD, of Icahn School of Medicine at Mount Sinai in New York.

The product has demonstrated “a response rate of 73% to 74% with both weekly and every 2-week schedules in a heavily treated patient population. Even in those patients with prior T-cell redirection, we see a 63% response rate,” said Dr. Chari, who reported the data at the American Society of Hematology annual meeting.

It is encouraging to see high response rates among patients with disease that is refractory to multiple prior lines of therapy, and the results suggest that talquetamab may buy time for patients with few other options, said Stephanie Lee, MD, MPH, of the Fred Hutchinson Cancer Center in Seattle, and a former ASH president.

“It looks like there are responses even in people who are heavily pretreated and have had other agents similar to it, “ she said. “We hear about ‘penta-refractory’ [disease] and everything, and I think we’re going to start hearing about ‘octo-refractory’ and ‘deci-refractory,’ and those things. It’s really exciting [to see these responses],” she said. Dr. Lee moderated a media briefing prior to Dr. Chari’s discussion of the data.

Talquetamab is a bispecific antibody directed against a novel target with the prosaic name of “G protein–coupled receptor, family C, group 5, member D” or simply GPRC5D. The antigen is a so-called “orphan” receptor with an unidentified ligand. The receptor is expressed in malignant plasma cells, making it a particularly attractive target for the treatment of patients with multiple myeloma.

“It’s important to pick the right target for these [patients] and GPRC5D is a good candidate for that because it’s highly expressed on myeloma cells but spares normal tissues, in particular the hematopoietic stem cells for the precursors to their blood,” Dr. Chari said.

The new drug could be available next year. The manufacturer, Janssen, announced last week that it had submitted an approval application with the Food and Drug Administration for talquetamab use in the treatment of patients with relapsed or refractory multiple myeloma.

The clinical results so far “indicate the potential of this treatment for heavily pretreated patients who have exhausted currently approved therapies,” Dr. Chari said in a statement.
 

MonumenTAL study

Dr. Chari and colleagues recently reported results of the phase 1 MonumenTAL-1 study in The New England Journal of Medicine. At ASH 2022, they reported phase 2 results from the same study, including some patients carried over from phase 1, but also a subgroup of patients with prior exposure to either chimeric antigen receptor T-cell (CAR-T) therapy or other bispecific T cell-engaging antibodies.

In the phase 1 dose-escalation study published in NEJM,  the response rates among patients who had a median of six prior lines of therapy ranged from 64% to 70%. The drug was delivered in this phase at a variety of dose levels and schedules, and both intravenously and subcutaneously.
 

Three cohorts, two doses

The phase 2 study enrolled patients who had a minimum of three prior lines of therapy including a proteasome inhibitor, immunomodulating agent, and anti-CD38 antibody, and who had good-to-fair performance status.

There were three cohorts. The first cohort comprised 21 patients from phase 1 and 122 from phase 2 who received talquetamab at a dose of 0.4 mg/kg subcutaneously once weekly. These patients were allowed to have received prior therapy with an antibody-drug conjugate (ADC) targeted against B-cell maturation antigen (BCMA), but could not have received a prior T-cell redirection therapy.

The second cohort comprised 36 patients in phase 1 and 109 in phase 2 who were treated with 0.8 mg/kg subcutaneously every 2 weeks. These patients had the same prior therapy allowances and restrictions as the first cohort.

The third cohort comprised 17 patients in phase 1 plus 34 patients in phase 2 who had received either CAR T-cell receptor therapy or a different bispecific T-cell engager. These patients received either 0.4 mg/kg weekly subcutaneous talquetamab, or 0.8 mg/kg every 2 weeks.
 

Phase 2 results

The overall response rate (ORR)  among patients treated at 0.4 mg/kg weekly was 74.1%, including 23.8% stringent complete responses (sCR), 9.8% complete response (CR), 25.9% very good partial responses (VGPR) and 14.7% partial responses (PR).

The ORR among patients treated at the 0.8 mg/kg every 2 week dose was 73.1%, consisting of 20% sCR, 12.4% CR, 24,8% VGPR, and 15.9% PR.

The response rates were consistent across subgroups, including baseline International Staging System (ISS) stage III disease, baseline cytogenetic risk, number of prior therapies, degree of refractoriness to prior therapy, and prior exposure to the anti-BCMA antibody belantamab (except patients with baseline plasmacytomas).

The median durations of responses were 9.3 months and 13 months in the 0.4 and 0.8 mg/kg doses, respectively. The median duration of response was not reached among patients who had achieved a CR or better in either dosing group.
 

Safety profile

Most adverse events of grade 3 or 4 were cytopenias, including anemia, neutropenia, lymphopenia, and thrombocytopenia. These adverse events were generally limited to the first three cycles, and less than a third of all cytopenias were grade 3 or greater.

Infection occurred in 57.3% of patients treated at 0.4 mg/kg weekly and 50.3% treated at 0.8 mg/kg every 2 weeks. Of these infections, 16.8% and 11.7%, respectively, were grade 3 or 4.

Opportunistic infections were seen in 3.5% of patients treated at 0.4 mg/kg and 2.8% of those treated at 0.8 mg/kg.

Taste alterations (dysgeusia) occurred in nearly half of patients in each dosing group. Dysgeusia was managed with supportive care, including hydration, and in some cases  with dose reductions.

Immune effector cell-associated neurotoxicity syndrome (ICANS) was observed in 10% to 11% of patients, but most of these events were grade 1 or 2.
 

What’s next?

At the briefing, this news organization asked Dr. Chari whether, given the evident efficacy and relative safety of this agent, it could be moved up higher in the therapeutic lines and combined with other agents such as proteasome inhibitors (bortezomib et al.), immunomodulators (lenalidomide and others) and CD38-directed antibodies (daratumumab, etc.)

Dr. Chari replied that several studies combining talquetamab with agents in all of these classes and with other bispecific T-cell engagers are currently underway.

Dr. Chari disclosed consulting fees from Janssen, which supported the study. Dr. Lee has received clinical trial research funding from Amgen, AstraZeneca, Incyte, Kadmon, Novartis, Pfizer, Syndax, and Takeda and has served as a consultant to Incyte.

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

NEW ORLEANS – A novel, off-the-shelf antibody, talquetamab, has shown high response rates among patients with heavily pretreated multiple myeloma in both phase 1 and now phase 2 studies, which have been submitted for approval.

“Talquetamab is a novel agent directed against a new antigen target in myeloma,” explained lead investigator Ajai Chari, MD, of Icahn School of Medicine at Mount Sinai in New York.

The product has demonstrated “a response rate of 73% to 74% with both weekly and every 2-week schedules in a heavily treated patient population. Even in those patients with prior T-cell redirection, we see a 63% response rate,” said Dr. Chari, who reported the data at the American Society of Hematology annual meeting.

It is encouraging to see high response rates among patients with disease that is refractory to multiple prior lines of therapy, and the results suggest that talquetamab may buy time for patients with few other options, said Stephanie Lee, MD, MPH, of the Fred Hutchinson Cancer Center in Seattle, and a former ASH president.

“It looks like there are responses even in people who are heavily pretreated and have had other agents similar to it, “ she said. “We hear about ‘penta-refractory’ [disease] and everything, and I think we’re going to start hearing about ‘octo-refractory’ and ‘deci-refractory,’ and those things. It’s really exciting [to see these responses],” she said. Dr. Lee moderated a media briefing prior to Dr. Chari’s discussion of the data.

Talquetamab is a bispecific antibody directed against a novel target with the prosaic name of “G protein–coupled receptor, family C, group 5, member D” or simply GPRC5D. The antigen is a so-called “orphan” receptor with an unidentified ligand. The receptor is expressed in malignant plasma cells, making it a particularly attractive target for the treatment of patients with multiple myeloma.

“It’s important to pick the right target for these [patients] and GPRC5D is a good candidate for that because it’s highly expressed on myeloma cells but spares normal tissues, in particular the hematopoietic stem cells for the precursors to their blood,” Dr. Chari said.

The new drug could be available next year. The manufacturer, Janssen, announced last week that it had submitted an approval application with the Food and Drug Administration for talquetamab use in the treatment of patients with relapsed or refractory multiple myeloma.

The clinical results so far “indicate the potential of this treatment for heavily pretreated patients who have exhausted currently approved therapies,” Dr. Chari said in a statement.
 

MonumenTAL study

Dr. Chari and colleagues recently reported results of the phase 1 MonumenTAL-1 study in The New England Journal of Medicine. At ASH 2022, they reported phase 2 results from the same study, including some patients carried over from phase 1, but also a subgroup of patients with prior exposure to either chimeric antigen receptor T-cell (CAR-T) therapy or other bispecific T cell-engaging antibodies.

In the phase 1 dose-escalation study published in NEJM,  the response rates among patients who had a median of six prior lines of therapy ranged from 64% to 70%. The drug was delivered in this phase at a variety of dose levels and schedules, and both intravenously and subcutaneously.
 

Three cohorts, two doses

The phase 2 study enrolled patients who had a minimum of three prior lines of therapy including a proteasome inhibitor, immunomodulating agent, and anti-CD38 antibody, and who had good-to-fair performance status.

There were three cohorts. The first cohort comprised 21 patients from phase 1 and 122 from phase 2 who received talquetamab at a dose of 0.4 mg/kg subcutaneously once weekly. These patients were allowed to have received prior therapy with an antibody-drug conjugate (ADC) targeted against B-cell maturation antigen (BCMA), but could not have received a prior T-cell redirection therapy.

