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Stem cell transplants for MS are a ‘reasonable option,’ but questions persist
NATIONAL HARBOR, MD. – .” But, he said, it remains unclear which patients should undergo the procedure.
An especially pressing question is “whether transplant is an alternative to our high-efficacy disease-modifying therapies” (DMTs) in some high-risk patients, Jeffrey A. Cohen, MD, director of experimental therapeutics at Cleveland Clinic’s Mellen Center, said in a presidential lecture at the annual meeting of the Consortium of Multiple Sclerosis Centers.
A handful of ongoing randomized controlled trials will bring answers, he said.
Stem cell therapy exists because there are gaps in MS treatment, Dr. Cohen said. “We have now more than 20 medications. However, none of these therapies is completely effective in all patients. In particular, there are some patients with very active disease who continue to have relapses or new MRI lesion activity despite treatment with all of the available therapies.”
And in progressive MS, the efficacy of a couple of agents is modest and mainly for people with ongoing focal lesion activity, he said. “Finally, all of these currently available therapies are intended primarily to prevent the accumulation of damage, and none of them directly promotes repair. So despite our progress in the field, there still are a number of unmet needs.”
‘Rebooting’ the immune system
Several types of stem cell therapy exist, including remyelination and anti-inflammatory therapy, Dr. Cohen said. In his lecture, he focused on immunoablative or myeloablative therapy followed by autologous hematopoietic stem cell transplantation.
This “complicated, multistep procedure” involves first eliminating the immune system to get rid of pathogenic inflammatory cells. This “big component is actually the therapy for MS. It’s also the step that has the most potential complications,” he said.
According to Dr. Cohen, the next step has been described as “rebooting” the immune system.
Does this procedure help patients with MS? In relapsing MS, reports suggest there’s “almost complete abrogation of disease activity following transplant,” he said, “a benefit that’s lasted 5-10-15 years. In addition, there’s also a benefit on the accumulation of CNS damage as measured by whole brain atrophy.”
Recent data, he said, suggests that MS patients most likely to benefit are young, developed MS relatively recently, are still ambulatory, and have highly active MS despite treatment with first- and second-line agents.
However, there have only been two randomized controlled trials of stem cell transplantation versus DMT, and Dr. Cohen said both studies have limitations. The first one, from 2015, is very small, with just 21 subjects. The second study – from 2019 – is larger (n = 103), but some patients weren’t taking higher-efficacy DMTs.
Other research is more promising: Dr. Cohen highlighted a 2017 analysis that found patients with relapsing/remitting MS who underwent stem-cell transplantation were more likely to be symptom-free at 2 years (78%-83%) than those who took DMTs in clinical trials (13%-46%).
Clinical concerns
As for side effects of stem cell transplantation, Dr. Cohen said, “most patients have some adverse effects during the procedure itself. There may be an MS relapse or pseudorelapses in association with the mobilization and the conditioning regimens.”
A wide range of other adverse effects is possible before the immune system is reconstituted, he said, including reactivation of various virus infections, such as HPV, CMV or EPV (Epstein-Barr virus), secondary autoimmune phenomenon, and secondary malignancy. EPV infection is also common after transplant, and is “probably the most troublesome posttransplant complication from a management point of view,” he said.
“Thankfully, once the patient ... recovers from the transplant procedure, late adverse effects are relatively uncommon, the most common of which would be infertility,” he said. “There have been some reports of successful pregnancies following transplant, but it’s important to advise people who are considering transplant that most men and women have infertility after the procedure. So if they desire to have children afterward, they need to be counseled on necessary preparations to do that.”
What about progressive multifocal leukoencephalopathy (PML), which seems a possible risk because of the suppression of the immune system? Dr. Cohen is aware of one case linked to a stem-cell transplant, and it may not have been caused by the procedure.
Cost is another potential obstacle, he noted. The National Multiple Sclerosis Society estimates that autologous hematopoietic stem cell transplants cost $150,000 on average in the U.S., although the expense varies widely.
Unanswered questions
Moving forward, Dr. Cohen said it remains unclear how these procedures fare against the newest generations of DMTs in MS. Five phase 3 randomized controlled trials are now trying to clarify the matter, he said, by pitting stem-cell transplantation against various MS drugs – alemtuzumab, cladribine, natalizumab, ocrelizumab, and rituximab.
There are also unanswered questions about the best conditioning regimens in the transplants, he said, and lack of clarity about where to draw the line between eligible and ineligible patients with MS. “How many DMTs does the person have to fail? What’s the upper level of disability beyond which it is unlikely to be helpful and more likely to cause harm?”
He added: “A particular profile that we’re seeing increasingly at our center is someone with very active disease and onset who gets started on a high-efficacy therapy as their first therapy and effectively stops relapses and MRI lesion activity. But within a couple of years, we can tell that they’re already starting to accumulate disability. Is this someone for whom transplant might be useful, and by extension, is transplant appropriate as the first therapy in some patients? And beyond MS, is transplant a consideration for other autoimmune CNS disorders? There are lots of unanswered questions, which future studies will hopefully begin to address.”
Dr. Cohen reports consulting for Biogen, Bristol‐Myers Squibb, Convelo, EMD Serono, GlaxoSmithKline (now GSK), Janssen, Mylan, and PSI. He serves as an editor of Multiple Sclerosis Journal.
NATIONAL HARBOR, MD. – .” But, he said, it remains unclear which patients should undergo the procedure.
An especially pressing question is “whether transplant is an alternative to our high-efficacy disease-modifying therapies” (DMTs) in some high-risk patients, Jeffrey A. Cohen, MD, director of experimental therapeutics at Cleveland Clinic’s Mellen Center, said in a presidential lecture at the annual meeting of the Consortium of Multiple Sclerosis Centers.
A handful of ongoing randomized controlled trials will bring answers, he said.
Stem cell therapy exists because there are gaps in MS treatment, Dr. Cohen said. “We have now more than 20 medications. However, none of these therapies is completely effective in all patients. In particular, there are some patients with very active disease who continue to have relapses or new MRI lesion activity despite treatment with all of the available therapies.”
And in progressive MS, the efficacy of a couple of agents is modest and mainly for people with ongoing focal lesion activity, he said. “Finally, all of these currently available therapies are intended primarily to prevent the accumulation of damage, and none of them directly promotes repair. So despite our progress in the field, there still are a number of unmet needs.”
‘Rebooting’ the immune system
Several types of stem cell therapy exist, including remyelination and anti-inflammatory therapy, Dr. Cohen said. In his lecture, he focused on immunoablative or myeloablative therapy followed by autologous hematopoietic stem cell transplantation.
This “complicated, multistep procedure” involves first eliminating the immune system to get rid of pathogenic inflammatory cells. This “big component is actually the therapy for MS. It’s also the step that has the most potential complications,” he said.
According to Dr. Cohen, the next step has been described as “rebooting” the immune system.
Does this procedure help patients with MS? In relapsing MS, reports suggest there’s “almost complete abrogation of disease activity following transplant,” he said, “a benefit that’s lasted 5-10-15 years. In addition, there’s also a benefit on the accumulation of CNS damage as measured by whole brain atrophy.”
Recent data, he said, suggests that MS patients most likely to benefit are young, developed MS relatively recently, are still ambulatory, and have highly active MS despite treatment with first- and second-line agents.
However, there have only been two randomized controlled trials of stem cell transplantation versus DMT, and Dr. Cohen said both studies have limitations. The first one, from 2015, is very small, with just 21 subjects. The second study – from 2019 – is larger (n = 103), but some patients weren’t taking higher-efficacy DMTs.
Other research is more promising: Dr. Cohen highlighted a 2017 analysis that found patients with relapsing/remitting MS who underwent stem-cell transplantation were more likely to be symptom-free at 2 years (78%-83%) than those who took DMTs in clinical trials (13%-46%).
Clinical concerns
As for side effects of stem cell transplantation, Dr. Cohen said, “most patients have some adverse effects during the procedure itself. There may be an MS relapse or pseudorelapses in association with the mobilization and the conditioning regimens.”
A wide range of other adverse effects is possible before the immune system is reconstituted, he said, including reactivation of various virus infections, such as HPV, CMV or EPV (Epstein-Barr virus), secondary autoimmune phenomenon, and secondary malignancy. EPV infection is also common after transplant, and is “probably the most troublesome posttransplant complication from a management point of view,” he said.
“Thankfully, once the patient ... recovers from the transplant procedure, late adverse effects are relatively uncommon, the most common of which would be infertility,” he said. “There have been some reports of successful pregnancies following transplant, but it’s important to advise people who are considering transplant that most men and women have infertility after the procedure. So if they desire to have children afterward, they need to be counseled on necessary preparations to do that.”
What about progressive multifocal leukoencephalopathy (PML), which seems a possible risk because of the suppression of the immune system? Dr. Cohen is aware of one case linked to a stem-cell transplant, and it may not have been caused by the procedure.
Cost is another potential obstacle, he noted. The National Multiple Sclerosis Society estimates that autologous hematopoietic stem cell transplants cost $150,000 on average in the U.S., although the expense varies widely.
Unanswered questions
Moving forward, Dr. Cohen said it remains unclear how these procedures fare against the newest generations of DMTs in MS. Five phase 3 randomized controlled trials are now trying to clarify the matter, he said, by pitting stem-cell transplantation against various MS drugs – alemtuzumab, cladribine, natalizumab, ocrelizumab, and rituximab.
There are also unanswered questions about the best conditioning regimens in the transplants, he said, and lack of clarity about where to draw the line between eligible and ineligible patients with MS. “How many DMTs does the person have to fail? What’s the upper level of disability beyond which it is unlikely to be helpful and more likely to cause harm?”
He added: “A particular profile that we’re seeing increasingly at our center is someone with very active disease and onset who gets started on a high-efficacy therapy as their first therapy and effectively stops relapses and MRI lesion activity. But within a couple of years, we can tell that they’re already starting to accumulate disability. Is this someone for whom transplant might be useful, and by extension, is transplant appropriate as the first therapy in some patients? And beyond MS, is transplant a consideration for other autoimmune CNS disorders? There are lots of unanswered questions, which future studies will hopefully begin to address.”
Dr. Cohen reports consulting for Biogen, Bristol‐Myers Squibb, Convelo, EMD Serono, GlaxoSmithKline (now GSK), Janssen, Mylan, and PSI. He serves as an editor of Multiple Sclerosis Journal.
NATIONAL HARBOR, MD. – .” But, he said, it remains unclear which patients should undergo the procedure.
An especially pressing question is “whether transplant is an alternative to our high-efficacy disease-modifying therapies” (DMTs) in some high-risk patients, Jeffrey A. Cohen, MD, director of experimental therapeutics at Cleveland Clinic’s Mellen Center, said in a presidential lecture at the annual meeting of the Consortium of Multiple Sclerosis Centers.
A handful of ongoing randomized controlled trials will bring answers, he said.
Stem cell therapy exists because there are gaps in MS treatment, Dr. Cohen said. “We have now more than 20 medications. However, none of these therapies is completely effective in all patients. In particular, there are some patients with very active disease who continue to have relapses or new MRI lesion activity despite treatment with all of the available therapies.”
And in progressive MS, the efficacy of a couple of agents is modest and mainly for people with ongoing focal lesion activity, he said. “Finally, all of these currently available therapies are intended primarily to prevent the accumulation of damage, and none of them directly promotes repair. So despite our progress in the field, there still are a number of unmet needs.”
‘Rebooting’ the immune system
Several types of stem cell therapy exist, including remyelination and anti-inflammatory therapy, Dr. Cohen said. In his lecture, he focused on immunoablative or myeloablative therapy followed by autologous hematopoietic stem cell transplantation.
This “complicated, multistep procedure” involves first eliminating the immune system to get rid of pathogenic inflammatory cells. This “big component is actually the therapy for MS. It’s also the step that has the most potential complications,” he said.
According to Dr. Cohen, the next step has been described as “rebooting” the immune system.
Does this procedure help patients with MS? In relapsing MS, reports suggest there’s “almost complete abrogation of disease activity following transplant,” he said, “a benefit that’s lasted 5-10-15 years. In addition, there’s also a benefit on the accumulation of CNS damage as measured by whole brain atrophy.”
Recent data, he said, suggests that MS patients most likely to benefit are young, developed MS relatively recently, are still ambulatory, and have highly active MS despite treatment with first- and second-line agents.
However, there have only been two randomized controlled trials of stem cell transplantation versus DMT, and Dr. Cohen said both studies have limitations. The first one, from 2015, is very small, with just 21 subjects. The second study – from 2019 – is larger (n = 103), but some patients weren’t taking higher-efficacy DMTs.
Other research is more promising: Dr. Cohen highlighted a 2017 analysis that found patients with relapsing/remitting MS who underwent stem-cell transplantation were more likely to be symptom-free at 2 years (78%-83%) than those who took DMTs in clinical trials (13%-46%).
Clinical concerns
As for side effects of stem cell transplantation, Dr. Cohen said, “most patients have some adverse effects during the procedure itself. There may be an MS relapse or pseudorelapses in association with the mobilization and the conditioning regimens.”
A wide range of other adverse effects is possible before the immune system is reconstituted, he said, including reactivation of various virus infections, such as HPV, CMV or EPV (Epstein-Barr virus), secondary autoimmune phenomenon, and secondary malignancy. EPV infection is also common after transplant, and is “probably the most troublesome posttransplant complication from a management point of view,” he said.
“Thankfully, once the patient ... recovers from the transplant procedure, late adverse effects are relatively uncommon, the most common of which would be infertility,” he said. “There have been some reports of successful pregnancies following transplant, but it’s important to advise people who are considering transplant that most men and women have infertility after the procedure. So if they desire to have children afterward, they need to be counseled on necessary preparations to do that.”
What about progressive multifocal leukoencephalopathy (PML), which seems a possible risk because of the suppression of the immune system? Dr. Cohen is aware of one case linked to a stem-cell transplant, and it may not have been caused by the procedure.
Cost is another potential obstacle, he noted. The National Multiple Sclerosis Society estimates that autologous hematopoietic stem cell transplants cost $150,000 on average in the U.S., although the expense varies widely.
Unanswered questions
Moving forward, Dr. Cohen said it remains unclear how these procedures fare against the newest generations of DMTs in MS. Five phase 3 randomized controlled trials are now trying to clarify the matter, he said, by pitting stem-cell transplantation against various MS drugs – alemtuzumab, cladribine, natalizumab, ocrelizumab, and rituximab.
There are also unanswered questions about the best conditioning regimens in the transplants, he said, and lack of clarity about where to draw the line between eligible and ineligible patients with MS. “How many DMTs does the person have to fail? What’s the upper level of disability beyond which it is unlikely to be helpful and more likely to cause harm?”
He added: “A particular profile that we’re seeing increasingly at our center is someone with very active disease and onset who gets started on a high-efficacy therapy as their first therapy and effectively stops relapses and MRI lesion activity. But within a couple of years, we can tell that they’re already starting to accumulate disability. Is this someone for whom transplant might be useful, and by extension, is transplant appropriate as the first therapy in some patients? And beyond MS, is transplant a consideration for other autoimmune CNS disorders? There are lots of unanswered questions, which future studies will hopefully begin to address.”