The second cohort comprised 36 patients in phase 1 and 109 in phase 2 who were treated with 0.8 mg/kg subcutaneously every 2 weeks. These patients had the same prior therapy allowances and restrictions as the first cohort.

The third cohort comprised 17 patients in phase 1 plus 34 patients in phase 2 who had received either CAR T-cell receptor therapy or a different bispecific T-cell engager. These patients received either 0.4 mg/kg weekly subcutaneous talquetamab, or 0.8 mg/kg every 2 weeks.
 

Phase 2 results

The overall response rate (ORR)  among patients treated at 0.4 mg/kg weekly was 74.1%, including 23.8% stringent complete responses (sCR), 9.8% complete response (CR), 25.9% very good partial responses (VGPR) and 14.7% partial responses (PR).

The ORR among patients treated at the 0.8 mg/kg every 2 week dose was 73.1%, consisting of 20% sCR, 12.4% CR, 24,8% VGPR, and 15.9% PR.

The response rates were consistent across subgroups, including baseline International Staging System (ISS) stage III disease, baseline cytogenetic risk, number of prior therapies, degree of refractoriness to prior therapy, and prior exposure to the anti-BCMA antibody belantamab (except patients with baseline plasmacytomas).

The median durations of responses were 9.3 months and 13 months in the 0.4 and 0.8 mg/kg doses, respectively. The median duration of response was not reached among patients who had achieved a CR or better in either dosing group.
 

Safety profile

Most adverse events of grade 3 or 4 were cytopenias, including anemia, neutropenia, lymphopenia, and thrombocytopenia. These adverse events were generally limited to the first three cycles, and less than a third of all cytopenias were grade 3 or greater.

Infection occurred in 57.3% of patients treated at 0.4 mg/kg weekly and 50.3% treated at 0.8 mg/kg every 2 weeks. Of these infections, 16.8% and 11.7%, respectively, were grade 3 or 4.

Opportunistic infections were seen in 3.5% of patients treated at 0.4 mg/kg and 2.8% of those treated at 0.8 mg/kg.

Taste alterations (dysgeusia) occurred in nearly half of patients in each dosing group. Dysgeusia was managed with supportive care, including hydration, and in some cases  with dose reductions.

Immune effector cell-associated neurotoxicity syndrome (ICANS) was observed in 10% to 11% of patients, but most of these events were grade 1 or 2.
 

What’s next?

At the briefing, this news organization asked Dr. Chari whether, given the evident efficacy and relative safety of this agent, it could be moved up higher in the therapeutic lines and combined with other agents such as proteasome inhibitors (bortezomib et al.), immunomodulators (lenalidomide and others) and CD38-directed antibodies (daratumumab, etc.)

Dr. Chari replied that several studies combining talquetamab with agents in all of these classes and with other bispecific T-cell engagers are currently underway.

Dr. Chari disclosed consulting fees from Janssen, which supported the study. Dr. Lee has received clinical trial research funding from Amgen, AstraZeneca, Incyte, Kadmon, Novartis, Pfizer, Syndax, and Takeda and has served as a consultant to Incyte.

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

NEW ORLEANS – A novel, off-the-shelf antibody, talquetamab, has shown high response rates among patients with heavily pretreated multiple myeloma in both phase 1 and now phase 2 studies, which have been submitted for approval.

“Talquetamab is a novel agent directed against a new antigen target in myeloma,” explained lead investigator Ajai Chari, MD, of Icahn School of Medicine at Mount Sinai in New York.

The product has demonstrated “a response rate of 73% to 74% with both weekly and every 2-week schedules in a heavily treated patient population. Even in those patients with prior T-cell redirection, we see a 63% response rate,” said Dr. Chari, who reported the data at the American Society of Hematology annual meeting.

It is encouraging to see high response rates among patients with disease that is refractory to multiple prior lines of therapy, and the results suggest that talquetamab may buy time for patients with few other options, said Stephanie Lee, MD, MPH, of the Fred Hutchinson Cancer Center in Seattle, and a former ASH president.

“It looks like there are responses even in people who are heavily pretreated and have had other agents similar to it, “ she said. “We hear about ‘penta-refractory’ [disease] and everything, and I think we’re going to start hearing about ‘octo-refractory’ and ‘deci-refractory,’ and those things. It’s really exciting [to see these responses],” she said. Dr. Lee moderated a media briefing prior to Dr. Chari’s discussion of the data.

Talquetamab is a bispecific antibody directed against a novel target with the prosaic name of “G protein–coupled receptor, family C, group 5, member D” or simply GPRC5D. The antigen is a so-called “orphan” receptor with an unidentified ligand. The receptor is expressed in malignant plasma cells, making it a particularly attractive target for the treatment of patients with multiple myeloma.

“It’s important to pick the right target for these [patients] and GPRC5D is a good candidate for that because it’s highly expressed on myeloma cells but spares normal tissues, in particular the hematopoietic stem cells for the precursors to their blood,” Dr. Chari said.

The new drug could be available next year. The manufacturer, Janssen, announced last week that it had submitted an approval application with the Food and Drug Administration for talquetamab use in the treatment of patients with relapsed or refractory multiple myeloma.

The clinical results so far “indicate the potential of this treatment for heavily pretreated patients who have exhausted currently approved therapies,” Dr. Chari said in a statement.
 

MonumenTAL study

Dr. Chari and colleagues recently reported results of the phase 1 MonumenTAL-1 study in The New England Journal of Medicine. At ASH 2022, they reported phase 2 results from the same study, including some patients carried over from phase 1, but also a subgroup of patients with prior exposure to either chimeric antigen receptor T-cell (CAR-T) therapy or other bispecific T cell-engaging antibodies.

In the phase 1 dose-escalation study published in NEJM,  the response rates among patients who had a median of six prior lines of therapy ranged from 64% to 70%. The drug was delivered in this phase at a variety of dose levels and schedules, and both intravenously and subcutaneously.
 

Three cohorts, two doses

The phase 2 study enrolled patients who had a minimum of three prior lines of therapy including a proteasome inhibitor, immunomodulating agent, and anti-CD38 antibody, and who had good-to-fair performance status.

There were three cohorts. The first cohort comprised 21 patients from phase 1 and 122 from phase 2 who received talquetamab at a dose of 0.4 mg/kg subcutaneously once weekly. These patients were allowed to have received prior therapy with an antibody-drug conjugate (ADC) targeted against B-cell maturation antigen (BCMA), but could not have received a prior T-cell redirection therapy.

The second cohort comprised 36 patients in phase 1 and 109 in phase 2 who were treated with 0.8 mg/kg subcutaneously every 2 weeks. These patients had the same prior therapy allowances and restrictions as the first cohort.

The third cohort comprised 17 patients in phase 1 plus 34 patients in phase 2 who had received either CAR T-cell receptor therapy or a different bispecific T-cell engager. These patients received either 0.4 mg/kg weekly subcutaneous talquetamab, or 0.8 mg/kg every 2 weeks.
 

Phase 2 results

The overall response rate (ORR)  among patients treated at 0.4 mg/kg weekly was 74.1%, including 23.8% stringent complete responses (sCR), 9.8% complete response (CR), 25.9% very good partial responses (VGPR) and 14.7% partial responses (PR).

The ORR among patients treated at the 0.8 mg/kg every 2 week dose was 73.1%, consisting of 20% sCR, 12.4% CR, 24,8% VGPR, and 15.9% PR.

The response rates were consistent across subgroups, including baseline International Staging System (ISS) stage III disease, baseline cytogenetic risk, number of prior therapies, degree of refractoriness to prior therapy, and prior exposure to the anti-BCMA antibody belantamab (except patients with baseline plasmacytomas).

The median durations of responses were 9.3 months and 13 months in the 0.4 and 0.8 mg/kg doses, respectively. The median duration of response was not reached among patients who had achieved a CR or better in either dosing group.
 

Safety profile

Most adverse events of grade 3 or 4 were cytopenias, including anemia, neutropenia, lymphopenia, and thrombocytopenia. These adverse events were generally limited to the first three cycles, and less than a third of all cytopenias were grade 3 or greater.

Infection occurred in 57.3% of patients treated at 0.4 mg/kg weekly and 50.3% treated at 0.8 mg/kg every 2 weeks. Of these infections, 16.8% and 11.7%, respectively, were grade 3 or 4.

Opportunistic infections were seen in 3.5% of patients treated at 0.4 mg/kg and 2.8% of those treated at 0.8 mg/kg.

Taste alterations (dysgeusia) occurred in nearly half of patients in each dosing group. Dysgeusia was managed with supportive care, including hydration, and in some cases  with dose reductions.

Immune effector cell-associated neurotoxicity syndrome (ICANS) was observed in 10% to 11% of patients, but most of these events were grade 1 or 2.
 

What’s next?

At the briefing, this news organization asked Dr. Chari whether, given the evident efficacy and relative safety of this agent, it could be moved up higher in the therapeutic lines and combined with other agents such as proteasome inhibitors (bortezomib et al.), immunomodulators (lenalidomide and others) and CD38-directed antibodies (daratumumab, etc.)

Dr. Chari replied that several studies combining talquetamab with agents in all of these classes and with other bispecific T-cell engagers are currently underway.