Dr. Cohen reports consulting for Biogen, Bristol‐Myers Squibb, Convelo, EMD Serono, GlaxoSmithKline (now GSK), Janssen, Mylan, and PSI. He serves as an editor of Multiple Sclerosis Journal.
At CMSC 2022
‘Great optimism’ greets immunotherapy responses in dMMR rectal cancer
Thus far, the study has involved only 12 patients, but all of them have had a clinical complete response to treatment. They continue to show no signs of cancer (during follow-up ranging from 6 to 25 months) and have not undergone surgery or had radiation and chemotherapy, which are the standard treatment approaches.
The results were presented (Abstract 16) at the American Society of Clinical Oncology annual meeting and simultaneously published in the New England Journal of Medicine.
“In our study, the elimination of tumors after 6 months of therapy with PD-1 blockade enabled us to omit both chemoradiotherapy and surgery and to proceed with observation alone,” said the authors, led by Andrea Cercek, MD, Memorial Sloan Kettering Cancer Center, New York.
About 5%-10% of patients with rectal cancer have tumors with dMMR.
“The implications for quality of life are substantial, especially among patients in whom standard treatment would affect child-bearing potential [and] given that the incidence of rectal cancer is rising among young adults of childbearing age, the use of PD-1 blockade to eliminate the need for chemoradiotherapy and surgery may confer a particular benefit in that age group,” the authors wrote.
The results of the current study are cause for “great optimism, but such an approach cannot yet supplant our current curative treatment approach,” Dr. Hanna K. Sanoff, MD, University of North Carolina at Chapel Hill, wrote in an accompanying editorial.
Single-agent dostarlimab
For the study, all patients were treated with single-agent dostarlimab every 3 weeks for 6 months.
Dostarlimab is already approved by the Food and Drug Administration for use in the treatment of recurrent or advanced endometrial cancer with dMMR. Rectal cancer is an off-label use.
All patients had mismatch repair-deficient stage 2 or 3 rectal adenocarcinoma. The authors noted that these tumors respond poorly to standard chemotherapy regimens, including neoadjuvant chemotherapy. The median age of enrolled patients was 54 years and 62% were women.
For the study, investigators planned that patients who had a clinical complete response after completion of dostarlimab were to proceed to observation without undergoing either chemoradiotherapy or surgery, while those who did not have a complete response were to have received these standard treatments.
As it turned out, all 12 patients achieved a complete response and have been followed by observation alone. The median follow-up from time of enrollment to data cutoff for the 12 patients was 12 months.
“Therapeutic responses were rapid,” the authors noted, “with resolution of symptoms within 8 weeks after initiation of dostarlimab in 81% of the patients.”
To date, four patients have had 1 year of sustained clinical complete response after completion of the anti-PD-1 course.
In addition to the 12 patients documented in the study, another four patients have received at least one dose of dostarlimab and continue to receive treatment.
Adverse events occurred in most patients but none were grade 3 or higher. The most common grade 1 or 2 adverse events were rash or dermatitis, pruritus, fatigue, nausea and, in one patient, thyroid-function abnormalities.
The authors speculated that in addition to the extremely high tumor mutational burden associated with mismatch-repair deficiency, a tumor cell–extrinsic factor such as the gut microbiome may be driving the exceptionally good response to PD-1 blockade seen in this patient population.
Editorial commentary
In the editorial, Dr. Sanoff emphasized that the approach remains experimental and should not replace current curative treatment. She noted that cancer recurrences have been seen in other studies using both chemotherapy and immunotherapy.
For example, with chemotherapy and radiation, those patients who achieve a clinical complete response have a better prognosis compared with those who do not, but she cautioned that “cancer regrowth occurs in 20% to 30% of such patients when the cancer is managed nonoperatively.”
Dr. Sanoff noted that recurrences were seen when this approach of PD-1 inhibition has been used for metastatic colorectal cancer with dMMR. In the KEYNOTE-177 trial with pembrolizumab (Keytruda), only 55% of patients were reported to be alive without cancer progression at 12 months, and of the patients who initially had a strong response, only 70% had an ongoing response 3 years later.
“These recurrence dynamics may (or may not) differ between immunotherapy and chemoradiotherapy and between early and late-stage disease,” Dr. Sanoff said.
“In fact, very little is known about the duration of time needed to find out whether a clinical complete response to dostarlimab equates to cure,” she added.
In addition, Dr. Sanoff warned that the decision not to pursue further treatment and to follow patients with observation alone requires very close monitoring.
The current study was conducted at a top U.S. cancer center, Memorial Sloan Kettering Cancer Center. The authors noted that the complete responses (after a minimum of 6 months of follow-up) were measured by the combination of rectal MRI, visual endoscopic inspection, and digital rectal examination.
The completeness of these responses was further supported by the absence of residual tumor on serial endoscopic biopsies and the resolution of 18F-fluorodeoxyglucose uptake on PET scans, the authors added.
In the editorial, Dr. Sanoff said that “safe nonoperative management [also] involves access to specialty care for direct intraluminal visualization and expertise in interpretation of rectal magnetic resonance imaging ... Such expertise is not available in all communities and without it, patients could miss the opportunity for curative resection if tumor regrowth occurred.”
The study was sponsored by the Simon and Eve Colin Foundation, GlaxoSmithKline, and Stand Up to Cancer, among others.
A version of this article first appeared on Medscape.com.
Thus far, the study has involved only 12 patients, but all of them have had a clinical complete response to treatment. They continue to show no signs of cancer (during follow-up ranging from 6 to 25 months) and have not undergone surgery or had radiation and chemotherapy, which are the standard treatment approaches.
The results were presented (Abstract 16) at the American Society of Clinical Oncology annual meeting and simultaneously published in the New England Journal of Medicine.
“In our study, the elimination of tumors after 6 months of therapy with PD-1 blockade enabled us to omit both chemoradiotherapy and surgery and to proceed with observation alone,” said the authors, led by Andrea Cercek, MD, Memorial Sloan Kettering Cancer Center, New York.
About 5%-10% of patients with rectal cancer have tumors with dMMR.
“The implications for quality of life are substantial, especially among patients in whom standard treatment would affect child-bearing potential [and] given that the incidence of rectal cancer is rising among young adults of childbearing age, the use of PD-1 blockade to eliminate the need for chemoradiotherapy and surgery may confer a particular benefit in that age group,” the authors wrote.
The results of the current study are cause for “great optimism, but such an approach cannot yet supplant our current curative treatment approach,” Dr. Hanna K. Sanoff, MD, University of North Carolina at Chapel Hill, wrote in an accompanying editorial.
Single-agent dostarlimab
For the study, all patients were treated with single-agent dostarlimab every 3 weeks for 6 months.
Dostarlimab is already approved by the Food and Drug Administration for use in the treatment of recurrent or advanced endometrial cancer with dMMR. Rectal cancer is an off-label use.
All patients had mismatch repair-deficient stage 2 or 3 rectal adenocarcinoma. The authors noted that these tumors respond poorly to standard chemotherapy regimens, including neoadjuvant chemotherapy. The median age of enrolled patients was 54 years and 62% were women.
For the study, investigators planned that patients who had a clinical complete response after completion of dostarlimab were to proceed to observation without undergoing either chemoradiotherapy or surgery, while those who did not have a complete response were to have received these standard treatments.