Dr. Chari disclosed consulting fees from Janssen, which supported the study. Dr. Lee has received clinical trial research funding from Amgen, AstraZeneca, Incyte, Kadmon, Novartis, Pfizer, Syndax, and Takeda and has served as a consultant to Incyte.

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

NEW ORLEANS – A gene therapy made headlines recently for becoming the most expensive pharmaceutical ever launched – the price tag was $3.5 million for a one-off treatment with etranacogene dezaparvovec (Hemgenix) for hemophilia B.

Another gene therapy, a treatment for sickle cell anemia now in late clinical development, is expected to come on the market soon. It, too, is expected to bear an exorbitant price tag.

Such potentially curative therapies put financial pressure on publicly and privately funded health insurance.

However, investigators said that the new treatment for patients with sickle cell disease (SCD) in the United States has the potential to be cost-effective. Those who analyzed the costs used a novel method that takes historical health inequities into account.

“When faced with costs of innovative, one-time-administered therapies, budgetary constraints, as we all know too well, can and have driven therapy availability or lack thereof for patients,” said George Goshua, MD, from the Yale University, New Haven, Conn., speaking here at the annual meeting of the American Society of Hematology.

“We believe that quantitative consideration of health inequities, in addition to the important quality considerations, may be an additional helpful metric in this decision-making context,” he said.

He noted that SCD predominantly affects Black Americans, “who have historically been a very marginalized population when it comes to health care.

“Our study shows that, when we compare the costs of gene therapy and existing standard-of-care treatment for SCD using a technique that accounts for historical health disparities, gene therapy could be an equitable therapeutic strategy for all patients with SCD, whether their disease is mild, moderate, or severe,” he said.

Commenting on the study for this news organization, Bosula Oluwole, MD, from the University of Washington, Seattle, who studies sickle cell disease but was not involved in this study, said the cost-analysis approach taken by Dr. Goshua and colleagues is interesting, but she added: “I think we still have a way to go in trying to fully understand the issue.

“When you look over time at the cost for a patient to get gene therapy vs. the standard of care, it might actually be beneficial to have the gene therapy,” Dr. Oluwole said.

She noted, however, that some patients start gene therapy for SCD at older ages and that it’s important to analyze whether the treatment can still be cost-effective or the best therapeutic option for such patients.
 

Adding a D to CEA

Dr. Goshua and colleagues at Yale University and the Harvard T.H. Chan School of Public Health in Boston conducted what they believe is the first study in hematology to use distributional cost-effectiveness analysis (DCEA), developed at the University of York, England.

A University of York website explains that DCEA “is a general umbrella term for economic evaluation studies that provide information about equity in the distribution of costs and effects as well as efficiency in terms of aggregate costs and effects. DCEA can provide distributional breakdowns of who gains most and who bears the largest burdens (opportunity costs) by equity-relevant social variables (e.g., socioeconomic status, ethnicity, location) and disease categories (e.g., severity of illness, rarity, disability).”

The technique can also employ equity weight to evaluate trade-offs between equity and efficiency, the website says.

As Dr. Goshua put it, equity weighting is “a way of quantifying how much we prioritize health care equity.”
 

QALYs considered

Dr. Goshua and colleagues included equity weight in an analysis of 10 years of data on annual health care costs for patients with SCD who were covered by private insurance and were treated with medications (for example, hydroxyurea), antibiotics, blood transfusion, and hematopoietic stem cell transplants. Sex and the frequency of hospitalizations for acute pain crises were factors in the Markov model they created.

The model assumes that a single course of gene therapy for SCD would cost $2.1 million. The estimate was based on the cost of U.S. Food and Drug Administration–approved gene therapies, and it was assumed that the therapy would result in permanent disease remission for all patients.

In addition, the model assumed that all eligible patients in the United States with SCD who are aged 12 years and older would be offered the gene therapy.

In their base-case analysis, gene therapy starting at age 12 would yield 25.5 discounted lifetime quality-adjusted life-years (QALYs) at a cost of $2.4 million, compared with 16.0 discounted lifetime QALYs at a cost of $1.1 million for standard care.

Under traditional cost-effectiveness calculations, the upper limit of the incremental cost-effectiveness ratio (ICER) is estimated to be $100,000 per QALY. Under this scenario, the ICER of gene therapy for SCD at $144,000 per QALY would be considered by health economists or insurers to be too steep a price to pay.

However, applying equity weighting to the formula would bring the price of gene therapy into the $1.4 million to $3 million range.

Dr. Goshua acknowledged that the study is limited by the assumption that gene therapy would be a one-time cost and that patients would not need to undergo repeat therapy or treatment for relapses.

Stephanie Lee, MD, MPH, from the Fred Hutchinson Cancer Center in Seattle, and a former ASH president, who moderated a briefing the day before Dr. Goshua presented his data, recommended that he and his colleagues use their technique to explore other health inequities, such as in the care of patients with multiple myeloma.

“There’s some evidence that Black patients are not using even the agents we have as [are] some of the other groups, so there may be some distributional inequities there as well,” she said.

The study was funded by ASH and the Yale School of Medicine. Dr. Goshua, Dr. Oluwole, and Dr. Lee have disclosed no relevant financial relationships.

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

NEW ORLEANS – A gene therapy made headlines recently for becoming the most expensive pharmaceutical ever launched – the price tag was $3.5 million for a one-off treatment with etranacogene dezaparvovec (Hemgenix) for hemophilia B.

Another gene therapy, a treatment for sickle cell anemia now in late clinical development, is expected to come on the market soon. It, too, is expected to bear an exorbitant price tag.

Such potentially curative therapies put financial pressure on publicly and privately funded health insurance.

However, investigators said that the new treatment for patients with sickle cell disease (SCD) in the United States has the potential to be cost-effective. Those who analyzed the costs used a novel method that takes historical health inequities into account.

“When faced with costs of innovative, one-time-administered therapies, budgetary constraints, as we all know too well, can and have driven therapy availability or lack thereof for patients,” said George Goshua, MD, from the Yale University, New Haven, Conn., speaking here at the annual meeting of the American Society of Hematology.

“We believe that quantitative consideration of health inequities, in addition to the important quality considerations, may be an additional helpful metric in this decision-making context,” he said.

He noted that SCD predominantly affects Black Americans, “who have historically been a very marginalized population when it comes to health care.

“Our study shows that, when we compare the costs of gene therapy and existing standard-of-care treatment for SCD using a technique that accounts for historical health disparities, gene therapy could be an equitable therapeutic strategy for all patients with SCD, whether their disease is mild, moderate, or severe,” he said.

Commenting on the study for this news organization, Bosula Oluwole, MD, from the University of Washington, Seattle, who studies sickle cell disease but was not involved in this study, said the cost-analysis approach taken by Dr. Goshua and colleagues is interesting, but she added: “I think we still have a way to go in trying to fully understand the issue.

“When you look over time at the cost for a patient to get gene therapy vs. the standard of care, it might actually be beneficial to have the gene therapy,” Dr. Oluwole said.

She noted, however, that some patients start gene therapy for SCD at older ages and that it’s important to analyze whether the treatment can still be cost-effective or the best therapeutic option for such patients.
 

Adding a D to CEA

Dr. Goshua and colleagues at Yale University and the Harvard T.H. Chan School of Public Health in Boston conducted what they believe is the first study in hematology to use distributional cost-effectiveness analysis (DCEA), developed at the University of York, England.

A University of York website explains that DCEA “is a general umbrella term for economic evaluation studies that provide information about equity in the distribution of costs and effects as well as efficiency in terms of aggregate costs and effects. DCEA can provide distributional breakdowns of who gains most and who bears the largest burdens (opportunity costs) by equity-relevant social variables (e.g., socioeconomic status, ethnicity, location) and disease categories (e.g., severity of illness, rarity, disability).”

The technique can also employ equity weight to evaluate trade-offs between equity and efficiency, the website says.

As Dr. Goshua put it, equity weighting is “a way of quantifying how much we prioritize health care equity.”
 

QALYs considered

Dr. Goshua and colleagues included equity weight in an analysis of 10 years of data on annual health care costs for patients with SCD who were covered by private insurance and were treated with medications (for example, hydroxyurea), antibiotics, blood transfusion, and hematopoietic stem cell transplants. Sex and the frequency of hospitalizations for acute pain crises were factors in the Markov model they created.

The model assumes that a single course of gene therapy for SCD would cost $2.1 million. The estimate was based on the cost of U.S. Food and Drug Administration–approved gene therapies, and it was assumed that the therapy would result in permanent disease remission for all patients.

In addition, the model assumed that all eligible patients in the United States with SCD who are aged 12 years and older would be offered the gene therapy.

In their base-case analysis, gene therapy starting at age 12 would yield 25.5 discounted lifetime quality-adjusted life-years (QALYs) at a cost of $2.4 million, compared with 16.0 discounted lifetime QALYs at a cost of $1.1 million for standard care.

Under traditional cost-effectiveness calculations, the upper limit of the incremental cost-effectiveness ratio (ICER) is estimated to be $100,000 per QALY. Under this scenario, the ICER of gene therapy for SCD at $144,000 per QALY would be considered by health economists or insurers to be too steep a price to pay.

However, applying equity weighting to the formula would bring the price of gene therapy into the $1.4 million to $3 million range.

Dr. Goshua acknowledged that the study is limited by the assumption that gene therapy would be a one-time cost and that patients would not need to undergo repeat therapy or treatment for relapses.

Stephanie Lee, MD, MPH, from the Fred Hutchinson Cancer Center in Seattle, and a former ASH president, who moderated a briefing the day before Dr. Goshua presented his data, recommended that he and his colleagues use their technique to explore other health inequities, such as in the care of patients with multiple myeloma.

“There’s some evidence that Black patients are not using even the agents we have as [are] some of the other groups, so there may be some distributional inequities there as well,” she said.

The study was funded by ASH and the Yale School of Medicine. Dr. Goshua, Dr. Oluwole, and Dr. Lee have disclosed no relevant financial relationships.

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

NEW ORLEANS – A gene therapy made headlines recently for becoming the most expensive pharmaceutical ever launched – the price tag was $3.5 million for a one-off treatment with etranacogene dezaparvovec (Hemgenix) for hemophilia B.

Another gene therapy, a treatment for sickle cell anemia now in late clinical development, is expected to come on the market soon. It, too, is expected to bear an exorbitant price tag.

Such potentially curative therapies put financial pressure on publicly and privately funded health insurance.

However, investigators said that the new treatment for patients with sickle cell disease (SCD) in the United States has the potential to be cost-effective. Those who analyzed the costs used a novel method that takes historical health inequities into account.

“When faced with costs of innovative, one-time-administered therapies, budgetary constraints, as we all know too well, can and have driven therapy availability or lack thereof for patients,” said George Goshua, MD, from the Yale University, New Haven, Conn., speaking here at the annual meeting of the American Society of Hematology.

“We believe that quantitative consideration of health inequities, in addition to the important quality considerations, may be an additional helpful metric in this decision-making context,” he said.

He noted that SCD predominantly affects Black Americans, “who have historically been a very marginalized population when it comes to health care.

“Our study shows that, when we compare the costs of gene therapy and existing standard-of-care treatment for SCD using a technique that accounts for historical health disparities, gene therapy could be an equitable therapeutic strategy for all patients with SCD, whether their disease is mild, moderate, or severe,” he said.

Commenting on the study for this news organization, Bosula Oluwole, MD, from the University of Washington, Seattle, who studies sickle cell disease but was not involved in this study, said the cost-analysis approach taken by Dr. Goshua and colleagues is interesting, but she added: “I think we still have a way to go in trying to fully understand the issue.

“When you look over time at the cost for a patient to get gene therapy vs. the standard of care, it might actually be beneficial to have the gene therapy,” Dr. Oluwole said.

She noted, however, that some patients start gene therapy for SCD at older ages and that it’s important to analyze whether the treatment can still be cost-effective or the best therapeutic option for such patients.
 

Adding a D to CEA

Dr. Goshua and colleagues at Yale University and the Harvard T.H. Chan School of Public Health in Boston conducted what they believe is the first study in hematology to use distributional cost-effectiveness analysis (DCEA), developed at the University of York, England.

A University of York website explains that DCEA “is a general umbrella term for economic evaluation studies that provide information about equity in the distribution of costs and effects as well as efficiency in terms of aggregate costs and effects. DCEA can provide distributional breakdowns of who gains most and who bears the largest burdens (opportunity costs) by equity-relevant social variables (e.g., socioeconomic status, ethnicity, location) and disease categories (e.g., severity of illness, rarity, disability).”

The technique can also employ equity weight to evaluate trade-offs between equity and efficiency, the website says.

As Dr. Goshua put it, equity weighting is “a way of quantifying how much we prioritize health care equity.”
 

QALYs considered

Dr. Goshua and colleagues included equity weight in an analysis of 10 years of data on annual health care costs for patients with SCD who were covered by private insurance and were treated with medications (for example, hydroxyurea), antibiotics, blood transfusion, and hematopoietic stem cell transplants. Sex and the frequency of hospitalizations for acute pain crises were factors in the Markov model they created.

The model assumes that a single course of gene therapy for SCD would cost $2.1 million. The estimate was based on the cost of U.S. Food and Drug Administration–approved gene therapies, and it was assumed that the therapy would result in permanent disease remission for all patients.

In addition, the model assumed that all eligible patients in the United States with SCD who are aged 12 years and older would be offered the gene therapy.

In their base-case analysis, gene therapy starting at age 12 would yield 25.5 discounted lifetime quality-adjusted life-years (QALYs) at a cost of $2.4 million, compared with 16.0 discounted lifetime QALYs at a cost of $1.1 million for standard care.

Under traditional cost-effectiveness calculations, the upper limit of the incremental cost-effectiveness ratio (ICER) is estimated to be $100,000 per QALY. Under this scenario, the ICER of gene therapy for SCD at $144,000 per QALY would be considered by health economists or insurers to be too steep a price to pay.

However, applying equity weighting to the formula would bring the price of gene therapy into the $1.4 million to $3 million range.

Dr. Goshua acknowledged that the study is limited by the assumption that gene therapy would be a one-time cost and that patients would not need to undergo repeat therapy or treatment for relapses.

Stephanie Lee, MD, MPH, from the Fred Hutchinson Cancer Center in Seattle, and a former ASH president, who moderated a briefing the day before Dr. Goshua presented his data, recommended that he and his colleagues use their technique to explore other health inequities, such as in the care of patients with multiple myeloma.

“There’s some evidence that Black patients are not using even the agents we have as [are] some of the other groups, so there may be some distributional inequities there as well,” she said.

The study was funded by ASH and the Yale School of Medicine. Dr. Goshua, Dr. Oluwole, and Dr. Lee have disclosed no relevant financial relationships.

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

WASHINGTON – “We don’t get to use the ‘eliminate’ word all that often with a disease that’s taking thousands or tens of thousands – or worldwide, hundreds of thousands – of lives every year, but we have that opportunity with hepatitis C.”

So said Francis S. Collins, MD, PhD, special projects advisor to the Executive Office of the President of the United States, and former director of the National Institutes of Health, speaking at a special session outlining ambitious goals for a national plan to eliminate hepatitis C virus (HCV) infections by the year 2050.

The session was held at the annual meeting of the American Association for the Study of Liver Diseases.
 

A public health crisis

Dr. Collins labeled HCV a public health crisis, citing statistics from the Centers for Disease Control and Prevention that show that the rate of reported acute HCV infection cases increased 400% between 2010 and 2020, with the highest rates among young adults aged 20-39 years.

In addition, an estimated 2.4 million people in the United States are living with chronic HCV infections, but as many as 40% of these people are unaware of their infection, despite broad recommendations for the screening of all adults aged 18 years and older, he said.

“Our goal is to try to do something to change this,” Dr. Collins said. He noted that for the past 8 years we have had highly effective oral agents that don’t just treat the disease but cure it – 95%-97% of the time, with only 8-12 weeks of oral therapy and relatively few side effects.

“A wonderful story, one of the most exciting stories that’s come out of biomedical research in the last couple of decades,” he said.

Yet Dr. Collins also acknowledged that the task of developing a national plan is daunting, despite that pharmaceutical triumph.

National pharmacy claims data show that the number of persons treated for HCV with direct-acting antiviral agents (DAAs) in the United States declined from a high of 164,247 in 2015 to 83,740 in 2020.

Furthermore, CDC data from 2019 and 2020 show that, of persons with a diagnosis of HCV infection, only 23% of those on Medicaid, 28% of those on Medicare, and 35% of those with private insurance were treated for their infections.

“We have a huge gap here between the ability to know you have the disease and to get treatment, and we don’t see the numbers here for the uninsured, or people in prisons, but they’re probably much worse,” he said.
 

Obstacles abound, as do ways to overcome them

Current barriers to treatment include the aforementioned lack of awareness of infection, a “clunky” two-step diagnosis requiring an antibody test followed by an RNA or core antigen test necessitating three visits often separated by several weeks, and the high cost of treatment (around $90,000 per patient).

In addition, insurers commonly require proof that patients remain sober for extended periods, insist that treatment monitoring be performed by specialists only, and often approve treatment only for those patients who have documented evidence of liver damage.

“Does that make sense to you?” Dr. Collins asked. “You’ve got a cure for a liver disease, and you have to wait and show that the liver’s been damaged before you receive it? That just doesn’t fit,” he said.

Dr. Collins also pointed out that we’re dealing with hard-to-reach populations (underserved, uninsured, justice-involved), and people who are in tough times. “Anything that you put in the way as a barrier is going to make this worse in terms of its ability to be implemented,” he said.

To demonstrate how a coordinated HCV-elimination program could work, Dr. Collins pointed to a Medicaid cohort study in Louisiana conducted from July 2019 through December 2021, in which 8,867 patients started on therapy, 7,763 (88%) completed therapy, and 5,882 (66%) returned for testing. Of those tested, 5,285 (90%) had sustained virologic responses.

Another model of a hepatitis C elimination program was provided by the Veterans Health Administration. They received funding for an effort for all veterans, and in the space of 7 years were able to reach out even to some of their difficult-to-reach populations and achieve high diagnosis and treatment rates in a way that could be a model for what we would want to do across the nation, Dr. Collins noted.
 

Doing the math

Also at the session, Jagpreet Chhatwal, PhD, director of the Massachusetts General Hospital Institute for Technology Assessment and associate professor of radiology at Harvard Medical School, Boston, described outcomes projected by a mathematical simulation model of the HCV epidemic that he and his colleagues developed.

The HEP-SIM (Hepatitis C Disease Burden Simulation) model evaluates HCV prevalence trends, the number needed to screen and treat to eliminate HCV, HCV-associated clinical outcomes, the cost of an elimination program, and the cost savings that could be realized from preventing long-term complications.