As it turned out, all 12 patients achieved a complete response and have been followed by observation alone. The median follow-up from time of enrollment to data cutoff for the 12 patients was 12 months.
“Therapeutic responses were rapid,” the authors noted, “with resolution of symptoms within 8 weeks after initiation of dostarlimab in 81% of the patients.”
To date, four patients have had 1 year of sustained clinical complete response after completion of the anti-PD-1 course.
In addition to the 12 patients documented in the study, another four patients have received at least one dose of dostarlimab and continue to receive treatment.
Adverse events occurred in most patients but none were grade 3 or higher. The most common grade 1 or 2 adverse events were rash or dermatitis, pruritus, fatigue, nausea and, in one patient, thyroid-function abnormalities.
The authors speculated that in addition to the extremely high tumor mutational burden associated with mismatch-repair deficiency, a tumor cell–extrinsic factor such as the gut microbiome may be driving the exceptionally good response to PD-1 blockade seen in this patient population.
Editorial commentary
In the editorial, Dr. Sanoff emphasized that the approach remains experimental and should not replace current curative treatment. She noted that cancer recurrences have been seen in other studies using both chemotherapy and immunotherapy.
For example, with chemotherapy and radiation, those patients who achieve a clinical complete response have a better prognosis compared with those who do not, but she cautioned that “cancer regrowth occurs in 20% to 30% of such patients when the cancer is managed nonoperatively.”
Dr. Sanoff noted that recurrences were seen when this approach of PD-1 inhibition has been used for metastatic colorectal cancer with dMMR. In the KEYNOTE-177 trial with pembrolizumab (Keytruda), only 55% of patients were reported to be alive without cancer progression at 12 months, and of the patients who initially had a strong response, only 70% had an ongoing response 3 years later.
“These recurrence dynamics may (or may not) differ between immunotherapy and chemoradiotherapy and between early and late-stage disease,” Dr. Sanoff said.
“In fact, very little is known about the duration of time needed to find out whether a clinical complete response to dostarlimab equates to cure,” she added.
In addition, Dr. Sanoff warned that the decision not to pursue further treatment and to follow patients with observation alone requires very close monitoring.
The current study was conducted at a top U.S. cancer center, Memorial Sloan Kettering Cancer Center. The authors noted that the complete responses (after a minimum of 6 months of follow-up) were measured by the combination of rectal MRI, visual endoscopic inspection, and digital rectal examination.
The completeness of these responses was further supported by the absence of residual tumor on serial endoscopic biopsies and the resolution of 18F-fluorodeoxyglucose uptake on PET scans, the authors added.
In the editorial, Dr. Sanoff said that “safe nonoperative management [also] involves access to specialty care for direct intraluminal visualization and expertise in interpretation of rectal magnetic resonance imaging ... Such expertise is not available in all communities and without it, patients could miss the opportunity for curative resection if tumor regrowth occurred.”
The study was sponsored by the Simon and Eve Colin Foundation, GlaxoSmithKline, and Stand Up to Cancer, among others.
A version of this article first appeared on Medscape.com.
Thus far, the study has involved only 12 patients, but all of them have had a clinical complete response to treatment. They continue to show no signs of cancer (during follow-up ranging from 6 to 25 months) and have not undergone surgery or had radiation and chemotherapy, which are the standard treatment approaches.
The results were presented (Abstract 16) at the American Society of Clinical Oncology annual meeting and simultaneously published in the New England Journal of Medicine.
“In our study, the elimination of tumors after 6 months of therapy with PD-1 blockade enabled us to omit both chemoradiotherapy and surgery and to proceed with observation alone,” said the authors, led by Andrea Cercek, MD, Memorial Sloan Kettering Cancer Center, New York.
About 5%-10% of patients with rectal cancer have tumors with dMMR.
“The implications for quality of life are substantial, especially among patients in whom standard treatment would affect child-bearing potential [and] given that the incidence of rectal cancer is rising among young adults of childbearing age, the use of PD-1 blockade to eliminate the need for chemoradiotherapy and surgery may confer a particular benefit in that age group,” the authors wrote.
The results of the current study are cause for “great optimism, but such an approach cannot yet supplant our current curative treatment approach,” Dr. Hanna K. Sanoff, MD, University of North Carolina at Chapel Hill, wrote in an accompanying editorial.
Single-agent dostarlimab
For the study, all patients were treated with single-agent dostarlimab every 3 weeks for 6 months.
Dostarlimab is already approved by the Food and Drug Administration for use in the treatment of recurrent or advanced endometrial cancer with dMMR. Rectal cancer is an off-label use.
All patients had mismatch repair-deficient stage 2 or 3 rectal adenocarcinoma. The authors noted that these tumors respond poorly to standard chemotherapy regimens, including neoadjuvant chemotherapy. The median age of enrolled patients was 54 years and 62% were women.
For the study, investigators planned that patients who had a clinical complete response after completion of dostarlimab were to proceed to observation without undergoing either chemoradiotherapy or surgery, while those who did not have a complete response were to have received these standard treatments.
As it turned out, all 12 patients achieved a complete response and have been followed by observation alone. The median follow-up from time of enrollment to data cutoff for the 12 patients was 12 months.
“Therapeutic responses were rapid,” the authors noted, “with resolution of symptoms within 8 weeks after initiation of dostarlimab in 81% of the patients.”
To date, four patients have had 1 year of sustained clinical complete response after completion of the anti-PD-1 course.
In addition to the 12 patients documented in the study, another four patients have received at least one dose of dostarlimab and continue to receive treatment.
Adverse events occurred in most patients but none were grade 3 or higher. The most common grade 1 or 2 adverse events were rash or dermatitis, pruritus, fatigue, nausea and, in one patient, thyroid-function abnormalities.
The authors speculated that in addition to the extremely high tumor mutational burden associated with mismatch-repair deficiency, a tumor cell–extrinsic factor such as the gut microbiome may be driving the exceptionally good response to PD-1 blockade seen in this patient population.
Editorial commentary
In the editorial, Dr. Sanoff emphasized that the approach remains experimental and should not replace current curative treatment. She noted that cancer recurrences have been seen in other studies using both chemotherapy and immunotherapy.
For example, with chemotherapy and radiation, those patients who achieve a clinical complete response have a better prognosis compared with those who do not, but she cautioned that “cancer regrowth occurs in 20% to 30% of such patients when the cancer is managed nonoperatively.”
Dr. Sanoff noted that recurrences were seen when this approach of PD-1 inhibition has been used for metastatic colorectal cancer with dMMR. In the KEYNOTE-177 trial with pembrolizumab (Keytruda), only 55% of patients were reported to be alive without cancer progression at 12 months, and of the patients who initially had a strong response, only 70% had an ongoing response 3 years later.
“These recurrence dynamics may (or may not) differ between immunotherapy and chemoradiotherapy and between early and late-stage disease,” Dr. Sanoff said.
“In fact, very little is known about the duration of time needed to find out whether a clinical complete response to dostarlimab equates to cure,” she added.
In addition, Dr. Sanoff warned that the decision not to pursue further treatment and to follow patients with observation alone requires very close monitoring.
The current study was conducted at a top U.S. cancer center, Memorial Sloan Kettering Cancer Center. The authors noted that the complete responses (after a minimum of 6 months of follow-up) were measured by the combination of rectal MRI, visual endoscopic inspection, and digital rectal examination.
The completeness of these responses was further supported by the absence of residual tumor on serial endoscopic biopsies and the resolution of 18F-fluorodeoxyglucose uptake on PET scans, the authors added.