The model seeks to determine whether the upfront costs of a national HCV elimination program could be offset by savings down the road. Specifically, it assumes that within the next 5 years 1.31 million individuals would be diagnosed with HCV and projects that within that time frame 1.52 million would need to be treated to meet HCV elimination goals.

The model shows that, compared with the status quo, a concerted campaign of screening and treatment would prevent more than 10,000 HCV-related deaths by 2030, and 91,000 deaths by 2050.

A coordinated screening program is also projected to prevent 17,000 cases of hepatocellular carcinoma by 2030 and 108,000 cases by 2050, as well as avert 29,000 cases of decompensated cirrhosis by 2030 and 93,000 such cases by 2050.

The cost savings associated with an HCV elimination plan would also be substantial, Dr. Chhatwal said.

According to the model, over the next decade the cumulative costs associated with HCV would decline by $14.2 billion, compared with the status quo. Nearly 80% of those savings ($11.2 billion) would be in Medicare and Medicaid.

The total projected savings from 2024 through 2050 – in disease management, testing, treatment, and pragmatic costs – are estimated at $59.3 billion, Dr. Chhatwal said.

“This is unprecedented,” he said. “We’re not just eliminating a disease as a public health threat but also saving money, which is not a common thing. That gives us a lot of impetus to implement such a program.”
 

Getting it done

Rachael L. Fleurence, PhD, MSc, a health economist currently serving as a senior advisor in the Executive Office of the President, summarized efforts to build a national HCV elimination program with input from federal health care agencies, state health leaders, patients, advocacy groups, drug manufacturers, and insurers.

She noted that a large component and focus of the program will be working on diagnostic test development but also accelerating bringing tests into the United States that are currently unavailable here. “These include point-of-care RNA diagnostic tests, as well as core antigen laboratory tests,” she said.

The program will be designed to offer broad access to curative anti-HCV drugs through a national subscription model that would make DAAs available to Medicaid recipients, justice-involved populations, the uninsured, and American Indians and Alaskan Natives who receive care through the Indian Health Service.

“On the Medicare and commercial insurance fronts, we’re still exploring different approaches, including potentially a co-pay assistance for Medicare beneficiaries, as well as working with commercial insurers to reduce barriers to access,” she said.

The program would also involve screening strategies extending to more settings, especially for high-risk populations, expanding the number of providers allowed to screen and treat HCV infections through telehealth, ensuring incentives for providers, and increasing the number of community health workers and case workers to improve linkage to care.

The next steps for the program would include funding to support the NIH’s RADx diagnostics program to accelerate access to testing, planning for the subscription model for DAA purchase, and launching pilot programs with the CDC, the Health Resources and Services Administration, the Substance Abuse and Mental Health Services Administration, and the Indian Health Service.
 

A call to action

Dr. Collins ended this portion of the program with an exhortation to AASLD members to do their part.

“We need your help,” Dr. Collins said. “This is a bold initiative, but it’s an opportunity. It’s even a responsibility. If we can actually succeed at this kind of outreach and save lives, and at the same time save money, how can we not do that?”

Dr. Collins, Dr. Chhatwal, and Dr. Fleurence each reported having no financial conflicts.

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

WASHINGTON – “We don’t get to use the ‘eliminate’ word all that often with a disease that’s taking thousands or tens of thousands – or worldwide, hundreds of thousands – of lives every year, but we have that opportunity with hepatitis C.”

So said Francis S. Collins, MD, PhD, special projects advisor to the Executive Office of the President of the United States, and former director of the National Institutes of Health, speaking at a special session outlining ambitious goals for a national plan to eliminate hepatitis C virus (HCV) infections by the year 2050.

The session was held at the annual meeting of the American Association for the Study of Liver Diseases.
 

A public health crisis

Dr. Collins labeled HCV a public health crisis, citing statistics from the Centers for Disease Control and Prevention that show that the rate of reported acute HCV infection cases increased 400% between 2010 and 2020, with the highest rates among young adults aged 20-39 years.

In addition, an estimated 2.4 million people in the United States are living with chronic HCV infections, but as many as 40% of these people are unaware of their infection, despite broad recommendations for the screening of all adults aged 18 years and older, he said.

“Our goal is to try to do something to change this,” Dr. Collins said. He noted that for the past 8 years we have had highly effective oral agents that don’t just treat the disease but cure it – 95%-97% of the time, with only 8-12 weeks of oral therapy and relatively few side effects.

“A wonderful story, one of the most exciting stories that’s come out of biomedical research in the last couple of decades,” he said.

Yet Dr. Collins also acknowledged that the task of developing a national plan is daunting, despite that pharmaceutical triumph.

National pharmacy claims data show that the number of persons treated for HCV with direct-acting antiviral agents (DAAs) in the United States declined from a high of 164,247 in 2015 to 83,740 in 2020.

Furthermore, CDC data from 2019 and 2020 show that, of persons with a diagnosis of HCV infection, only 23% of those on Medicaid, 28% of those on Medicare, and 35% of those with private insurance were treated for their infections.

“We have a huge gap here between the ability to know you have the disease and to get treatment, and we don’t see the numbers here for the uninsured, or people in prisons, but they’re probably much worse,” he said.
 

Obstacles abound, as do ways to overcome them

Current barriers to treatment include the aforementioned lack of awareness of infection, a “clunky” two-step diagnosis requiring an antibody test followed by an RNA or core antigen test necessitating three visits often separated by several weeks, and the high cost of treatment (around $90,000 per patient).

In addition, insurers commonly require proof that patients remain sober for extended periods, insist that treatment monitoring be performed by specialists only, and often approve treatment only for those patients who have documented evidence of liver damage.

“Does that make sense to you?” Dr. Collins asked. “You’ve got a cure for a liver disease, and you have to wait and show that the liver’s been damaged before you receive it? That just doesn’t fit,” he said.

Dr. Collins also pointed out that we’re dealing with hard-to-reach populations (underserved, uninsured, justice-involved), and people who are in tough times. “Anything that you put in the way as a barrier is going to make this worse in terms of its ability to be implemented,” he said.

To demonstrate how a coordinated HCV-elimination program could work, Dr. Collins pointed to a Medicaid cohort study in Louisiana conducted from July 2019 through December 2021, in which 8,867 patients started on therapy, 7,763 (88%) completed therapy, and 5,882 (66%) returned for testing. Of those tested, 5,285 (90%) had sustained virologic responses.

Another model of a hepatitis C elimination program was provided by the Veterans Health Administration. They received funding for an effort for all veterans, and in the space of 7 years were able to reach out even to some of their difficult-to-reach populations and achieve high diagnosis and treatment rates in a way that could be a model for what we would want to do across the nation, Dr. Collins noted.
 

Doing the math

Also at the session, Jagpreet Chhatwal, PhD, director of the Massachusetts General Hospital Institute for Technology Assessment and associate professor of radiology at Harvard Medical School, Boston, described outcomes projected by a mathematical simulation model of the HCV epidemic that he and his colleagues developed.

The HEP-SIM (Hepatitis C Disease Burden Simulation) model evaluates HCV prevalence trends, the number needed to screen and treat to eliminate HCV, HCV-associated clinical outcomes, the cost of an elimination program, and the cost savings that could be realized from preventing long-term complications.

The model seeks to determine whether the upfront costs of a national HCV elimination program could be offset by savings down the road. Specifically, it assumes that within the next 5 years 1.31 million individuals would be diagnosed with HCV and projects that within that time frame 1.52 million would need to be treated to meet HCV elimination goals.

The model shows that, compared with the status quo, a concerted campaign of screening and treatment would prevent more than 10,000 HCV-related deaths by 2030, and 91,000 deaths by 2050.

A coordinated screening program is also projected to prevent 17,000 cases of hepatocellular carcinoma by 2030 and 108,000 cases by 2050, as well as avert 29,000 cases of decompensated cirrhosis by 2030 and 93,000 such cases by 2050.

The cost savings associated with an HCV elimination plan would also be substantial, Dr. Chhatwal said.

According to the model, over the next decade the cumulative costs associated with HCV would decline by $14.2 billion, compared with the status quo. Nearly 80% of those savings ($11.2 billion) would be in Medicare and Medicaid.

The total projected savings from 2024 through 2050 – in disease management, testing, treatment, and pragmatic costs – are estimated at $59.3 billion, Dr. Chhatwal said.

“This is unprecedented,” he said. “We’re not just eliminating a disease as a public health threat but also saving money, which is not a common thing. That gives us a lot of impetus to implement such a program.”
 

Getting it done

Rachael L. Fleurence, PhD, MSc, a health economist currently serving as a senior advisor in the Executive Office of the President, summarized efforts to build a national HCV elimination program with input from federal health care agencies, state health leaders, patients, advocacy groups, drug manufacturers, and insurers.

She noted that a large component and focus of the program will be working on diagnostic test development but also accelerating bringing tests into the United States that are currently unavailable here. “These include point-of-care RNA diagnostic tests, as well as core antigen laboratory tests,” she said.

The program will be designed to offer broad access to curative anti-HCV drugs through a national subscription model that would make DAAs available to Medicaid recipients, justice-involved populations, the uninsured, and American Indians and Alaskan Natives who receive care through the Indian Health Service.

“On the Medicare and commercial insurance fronts, we’re still exploring different approaches, including potentially a co-pay assistance for Medicare beneficiaries, as well as working with commercial insurers to reduce barriers to access,” she said.

The program would also involve screening strategies extending to more settings, especially for high-risk populations, expanding the number of providers allowed to screen and treat HCV infections through telehealth, ensuring incentives for providers, and increasing the number of community health workers and case workers to improve linkage to care.

The next steps for the program would include funding to support the NIH’s RADx diagnostics program to accelerate access to testing, planning for the subscription model for DAA purchase, and launching pilot programs with the CDC, the Health Resources and Services Administration, the Substance Abuse and Mental Health Services Administration, and the Indian Health Service.
 

A call to action

Dr. Collins ended this portion of the program with an exhortation to AASLD members to do their part.

“We need your help,” Dr. Collins said. “This is a bold initiative, but it’s an opportunity. It’s even a responsibility. If we can actually succeed at this kind of outreach and save lives, and at the same time save money, how can we not do that?”

Dr. Collins, Dr. Chhatwal, and Dr. Fleurence each reported having no financial conflicts.

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

WASHINGTON – “We don’t get to use the ‘eliminate’ word all that often with a disease that’s taking thousands or tens of thousands – or worldwide, hundreds of thousands – of lives every year, but we have that opportunity with hepatitis C.”

So said Francis S. Collins, MD, PhD, special projects advisor to the Executive Office of the President of the United States, and former director of the National Institutes of Health, speaking at a special session outlining ambitious goals for a national plan to eliminate hepatitis C virus (HCV) infections by the year 2050.

The session was held at the annual meeting of the American Association for the Study of Liver Diseases.
 

A public health crisis

Dr. Collins labeled HCV a public health crisis, citing statistics from the Centers for Disease Control and Prevention that show that the rate of reported acute HCV infection cases increased 400% between 2010 and 2020, with the highest rates among young adults aged 20-39 years.

In addition, an estimated 2.4 million people in the United States are living with chronic HCV infections, but as many as 40% of these people are unaware of their infection, despite broad recommendations for the screening of all adults aged 18 years and older, he said.

“Our goal is to try to do something to change this,” Dr. Collins said. He noted that for the past 8 years we have had highly effective oral agents that don’t just treat the disease but cure it – 95%-97% of the time, with only 8-12 weeks of oral therapy and relatively few side effects.

“A wonderful story, one of the most exciting stories that’s come out of biomedical research in the last couple of decades,” he said.

Yet Dr. Collins also acknowledged that the task of developing a national plan is daunting, despite that pharmaceutical triumph.

National pharmacy claims data show that the number of persons treated for HCV with direct-acting antiviral agents (DAAs) in the United States declined from a high of 164,247 in 2015 to 83,740 in 2020.

Furthermore, CDC data from 2019 and 2020 show that, of persons with a diagnosis of HCV infection, only 23% of those on Medicaid, 28% of those on Medicare, and 35% of those with private insurance were treated for their infections.

“We have a huge gap here between the ability to know you have the disease and to get treatment, and we don’t see the numbers here for the uninsured, or people in prisons, but they’re probably much worse,” he said.
 

Obstacles abound, as do ways to overcome them

Current barriers to treatment include the aforementioned lack of awareness of infection, a “clunky” two-step diagnosis requiring an antibody test followed by an RNA or core antigen test necessitating three visits often separated by several weeks, and the high cost of treatment (around $90,000 per patient).

In addition, insurers commonly require proof that patients remain sober for extended periods, insist that treatment monitoring be performed by specialists only, and often approve treatment only for those patients who have documented evidence of liver damage.

“Does that make sense to you?” Dr. Collins asked. “You’ve got a cure for a liver disease, and you have to wait and show that the liver’s been damaged before you receive it? That just doesn’t fit,” he said.

Dr. Collins also pointed out that we’re dealing with hard-to-reach populations (underserved, uninsured, justice-involved), and people who are in tough times. “Anything that you put in the way as a barrier is going to make this worse in terms of its ability to be implemented,” he said.

To demonstrate how a coordinated HCV-elimination program could work, Dr. Collins pointed to a Medicaid cohort study in Louisiana conducted from July 2019 through December 2021, in which 8,867 patients started on therapy, 7,763 (88%) completed therapy, and 5,882 (66%) returned for testing. Of those tested, 5,285 (90%) had sustained virologic responses.

Another model of a hepatitis C elimination program was provided by the Veterans Health Administration. They received funding for an effort for all veterans, and in the space of 7 years were able to reach out even to some of their difficult-to-reach populations and achieve high diagnosis and treatment rates in a way that could be a model for what we would want to do across the nation, Dr. Collins noted.
 

Doing the math

Also at the session, Jagpreet Chhatwal, PhD, director of the Massachusetts General Hospital Institute for Technology Assessment and associate professor of radiology at Harvard Medical School, Boston, described outcomes projected by a mathematical simulation model of the HCV epidemic that he and his colleagues developed.

The HEP-SIM (Hepatitis C Disease Burden Simulation) model evaluates HCV prevalence trends, the number needed to screen and treat to eliminate HCV, HCV-associated clinical outcomes, the cost of an elimination program, and the cost savings that could be realized from preventing long-term complications.

The model seeks to determine whether the upfront costs of a national HCV elimination program could be offset by savings down the road. Specifically, it assumes that within the next 5 years 1.31 million individuals would be diagnosed with HCV and projects that within that time frame 1.52 million would need to be treated to meet HCV elimination goals.

The model shows that, compared with the status quo, a concerted campaign of screening and treatment would prevent more than 10,000 HCV-related deaths by 2030, and 91,000 deaths by 2050.

A coordinated screening program is also projected to prevent 17,000 cases of hepatocellular carcinoma by 2030 and 108,000 cases by 2050, as well as avert 29,000 cases of decompensated cirrhosis by 2030 and 93,000 such cases by 2050.

The cost savings associated with an HCV elimination plan would also be substantial, Dr. Chhatwal said.

According to the model, over the next decade the cumulative costs associated with HCV would decline by $14.2 billion, compared with the status quo. Nearly 80% of those savings ($11.2 billion) would be in Medicare and Medicaid.

The total projected savings from 2024 through 2050 – in disease management, testing, treatment, and pragmatic costs – are estimated at $59.3 billion, Dr. Chhatwal said.

“This is unprecedented,” he said. “We’re not just eliminating a disease as a public health threat but also saving money, which is not a common thing. That gives us a lot of impetus to implement such a program.”
 

Getting it done

Rachael L. Fleurence, PhD, MSc, a health economist currently serving as a senior advisor in the Executive Office of the President, summarized efforts to build a national HCV elimination program with input from federal health care agencies, state health leaders, patients, advocacy groups, drug manufacturers, and insurers.

She noted that a large component and focus of the program will be working on diagnostic test development but also accelerating bringing tests into the United States that are currently unavailable here. “These include point-of-care RNA diagnostic tests, as well as core antigen laboratory tests,” she said.

The program will be designed to offer broad access to curative anti-HCV drugs through a national subscription model that would make DAAs available to Medicaid recipients, justice-involved populations, the uninsured, and American Indians and Alaskan Natives who receive care through the Indian Health Service.

“On the Medicare and commercial insurance fronts, we’re still exploring different approaches, including potentially a co-pay assistance for Medicare beneficiaries, as well as working with commercial insurers to reduce barriers to access,” she said.

The program would also involve screening strategies extending to more settings, especially for high-risk populations, expanding the number of providers allowed to screen and treat HCV infections through telehealth, ensuring incentives for providers, and increasing the number of community health workers and case workers to improve linkage to care.

The next steps for the program would include funding to support the NIH’s RADx diagnostics program to accelerate access to testing, planning for the subscription model for DAA purchase, and launching pilot programs with the CDC, the Health Resources and Services Administration, the Substance Abuse and Mental Health Services Administration, and the Indian Health Service.
 

A call to action

Dr. Collins ended this portion of the program with an exhortation to AASLD members to do their part.

“We need your help,” Dr. Collins said. “This is a bold initiative, but it’s an opportunity. It’s even a responsibility. If we can actually succeed at this kind of outreach and save lives, and at the same time save money, how can we not do that?”

Dr. Collins, Dr. Chhatwal, and Dr. Fleurence each reported having no financial conflicts.

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

SAN Antonio – How do you shoot at an invisible target? It seems counterintuitive, but trastuzumab deruxtecan (T-DXd) (Enhertu), which combines an antibody targeted to HER2 with a toxic payload, showed promising preliminary activity against localized hormone receptor–positive breast cancers with only low levels of HER2 expression (HR+/HER2-low).

In the investigator-initiated TRIO-US B-12 TALENT study looking at neoadjuvant T-DXd either alone or in combination with the hormone therapy anastrazole, the objective response rate (ORR) with T-DXd alone was 68%, compared with 58% for T-DXd plus anastrazole, reported Aditya Bardia, MD, MPH, a medical oncologist with Massachusetts General Hospital Cancer Center in Boston. He recently presented the study findings at the 2022 San Antonio Breast Cancer Symposium.

“The study provides a rich platform for additional translational research to evaluate more sensitive methods of HER2 detection, develop predictive biomarkers, and understand mechanisms of resistance in residual disease which would guide subsequent therapeutic strategies, including combination therapy,” he said in an oral abstract session at the meeting.
 

Not-so-innocent bystander

In an interview, Dr. Bardia explained that the T-DXd may have efficacy in HER2-low cancers because of a bystander effect.