In the editorial, Dr. Sanoff said that “safe nonoperative management [also] involves access to specialty care for direct intraluminal visualization and expertise in interpretation of rectal magnetic resonance imaging ... Such expertise is not available in all communities and without it, patients could miss the opportunity for curative resection if tumor regrowth occurred.”
The study was sponsored by the Simon and Eve Colin Foundation, GlaxoSmithKline, and Stand Up to Cancer, among others.
A version of this article first appeared on Medscape.com.
FROM ASCO 2022
‘Remission is possible’ for patients with type 2 diabetes
A novel approach that involves sensors, artificial intelligence, and real-time individualized lifestyle guidance from an app and live coaches led to a high rate of remission of type 2 diabetes in a new study.
Specifically, among 199 patients with type 2 diabetes in India who received the app-delivered lifestyle guidance developed by Twin Health, Mountain View, Calif., mean hemoglobin A1c dropped from 9.0% to 5.7% at 6 months.
This is “huge,” Paramesh Shamanna, MD, told a press briefing at the annual scientific sessions of the American Diabetes Association. The research was presented as three posters by the group at the meeting.
Patients were a mean age of 43 and had diabetes for a mean of 3.7 years and up to 8 years.
An “unprecedented” 84% of patients had remission of diabetes at 6 months, Dr. Shamanna, medical director at Twin Health, noted.
Diabetes remission was defined according to the 2021 joint consensus statement from the ADA and other organizations as an A1c less than 6.5% without the use of diabetes medications for at least 3 months.
Importantly, patients’ time in range (percentage of time spent in target blood glucose range) increased from 53% to 81%, Dr. Shamanna pointed out. On average, patients’ waist circumference decreased by 10 cm (3.9 inches) and their weight dropped from 79 kg (approximately 174 lb) to 68 kg (150 lb).
These results are driven by “the continuous individualized and precise guidance regarding nutrition, activity, and sleep,” Dr. Shamanna said in an interview.
Remission is not reversal or cure ...
“Remission” from type 2 diabetes is not “reversal” or a “cure,” Robert A. Gabbay, MD, PhD, chief scientific and medical officer of the ADA, stressed to the press. Just like cancer, diabetes can return after remission
Therefore, it is important to follow the lifestyle guidance. Patients may still be at risk for diabetes complications after diabetes remission, so it’s also important to continue to be screened for eye disease, nerve damage, and lipid levels.
However, “remission can be made to last,” Dr. Shamanna said, by continuing to follow the lifestyle advice and getting back on track after a relapse.
“We’re in a different time right now,” Lisa Shah, MD, chief medical officer, Twin Health, noted. “This is very different from management of blood glucose to a certain number.”
This study shows that “remission [from type 2 diabetes] is possible. How you achieve it can be precise for you.”
The program is designed to consider the health and happiness of the patient, added Shashank R. Joshi, MD, chief scientist, Twin Health. “We want remission to be complication free. These findings give patients hope.”
“It’s exciting now that we can really start thinking about remission as an option for people with [type 2] diabetes, and that just provides such incredible hope for all of those living with [type 2] diabetes,” Dr. Gabbay said in an interview.
How the intervention works
The Twin Precision Treatment (TPT) intervention integrates multiple data – glucose values from a continuous glucose monitor (CGM); heart rate, activity, and sleep time from a fitness tracker; blood pressure values from a blood pressure cuff; food intake from the patient’s food log; and weight and body fat data from a smart scale – and provides the patient with precise, individualized nutrition and health guidance.
The four most critical sensors are the CGM, the fitness tracker, the smart scale, and the blood pressure cuff, Dr. Shah explained. The system gathers thousands of signals combined with patient self-reported data including mood or anxiety.
The CGM is used to build the initial nutrition guidance during the first 30 days. Once a patient is in remission, he or she can just keep the fitness tracker and smart scale.
The coaches who are part of this program include dietitians who are trained to provide compassionate patient education and help patients avoid diabetes relapse, and they are overseen by a licensed provider.
The program does not restrict calories. “It is not a diet,” Dr. Shah stressed.
The algorithm makes mini adjustments to the food a person is already eating to improve nutrition, Dr. Joshi explained. “This is personalized medicine at its best.” Patients eat food that they like and are guided to make small changes to get glucose under control and avoid glucose spikes.
The program is designed to safely deescalate diabetes medications as A1c decreases, Dr. Shamanna added.
U.S. clinical trial, health insurance coverage
The 1-year results of the current trial are expected in August, and the trial will continue for 2-=5 years, Dr. Shamanna said.
The company has started a clinical trial in the United States, with 5-year results expected in 2027.
“Currently, in the United States, we are partnering with self-insured employers and select health plans that offer [Twin Precision Treatment ] as an available benefit for their members,” Dr. Shah said. It “is suitable for most members living with type 2 diabetes, with rare exclusion situations.”
The study was funded by Twin Health. Dr. Shamanna, Dr. Shah, and Dr. Joshi are employees of Twin Health.
A version of this article first appeared on Medscape.com.
A novel approach that involves sensors, artificial intelligence, and real-time individualized lifestyle guidance from an app and live coaches led to a high rate of remission of type 2 diabetes in a new study.
Specifically, among 199 patients with type 2 diabetes in India who received the app-delivered lifestyle guidance developed by Twin Health, Mountain View, Calif., mean hemoglobin A1c dropped from 9.0% to 5.7% at 6 months.
This is “huge,” Paramesh Shamanna, MD, told a press briefing at the annual scientific sessions of the American Diabetes Association. The research was presented as three posters by the group at the meeting.
Patients were a mean age of 43 and had diabetes for a mean of 3.7 years and up to 8 years.
An “unprecedented” 84% of patients had remission of diabetes at 6 months, Dr. Shamanna, medical director at Twin Health, noted.
Diabetes remission was defined according to the 2021 joint consensus statement from the ADA and other organizations as an A1c less than 6.5% without the use of diabetes medications for at least 3 months.
Importantly, patients’ time in range (percentage of time spent in target blood glucose range) increased from 53% to 81%, Dr. Shamanna pointed out. On average, patients’ waist circumference decreased by 10 cm (3.9 inches) and their weight dropped from 79 kg (approximately 174 lb) to 68 kg (150 lb).
These results are driven by “the continuous individualized and precise guidance regarding nutrition, activity, and sleep,” Dr. Shamanna said in an interview.
Remission is not reversal or cure ...
“Remission” from type 2 diabetes is not “reversal” or a “cure,” Robert A. Gabbay, MD, PhD, chief scientific and medical officer of the ADA, stressed to the press. Just like cancer, diabetes can return after remission
Therefore, it is important to follow the lifestyle guidance. Patients may still be at risk for diabetes complications after diabetes remission, so it’s also important to continue to be screened for eye disease, nerve damage, and lipid levels.
However, “remission can be made to last,” Dr. Shamanna said, by continuing to follow the lifestyle advice and getting back on track after a relapse.
“We’re in a different time right now,” Lisa Shah, MD, chief medical officer, Twin Health, noted. “This is very different from management of blood glucose to a certain number.”
This study shows that “remission [from type 2 diabetes] is possible. How you achieve it can be precise for you.”
The program is designed to consider the health and happiness of the patient, added Shashank R. Joshi, MD, chief scientist, Twin Health. “We want remission to be complication free. These findings give patients hope.”
“It’s exciting now that we can really start thinking about remission as an option for people with [type 2] diabetes, and that just provides such incredible hope for all of those living with [type 2] diabetes,” Dr. Gabbay said in an interview.
How the intervention works
The Twin Precision Treatment (TPT) intervention integrates multiple data – glucose values from a continuous glucose monitor (CGM); heart rate, activity, and sleep time from a fitness tracker; blood pressure values from a blood pressure cuff; food intake from the patient’s food log; and weight and body fat data from a smart scale – and provides the patient with precise, individualized nutrition and health guidance.
The four most critical sensors are the CGM, the fitness tracker, the smart scale, and the blood pressure cuff, Dr. Shah explained. The system gathers thousands of signals combined with patient self-reported data including mood or anxiety.
The CGM is used to build the initial nutrition guidance during the first 30 days. Once a patient is in remission, he or she can just keep the fitness tracker and smart scale.
The coaches who are part of this program include dietitians who are trained to provide compassionate patient education and help patients avoid diabetes relapse, and they are overseen by a licensed provider.
The program does not restrict calories. “It is not a diet,” Dr. Shah stressed.
The algorithm makes mini adjustments to the food a person is already eating to improve nutrition, Dr. Joshi explained. “This is personalized medicine at its best.” Patients eat food that they like and are guided to make small changes to get glucose under control and avoid glucose spikes.
The program is designed to safely deescalate diabetes medications as A1c decreases, Dr. Shamanna added.
U.S. clinical trial, health insurance coverage
The 1-year results of the current trial are expected in August, and the trial will continue for 2-=5 years, Dr. Shamanna said.
The company has started a clinical trial in the United States, with 5-year results expected in 2027.
“Currently, in the United States, we are partnering with self-insured employers and select health plans that offer [Twin Precision Treatment ] as an available benefit for their members,” Dr. Shah said. It “is suitable for most members living with type 2 diabetes, with rare exclusion situations.”
The study was funded by Twin Health. Dr. Shamanna, Dr. Shah, and Dr. Joshi are employees of Twin Health.
A version of this article first appeared on Medscape.com.
A novel approach that involves sensors, artificial intelligence, and real-time individualized lifestyle guidance from an app and live coaches led to a high rate of remission of type 2 diabetes in a new study.
Specifically, among 199 patients with type 2 diabetes in India who received the app-delivered lifestyle guidance developed by Twin Health, Mountain View, Calif., mean hemoglobin A1c dropped from 9.0% to 5.7% at 6 months.
This is “huge,” Paramesh Shamanna, MD, told a press briefing at the annual scientific sessions of the American Diabetes Association. The research was presented as three posters by the group at the meeting.
Patients were a mean age of 43 and had diabetes for a mean of 3.7 years and up to 8 years.
An “unprecedented” 84% of patients had remission of diabetes at 6 months, Dr. Shamanna, medical director at Twin Health, noted.
Diabetes remission was defined according to the 2021 joint consensus statement from the ADA and other organizations as an A1c less than 6.5% without the use of diabetes medications for at least 3 months.
Importantly, patients’ time in range (percentage of time spent in target blood glucose range) increased from 53% to 81%, Dr. Shamanna pointed out. On average, patients’ waist circumference decreased by 10 cm (3.9 inches) and their weight dropped from 79 kg (approximately 174 lb) to 68 kg (150 lb).
These results are driven by “the continuous individualized and precise guidance regarding nutrition, activity, and sleep,” Dr. Shamanna said in an interview.
Remission is not reversal or cure ...
“Remission” from type 2 diabetes is not “reversal” or a “cure,” Robert A. Gabbay, MD, PhD, chief scientific and medical officer of the ADA, stressed to the press. Just like cancer, diabetes can return after remission
Therefore, it is important to follow the lifestyle guidance. Patients may still be at risk for diabetes complications after diabetes remission, so it’s also important to continue to be screened for eye disease, nerve damage, and lipid levels.
However, “remission can be made to last,” Dr. Shamanna said, by continuing to follow the lifestyle advice and getting back on track after a relapse.
“We’re in a different time right now,” Lisa Shah, MD, chief medical officer, Twin Health, noted. “This is very different from management of blood glucose to a certain number.”
This study shows that “remission [from type 2 diabetes] is possible. How you achieve it can be precise for you.”
The program is designed to consider the health and happiness of the patient, added Shashank R. Joshi, MD, chief scientist, Twin Health. “We want remission to be complication free. These findings give patients hope.”
“It’s exciting now that we can really start thinking about remission as an option for people with [type 2] diabetes, and that just provides such incredible hope for all of those living with [type 2] diabetes,” Dr. Gabbay said in an interview.
How the intervention works
The Twin Precision Treatment (TPT) intervention integrates multiple data – glucose values from a continuous glucose monitor (CGM); heart rate, activity, and sleep time from a fitness tracker; blood pressure values from a blood pressure cuff; food intake from the patient’s food log; and weight and body fat data from a smart scale – and provides the patient with precise, individualized nutrition and health guidance.
The four most critical sensors are the CGM, the fitness tracker, the smart scale, and the blood pressure cuff, Dr. Shah explained. The system gathers thousands of signals combined with patient self-reported data including mood or anxiety.
The CGM is used to build the initial nutrition guidance during the first 30 days. Once a patient is in remission, he or she can just keep the fitness tracker and smart scale.
The coaches who are part of this program include dietitians who are trained to provide compassionate patient education and help patients avoid diabetes relapse, and they are overseen by a licensed provider.
The program does not restrict calories. “It is not a diet,” Dr. Shah stressed.
The algorithm makes mini adjustments to the food a person is already eating to improve nutrition, Dr. Joshi explained. “This is personalized medicine at its best.” Patients eat food that they like and are guided to make small changes to get glucose under control and avoid glucose spikes.
The program is designed to safely deescalate diabetes medications as A1c decreases, Dr. Shamanna added.
U.S. clinical trial, health insurance coverage
The 1-year results of the current trial are expected in August, and the trial will continue for 2-=5 years, Dr. Shamanna said.
The company has started a clinical trial in the United States, with 5-year results expected in 2027.
“Currently, in the United States, we are partnering with self-insured employers and select health plans that offer [Twin Precision Treatment ] as an available benefit for their members,” Dr. Shah said. It “is suitable for most members living with type 2 diabetes, with rare exclusion situations.”
The study was funded by Twin Health. Dr. Shamanna, Dr. Shah, and Dr. Joshi are employees of Twin Health.
A version of this article first appeared on Medscape.com.
FROM ADA 2022
Methotrexate enhances pegloticase response in uncontrolled gout
In patients with uncontrolled gout, response rates were increased by 32% when methotrexate was used in conjunction with pegloticase versus pegloticase plus a placebo, it was reported at the annual European Congress of Rheumatology.
In the phase 4 MIRROR trial, 71% of patients who received pretreatment with methotrexate and then the combination of methotrexate and pegloticase achieved uric-acid levels lower than 6 mg/dL for more than 80% of the time during weeks 20-24 of the 52-week study. By comparison, only 39% of those treated with pegloticase plus a placebo achieved this primary endpoint (P < .0001).
“This trial confirms not only improved efficacy but improved safety in patients treated with pegloticase in combination with methotrexate 15 mg orally once weekly,” study investigator John K. Botson, MD, RPh, CCD, said in reporting the trial’s findings.
This is good news for patients, suggested two rheumatologists who were not involved in the study. The combination appears “useful for a select group of gout patients,” observed Christian Ammitzbøll, MD, PhD, from Aarhus University Hospital, Denmark.
“Very promising in refractory gout,” agreed Emre Bilgin, MD, from Ankara, Turkey.
Rationale for using methotrexate
“Oral urate lowering agents are the mainstay of treatment of gout, but there are patients that just don’t respond to oral agents,” said Dr. Botson, a rheumatologist in private practice from Anchorage, Alaska.