“With these antibody drug conjugates, if you have the antigen, the ADC binds to the antigen, gets internalized, and releases the payload, but the payload has a bystander effect ... it’s membrane permeable, so it can go outside and affect other cells that do not express the antigen. So for HER2-low tumors, even if there is HER2 heterogeneity or if there are some cells that do not express HER2, this would work because of the bystander effect,” he said.

Although neoadjuvant chemotherapy with an anthracycline and taxane is often used to treat patients with high-risk localized HR-positive breast cancer, the therapy is associated with low pathologic complete response (pCR) rates, radiological response rates of around 50%, and significant toxicities, including myelosuppression, neuropathy, cardiomyopathy, and leukemia risk, Dr. Bardia said.
 

At cross purposes

The trial included both a T-DXd monotherapy arm and a second arm containing the antibody drug conjugate (ADC) with endocrine therapy. The rationale for the latter is that there is documented “cross-talk” between the estrogen receptor (ER) and HER2.

“In tumors that become endocrine resistant, you see an increase in the HER2 pathway, and if you block ER, you see that HER2 goes up and vice versa. If you just block HER2 alone, the expression of ER can go up, and if you block the PI3 kinase alone, the expression of ER goes up,” he said.

Dual blockade can be effective with antibody-based therapy or with tyrosine kinase inhibitors, but with an ADC, the dual blockade strategy may be less effective, Dr. Bardia said, “because if you have an ADC, you need HER2, the ADC binds to HER2, then gives the payload to the cancer cells and essentially kills the cancer cells,” Dr. Bardia explained in a media briefing held prior to his presentation.

In fact, the T-DXd–anastrozole combination was associated with a lower overall response rate in the study than T-DXd alone, but Dr. Bardia cautioned about overinterpreting these results, as the study included only 39 patients.
 

Study details

The investigators enrolled 58 patients – 56 pre- and postmenopausal women and 2 men – with HR+/HER2-low tumors determined by local and/or central review, and operable stage II or III cancers.

After stratification by HER2 expression level and menopausal status, the patients were randomized to receive either T-DXd alone at a dose of 5.4 mg/kg, or with T-DXd at the same dose plus anastrozole, with men and premenopausal women also receiving a gonadotropin-releasing hormone analog.

The protocol originally called for six cycles of therapy, but was amended in February 2022 to increase the number to eight for newly enrolled participants and patients who were already on study treatment but had not yet had surgery.

The majority of patients in each arm had invasive ductal cancers, and most had HER2 expression on immunohistochemistry (IHC) of 1+, which is generally considered to be HER2-negative. However, there was only modest concordance between local and central review in determining HER2 expression levels, Dr. Bardia noted. Indeed, the entire question of HER2-low cancers, whether they compose a separate clinical entity from other cancers and how to standardize testing, was the subject of a special session at this year’s SABCS.
 

Results

Overall response rate, the primary endpoint, was 68% in the T-DXd arm and 58% in the T-DXd plus anastrazole arm.

Although the low response rate with the combination suggests that endocrine therapy may not be helpful in this patient population, it’s still too early to say so conclusively, Dr. Bardia said.

Looking at the change in HER2 expression by IHC from baseline to surgery, they found that 48.6% of patients had a change in HER2 IHC expression after T-DXd treatment, and that nearly 90% of these patients had a decrease in expression levels.

Among 42 patients with available data on residual cancer burden (RCB) at the time of data cutoff, one patient in the T-DXd alone arm with stage 3A disease had an RCB of 0, equivalent to a pathologic complete response (pCR). There were no other RCB 0 tumors after surgery in either study arm. The rate of combined RCB and RCB 1 (near pCR) was about 15% in each arm.

In all, 3 of the 58 patients in the study (5.2%) required dose reductions because of adverse events. There were no cases of grade 3 or greater pneumonitis, and no cases of either cardiomyopathy or neuropathy.
 

Way better than chemotherapy?

“It was very exciting when we got the DESTINY-Breast04 results showing this impressive activity of trastuzumab deruxtecan in this HER2-low entity, and now we know that hormone-positive [tumors], the majority of them are HER2-low. It was really encouraging, it was practice changing, but we were left wondering about this HER2-low entity, and can we act on it in the earlier setting,” commented Jason A. Mouabbi, MD, from the University of Texas MD Anderson Cancer Center in Houston.

“The beauty of the TRIO-US B-12 TALENT study is that it looked at the neoadjuvant setting where we know those patients who are hormone-positive usually do not respond well to chemotherapy,” he said in an interview.

He said that although the study didn’t compare T-DXd to chemotherapy, “it’s an excellent first start.”

An overall response rate near 70% “is something amazing. I’m really excited to see it against chemo. I think it’s going to do way better,” Dr. Mouabbi said.

The study was conducted by the Translational Research In Oncology (TRIO)-US network. Funding was provided by Daiichi Sankyo, the maker of trastuzumab deruxtecan (Enhertu). Dr. Bardia serves as a consultant or advisory board member for Pfizer, Novartis, Genentech, Merck, Radius Health, Immunomedics/Gilead Sciences, Sanofi, Daiichi Sankyo, AstraZeneca, and Eli Lilly, and has received research funding from Genentech, Novartis, Pfizer, Merck, Sanofi, Radius Health, Immunomedics/Gilead Sciences, Daiichi Sankyo, AstraZeneca, and Eli Lilly.

Dr. Mouabbi disclosed honoraria from BostonGene, Cardinal Health, Napo Pharmaceuticals, and Fresenius Kabi.

SAN Antonio – How do you shoot at an invisible target? It seems counterintuitive, but trastuzumab deruxtecan (T-DXd) (Enhertu), which combines an antibody targeted to HER2 with a toxic payload, showed promising preliminary activity against localized hormone receptor–positive breast cancers with only low levels of HER2 expression (HR+/HER2-low).

In the investigator-initiated TRIO-US B-12 TALENT study looking at neoadjuvant T-DXd either alone or in combination with the hormone therapy anastrazole, the objective response rate (ORR) with T-DXd alone was 68%, compared with 58% for T-DXd plus anastrazole, reported Aditya Bardia, MD, MPH, a medical oncologist with Massachusetts General Hospital Cancer Center in Boston. He recently presented the study findings at the 2022 San Antonio Breast Cancer Symposium.

“The study provides a rich platform for additional translational research to evaluate more sensitive methods of HER2 detection, develop predictive biomarkers, and understand mechanisms of resistance in residual disease which would guide subsequent therapeutic strategies, including combination therapy,” he said in an oral abstract session at the meeting.
 

Not-so-innocent bystander

In an interview, Dr. Bardia explained that the T-DXd may have efficacy in HER2-low cancers because of a bystander effect.

“With these antibody drug conjugates, if you have the antigen, the ADC binds to the antigen, gets internalized, and releases the payload, but the payload has a bystander effect ... it’s membrane permeable, so it can go outside and affect other cells that do not express the antigen. So for HER2-low tumors, even if there is HER2 heterogeneity or if there are some cells that do not express HER2, this would work because of the bystander effect,” he said.

Although neoadjuvant chemotherapy with an anthracycline and taxane is often used to treat patients with high-risk localized HR-positive breast cancer, the therapy is associated with low pathologic complete response (pCR) rates, radiological response rates of around 50%, and significant toxicities, including myelosuppression, neuropathy, cardiomyopathy, and leukemia risk, Dr. Bardia said.
 

At cross purposes

The trial included both a T-DXd monotherapy arm and a second arm containing the antibody drug conjugate (ADC) with endocrine therapy. The rationale for the latter is that there is documented “cross-talk” between the estrogen receptor (ER) and HER2.

“In tumors that become endocrine resistant, you see an increase in the HER2 pathway, and if you block ER, you see that HER2 goes up and vice versa. If you just block HER2 alone, the expression of ER can go up, and if you block the PI3 kinase alone, the expression of ER goes up,” he said.

Dual blockade can be effective with antibody-based therapy or with tyrosine kinase inhibitors, but with an ADC, the dual blockade strategy may be less effective, Dr. Bardia said, “because if you have an ADC, you need HER2, the ADC binds to HER2, then gives the payload to the cancer cells and essentially kills the cancer cells,” Dr. Bardia explained in a media briefing held prior to his presentation.

In fact, the T-DXd–anastrozole combination was associated with a lower overall response rate in the study than T-DXd alone, but Dr. Bardia cautioned about overinterpreting these results, as the study included only 39 patients.
 

Study details

The investigators enrolled 58 patients – 56 pre- and postmenopausal women and 2 men – with HR+/HER2-low tumors determined by local and/or central review, and operable stage II or III cancers.

After stratification by HER2 expression level and menopausal status, the patients were randomized to receive either T-DXd alone at a dose of 5.4 mg/kg, or with T-DXd at the same dose plus anastrozole, with men and premenopausal women also receiving a gonadotropin-releasing hormone analog.

The protocol originally called for six cycles of therapy, but was amended in February 2022 to increase the number to eight for newly enrolled participants and patients who were already on study treatment but had not yet had surgery.

The majority of patients in each arm had invasive ductal cancers, and most had HER2 expression on immunohistochemistry (IHC) of 1+, which is generally considered to be HER2-negative. However, there was only modest concordance between local and central review in determining HER2 expression levels, Dr. Bardia noted. Indeed, the entire question of HER2-low cancers, whether they compose a separate clinical entity from other cancers and how to standardize testing, was the subject of a special session at this year’s SABCS.
 

Results

Overall response rate, the primary endpoint, was 68% in the T-DXd arm and 58% in the T-DXd plus anastrazole arm.

Although the low response rate with the combination suggests that endocrine therapy may not be helpful in this patient population, it’s still too early to say so conclusively, Dr. Bardia said.

Looking at the change in HER2 expression by IHC from baseline to surgery, they found that 48.6% of patients had a change in HER2 IHC expression after T-DXd treatment, and that nearly 90% of these patients had a decrease in expression levels.

Among 42 patients with available data on residual cancer burden (RCB) at the time of data cutoff, one patient in the T-DXd alone arm with stage 3A disease had an RCB of 0, equivalent to a pathologic complete response (pCR). There were no other RCB 0 tumors after surgery in either study arm. The rate of combined RCB and RCB 1 (near pCR) was about 15% in each arm.

In all, 3 of the 58 patients in the study (5.2%) required dose reductions because of adverse events. There were no cases of grade 3 or greater pneumonitis, and no cases of either cardiomyopathy or neuropathy.
 

Way better than chemotherapy?

“It was very exciting when we got the DESTINY-Breast04 results showing this impressive activity of trastuzumab deruxtecan in this HER2-low entity, and now we know that hormone-positive [tumors], the majority of them are HER2-low. It was really encouraging, it was practice changing, but we were left wondering about this HER2-low entity, and can we act on it in the earlier setting,” commented Jason A. Mouabbi, MD, from the University of Texas MD Anderson Cancer Center in Houston.

“The beauty of the TRIO-US B-12 TALENT study is that it looked at the neoadjuvant setting where we know those patients who are hormone-positive usually do not respond well to chemotherapy,” he said in an interview.

He said that although the study didn’t compare T-DXd to chemotherapy, “it’s an excellent first start.”

An overall response rate near 70% “is something amazing. I’m really excited to see it against chemo. I think it’s going to do way better,” Dr. Mouabbi said.

The study was conducted by the Translational Research In Oncology (TRIO)-US network. Funding was provided by Daiichi Sankyo, the maker of trastuzumab deruxtecan (Enhertu). Dr. Bardia serves as a consultant or advisory board member for Pfizer, Novartis, Genentech, Merck, Radius Health, Immunomedics/Gilead Sciences, Sanofi, Daiichi Sankyo, AstraZeneca, and Eli Lilly, and has received research funding from Genentech, Novartis, Pfizer, Merck, Sanofi, Radius Health, Immunomedics/Gilead Sciences, Daiichi Sankyo, AstraZeneca, and Eli Lilly.

Dr. Mouabbi disclosed honoraria from BostonGene, Cardinal Health, Napo Pharmaceuticals, and Fresenius Kabi.

SAN Antonio – How do you shoot at an invisible target? It seems counterintuitive, but trastuzumab deruxtecan (T-DXd) (Enhertu), which combines an antibody targeted to HER2 with a toxic payload, showed promising preliminary activity against localized hormone receptor–positive breast cancers with only low levels of HER2 expression (HR+/HER2-low).

In the investigator-initiated TRIO-US B-12 TALENT study looking at neoadjuvant T-DXd either alone or in combination with the hormone therapy anastrazole, the objective response rate (ORR) with T-DXd alone was 68%, compared with 58% for T-DXd plus anastrazole, reported Aditya Bardia, MD, MPH, a medical oncologist with Massachusetts General Hospital Cancer Center in Boston. He recently presented the study findings at the 2022 San Antonio Breast Cancer Symposium.

“The study provides a rich platform for additional translational research to evaluate more sensitive methods of HER2 detection, develop predictive biomarkers, and understand mechanisms of resistance in residual disease which would guide subsequent therapeutic strategies, including combination therapy,” he said in an oral abstract session at the meeting.
 

Not-so-innocent bystander

In an interview, Dr. Bardia explained that the T-DXd may have efficacy in HER2-low cancers because of a bystander effect.

“With these antibody drug conjugates, if you have the antigen, the ADC binds to the antigen, gets internalized, and releases the payload, but the payload has a bystander effect ... it’s membrane permeable, so it can go outside and affect other cells that do not express the antigen. So for HER2-low tumors, even if there is HER2 heterogeneity or if there are some cells that do not express HER2, this would work because of the bystander effect,” he said.

Although neoadjuvant chemotherapy with an anthracycline and taxane is often used to treat patients with high-risk localized HR-positive breast cancer, the therapy is associated with low pathologic complete response (pCR) rates, radiological response rates of around 50%, and significant toxicities, including myelosuppression, neuropathy, cardiomyopathy, and leukemia risk, Dr. Bardia said.
 

At cross purposes

The trial included both a T-DXd monotherapy arm and a second arm containing the antibody drug conjugate (ADC) with endocrine therapy. The rationale for the latter is that there is documented “cross-talk” between the estrogen receptor (ER) and HER2.

“In tumors that become endocrine resistant, you see an increase in the HER2 pathway, and if you block ER, you see that HER2 goes up and vice versa. If you just block HER2 alone, the expression of ER can go up, and if you block the PI3 kinase alone, the expression of ER goes up,” he said.

Dual blockade can be effective with antibody-based therapy or with tyrosine kinase inhibitors, but with an ADC, the dual blockade strategy may be less effective, Dr. Bardia said, “because if you have an ADC, you need HER2, the ADC binds to HER2, then gives the payload to the cancer cells and essentially kills the cancer cells,” Dr. Bardia explained in a media briefing held prior to his presentation.

In fact, the T-DXd–anastrozole combination was associated with a lower overall response rate in the study than T-DXd alone, but Dr. Bardia cautioned about overinterpreting these results, as the study included only 39 patients.
 

Study details

The investigators enrolled 58 patients – 56 pre- and postmenopausal women and 2 men – with HR+/HER2-low tumors determined by local and/or central review, and operable stage II or III cancers.

After stratification by HER2 expression level and menopausal status, the patients were randomized to receive either T-DXd alone at a dose of 5.4 mg/kg, or with T-DXd at the same dose plus anastrozole, with men and premenopausal women also receiving a gonadotropin-releasing hormone analog.

The protocol originally called for six cycles of therapy, but was amended in February 2022 to increase the number to eight for newly enrolled participants and patients who were already on study treatment but had not yet had surgery.

The majority of patients in each arm had invasive ductal cancers, and most had HER2 expression on immunohistochemistry (IHC) of 1+, which is generally considered to be HER2-negative. However, there was only modest concordance between local and central review in determining HER2 expression levels, Dr. Bardia noted. Indeed, the entire question of HER2-low cancers, whether they compose a separate clinical entity from other cancers and how to standardize testing, was the subject of a special session at this year’s SABCS.
 

Results

Overall response rate, the primary endpoint, was 68% in the T-DXd arm and 58% in the T-DXd plus anastrazole arm.

Although the low response rate with the combination suggests that endocrine therapy may not be helpful in this patient population, it’s still too early to say so conclusively, Dr. Bardia said.

Looking at the change in HER2 expression by IHC from baseline to surgery, they found that 48.6% of patients had a change in HER2 IHC expression after T-DXd treatment, and that nearly 90% of these patients had a decrease in expression levels.

Among 42 patients with available data on residual cancer burden (RCB) at the time of data cutoff, one patient in the T-DXd alone arm with stage 3A disease had an RCB of 0, equivalent to a pathologic complete response (pCR). There were no other RCB 0 tumors after surgery in either study arm. The rate of combined RCB and RCB 1 (near pCR) was about 15% in each arm.

In all, 3 of the 58 patients in the study (5.2%) required dose reductions because of adverse events. There were no cases of grade 3 or greater pneumonitis, and no cases of either cardiomyopathy or neuropathy.
 

Way better than chemotherapy?

“It was very exciting when we got the DESTINY-Breast04 results showing this impressive activity of trastuzumab deruxtecan in this HER2-low entity, and now we know that hormone-positive [tumors], the majority of them are HER2-low. It was really encouraging, it was practice changing, but we were left wondering about this HER2-low entity, and can we act on it in the earlier setting,” commented Jason A. Mouabbi, MD, from the University of Texas MD Anderson Cancer Center in Houston.

“The beauty of the TRIO-US B-12 TALENT study is that it looked at the neoadjuvant setting where we know those patients who are hormone-positive usually do not respond well to chemotherapy,” he said in an interview.

He said that although the study didn’t compare T-DXd to chemotherapy, “it’s an excellent first start.”

An overall response rate near 70% “is something amazing. I’m really excited to see it against chemo. I think it’s going to do way better,” Dr. Mouabbi said.

The study was conducted by the Translational Research In Oncology (TRIO)-US network. Funding was provided by Daiichi Sankyo, the maker of trastuzumab deruxtecan (Enhertu). Dr. Bardia serves as a consultant or advisory board member for Pfizer, Novartis, Genentech, Merck, Radius Health, Immunomedics/Gilead Sciences, Sanofi, Daiichi Sankyo, AstraZeneca, and Eli Lilly, and has received research funding from Genentech, Novartis, Pfizer, Merck, Sanofi, Radius Health, Immunomedics/Gilead Sciences, Daiichi Sankyo, AstraZeneca, and Eli Lilly.

Dr. Mouabbi disclosed honoraria from BostonGene, Cardinal Health, Napo Pharmaceuticals, and Fresenius Kabi.