“These patients are very difficult to treat,” he added. “They have a lot of physical disabilities, they have high medical comorbidities, and they have a low quality of life. Their treatment options are extremely limited.”
One of the few options they have is pegloticase, a pegylated uric acid specific enzyme sold under the brand name Krystexxa for the past 12 years. It lowers serum uric acid by converting it to allantoin, which is more water soluble and thus is easier to excrete from the body.
However, one of the problems of using the drug is that anti-drug antibodies frequently develop, meaning that discontinuation rates can be as high as 50%, with around a quarter of patients at high risk of experiencing an infusion reaction.
“Methotrexate is a medication we’re very familiar with for other rheumatologic conditions that use biologic medications, and we use this to prevent anti-drug antibodies. So, the MIRROR RCT was a study we performed to examine the pegloticase therapy in combination with methotrexate co therapy,” explained Dr. Botson.
In fact, co-administration of methotrexate and pegloticase was associated with fewer infusion reactions than using pegloticase alone (3% vs. 31%).
Study design and results
A total of 152 patients were included in the trial and were treated with methotrexate at a weekly dose of 15 mg for 2 weeks before being randomized, 2:1, to either continue methotrexate and then receive intravenous pegloticase or receive the latter with a placebo. Pegloticase was given at a dose of 8 mg every 2 weeks. Treatment was for 52 weeks, with the primary endpoint of serum uric acid response tested at 6 months.
The reason for the 2-week run-in period with methotrexate was to check that patients would be able to tolerate it, Dr. Botson explained.
The mean age of patients was around 54 years, the majority (> 84%) were male and were White (69%). The average duration of gout was about 14 years, with over 74% having tophi present at screening and experiencing 10-11 flares in the previous year. Baseline serum uric acid averaged at about 9 mg/dL.
Almost three-quarters of the 100 patients (73%) who were treated with the combination completed treatment to week 24 while the corresponding percentage in the placebo arm (n = 52) was 39%. The main reason for stopping was due to lack of efficacy (27% and 61% of cases, respectively), defined as having serum uric acid levels above 6 mg/dL on two consecutive measurements.
The median time to discontinuation was 69 days for those in the placebo arm; “it was non-estimable” in the methotrexate arm, Dr. Botson reported.
The mean change in serum uric acid through to week 24 was higher in the methotrexate than placebo arm, at a respective 7.66 and 5.23 mg/dL, giving a significant mean difference of 2.43 mg/dL.
There was a “dramatic resolution of tophaceous deposits,” Dr. Botson said. Complete resolution of tophi was seen in 34.6% of methotrexate-treated patients versus 13.8% of pegloticase-placebo–treated patients (P = .043).
One of the most common adverse events associated with pegloticase treatment is gout flare, which occurred in about 70% of participants in both study arms. Overall, the addition of methotrexate did not increase the risk for adverse events in general, and of the two deaths seen in the study – both in methotrexate-treated patients – one was because of a heart attack and another due COVID-19, so they were unrelated to study treatment.
In patients with renal insufficiency
Concern was raised during the discussion, however, on how to handle methotrexate use in patients with renal insufficiency.
“That’s been a debate that we’ve had in this study and others,” said Dr. Botson, acknowledging that “methotrexate is often a concern for the nephrologist that we’re co-treating these patients with.” However, no dose adjustments were needed in the study.
“There are some other studies with other immunomodulators that do suggest that other agents could be used that may be a little less potentially renal toxic, but we didn’t see any toxicity in the patients that we had, even in those that had a reduced [glomerular filtration rate],” he added.
Dr. Botson has received research support from Horizon and Radius Health. He also acknowledged receiving speakers fees from AbbVie, Amgen, Aurinia, ChemoCentryx*, Horizon, Eli Lilly, and Novartis.
Correction, 6/7/22: The name of the company ChemoCentryx was misstated.
In patients with uncontrolled gout, response rates were increased by 32% when methotrexate was used in conjunction with pegloticase versus pegloticase plus a placebo, it was reported at the annual European Congress of Rheumatology.
In the phase 4 MIRROR trial, 71% of patients who received pretreatment with methotrexate and then the combination of methotrexate and pegloticase achieved uric-acid levels lower than 6 mg/dL for more than 80% of the time during weeks 20-24 of the 52-week study. By comparison, only 39% of those treated with pegloticase plus a placebo achieved this primary endpoint (P < .0001).
“This trial confirms not only improved efficacy but improved safety in patients treated with pegloticase in combination with methotrexate 15 mg orally once weekly,” study investigator John K. Botson, MD, RPh, CCD, said in reporting the trial’s findings.
This is good news for patients, suggested two rheumatologists who were not involved in the study. The combination appears “useful for a select group of gout patients,” observed Christian Ammitzbøll, MD, PhD, from Aarhus University Hospital, Denmark.
“Very promising in refractory gout,” agreed Emre Bilgin, MD, from Ankara, Turkey.
Rationale for using methotrexate
“Oral urate lowering agents are the mainstay of treatment of gout, but there are patients that just don’t respond to oral agents,” said Dr. Botson, a rheumatologist in private practice from Anchorage, Alaska.
“These patients are very difficult to treat,” he added. “They have a lot of physical disabilities, they have high medical comorbidities, and they have a low quality of life. Their treatment options are extremely limited.”
One of the few options they have is pegloticase, a pegylated uric acid specific enzyme sold under the brand name Krystexxa for the past 12 years. It lowers serum uric acid by converting it to allantoin, which is more water soluble and thus is easier to excrete from the body.
However, one of the problems of using the drug is that anti-drug antibodies frequently develop, meaning that discontinuation rates can be as high as 50%, with around a quarter of patients at high risk of experiencing an infusion reaction.
“Methotrexate is a medication we’re very familiar with for other rheumatologic conditions that use biologic medications, and we use this to prevent anti-drug antibodies. So, the MIRROR RCT was a study we performed to examine the pegloticase therapy in combination with methotrexate co therapy,” explained Dr. Botson.
In fact, co-administration of methotrexate and pegloticase was associated with fewer infusion reactions than using pegloticase alone (3% vs. 31%).
Study design and results
A total of 152 patients were included in the trial and were treated with methotrexate at a weekly dose of 15 mg for 2 weeks before being randomized, 2:1, to either continue methotrexate and then receive intravenous pegloticase or receive the latter with a placebo. Pegloticase was given at a dose of 8 mg every 2 weeks. Treatment was for 52 weeks, with the primary endpoint of serum uric acid response tested at 6 months.
The reason for the 2-week run-in period with methotrexate was to check that patients would be able to tolerate it, Dr. Botson explained.
The mean age of patients was around 54 years, the majority (> 84%) were male and were White (69%). The average duration of gout was about 14 years, with over 74% having tophi present at screening and experiencing 10-11 flares in the previous year. Baseline serum uric acid averaged at about 9 mg/dL.
Almost three-quarters of the 100 patients (73%) who were treated with the combination completed treatment to week 24 while the corresponding percentage in the placebo arm (n = 52) was 39%. The main reason for stopping was due to lack of efficacy (27% and 61% of cases, respectively), defined as having serum uric acid levels above 6 mg/dL on two consecutive measurements.
The median time to discontinuation was 69 days for those in the placebo arm; “it was non-estimable” in the methotrexate arm, Dr. Botson reported.
The mean change in serum uric acid through to week 24 was higher in the methotrexate than placebo arm, at a respective 7.66 and 5.23 mg/dL, giving a significant mean difference of 2.43 mg/dL.
There was a “dramatic resolution of tophaceous deposits,” Dr. Botson said. Complete resolution of tophi was seen in 34.6% of methotrexate-treated patients versus 13.8% of pegloticase-placebo–treated patients (P = .043).
One of the most common adverse events associated with pegloticase treatment is gout flare, which occurred in about 70% of participants in both study arms. Overall, the addition of methotrexate did not increase the risk for adverse events in general, and of the two deaths seen in the study – both in methotrexate-treated patients – one was because of a heart attack and another due COVID-19, so they were unrelated to study treatment.
In patients with renal insufficiency
Concern was raised during the discussion, however, on how to handle methotrexate use in patients with renal insufficiency.
“That’s been a debate that we’ve had in this study and others,” said Dr. Botson, acknowledging that “methotrexate is often a concern for the nephrologist that we’re co-treating these patients with.” However, no dose adjustments were needed in the study.
“There are some other studies with other immunomodulators that do suggest that other agents could be used that may be a little less potentially renal toxic, but we didn’t see any toxicity in the patients that we had, even in those that had a reduced [glomerular filtration rate],” he added.
Dr. Botson has received research support from Horizon and Radius Health. He also acknowledged receiving speakers fees from AbbVie, Amgen, Aurinia, ChemoCentryx*, Horizon, Eli Lilly, and Novartis.
Correction, 6/7/22: The name of the company ChemoCentryx was misstated.
In patients with uncontrolled gout, response rates were increased by 32% when methotrexate was used in conjunction with pegloticase versus pegloticase plus a placebo, it was reported at the annual European Congress of Rheumatology.
In the phase 4 MIRROR trial, 71% of patients who received pretreatment with methotrexate and then the combination of methotrexate and pegloticase achieved uric-acid levels lower than 6 mg/dL for more than 80% of the time during weeks 20-24 of the 52-week study. By comparison, only 39% of those treated with pegloticase plus a placebo achieved this primary endpoint (P < .0001).
“This trial confirms not only improved efficacy but improved safety in patients treated with pegloticase in combination with methotrexate 15 mg orally once weekly,” study investigator John K. Botson, MD, RPh, CCD, said in reporting the trial’s findings.
This is good news for patients, suggested two rheumatologists who were not involved in the study. The combination appears “useful for a select group of gout patients,” observed Christian Ammitzbøll, MD, PhD, from Aarhus University Hospital, Denmark.
“Very promising in refractory gout,” agreed Emre Bilgin, MD, from Ankara, Turkey.
Rationale for using methotrexate
“Oral urate lowering agents are the mainstay of treatment of gout, but there are patients that just don’t respond to oral agents,” said Dr. Botson, a rheumatologist in private practice from Anchorage, Alaska.
“These patients are very difficult to treat,” he added. “They have a lot of physical disabilities, they have high medical comorbidities, and they have a low quality of life. Their treatment options are extremely limited.”
One of the few options they have is pegloticase, a pegylated uric acid specific enzyme sold under the brand name Krystexxa for the past 12 years. It lowers serum uric acid by converting it to allantoin, which is more water soluble and thus is easier to excrete from the body.
However, one of the problems of using the drug is that anti-drug antibodies frequently develop, meaning that discontinuation rates can be as high as 50%, with around a quarter of patients at high risk of experiencing an infusion reaction.
“Methotrexate is a medication we’re very familiar with for other rheumatologic conditions that use biologic medications, and we use this to prevent anti-drug antibodies. So, the MIRROR RCT was a study we performed to examine the pegloticase therapy in combination with methotrexate co therapy,” explained Dr. Botson.
In fact, co-administration of methotrexate and pegloticase was associated with fewer infusion reactions than using pegloticase alone (3% vs. 31%).
Study design and results
A total of 152 patients were included in the trial and were treated with methotrexate at a weekly dose of 15 mg for 2 weeks before being randomized, 2:1, to either continue methotrexate and then receive intravenous pegloticase or receive the latter with a placebo. Pegloticase was given at a dose of 8 mg every 2 weeks. Treatment was for 52 weeks, with the primary endpoint of serum uric acid response tested at 6 months.
The reason for the 2-week run-in period with methotrexate was to check that patients would be able to tolerate it, Dr. Botson explained.
The mean age of patients was around 54 years, the majority (> 84%) were male and were White (69%). The average duration of gout was about 14 years, with over 74% having tophi present at screening and experiencing 10-11 flares in the previous year. Baseline serum uric acid averaged at about 9 mg/dL.
Almost three-quarters of the 100 patients (73%) who were treated with the combination completed treatment to week 24 while the corresponding percentage in the placebo arm (n = 52) was 39%. The main reason for stopping was due to lack of efficacy (27% and 61% of cases, respectively), defined as having serum uric acid levels above 6 mg/dL on two consecutive measurements.
The median time to discontinuation was 69 days for those in the placebo arm; “it was non-estimable” in the methotrexate arm, Dr. Botson reported.
The mean change in serum uric acid through to week 24 was higher in the methotrexate than placebo arm, at a respective 7.66 and 5.23 mg/dL, giving a significant mean difference of 2.43 mg/dL.
There was a “dramatic resolution of tophaceous deposits,” Dr. Botson said. Complete resolution of tophi was seen in 34.6% of methotrexate-treated patients versus 13.8% of pegloticase-placebo–treated patients (P = .043).
One of the most common adverse events associated with pegloticase treatment is gout flare, which occurred in about 70% of participants in both study arms. Overall, the addition of methotrexate did not increase the risk for adverse events in general, and of the two deaths seen in the study – both in methotrexate-treated patients – one was because of a heart attack and another due COVID-19, so they were unrelated to study treatment.
In patients with renal insufficiency
Concern was raised during the discussion, however, on how to handle methotrexate use in patients with renal insufficiency.
“That’s been a debate that we’ve had in this study and others,” said Dr. Botson, acknowledging that “methotrexate is often a concern for the nephrologist that we’re co-treating these patients with.” However, no dose adjustments were needed in the study.
“There are some other studies with other immunomodulators that do suggest that other agents could be used that may be a little less potentially renal toxic, but we didn’t see any toxicity in the patients that we had, even in those that had a reduced [glomerular filtration rate],” he added.
Dr. Botson has received research support from Horizon and Radius Health. He also acknowledged receiving speakers fees from AbbVie, Amgen, Aurinia, ChemoCentryx*, Horizon, Eli Lilly, and Novartis.
Correction, 6/7/22: The name of the company ChemoCentryx was misstated.
FROM THE EULAR 2022 CONGRESS
MS and COVID-19: Conflicting signs on risk but some trends are clearer
NATIONAL HARBOR, MD. – While patients with multiple sclerosis (MS) don’t seem to be more likely to be infected with COVID-19, a neurologist told colleagues, the jury is still out over whether they face a higher mortality risk, especially if they take certain disease-modifying therapies (DMTs)
In regard to MS overall, “the data is conflicting, but any increased risk of mortality appears to be slight. And it appears to be chiefly the consequences associated with comorbidities as seen in other populations,” Joseph R. Berger, MD, said at the John F. Kurtzke Memorial Lecture at the annual meeting of the Consortium of Multiple Sclerosis Centers. “If you’re old, if you’re infirm, if you have obesity and cardiovascular disease and underlying pulmonary disease, you’re at risk of dying yourself. It’s not so much the MS,” said Dr. Berger, professor of neurology at the Hospital of the University of Pennsylvania and chief of the multiple sclerosis division at the University of Pennsylvania, Philadelphia.
Dr. Berger had his own COVID-19 story to tell: He couldn’t attend the conference in person because he was quarantining in Portugal since he tested positive. At press time, he was faring well but had reported 4 days of intense back pain.
In regard to MS and COVID-19, Dr. Berger said consistent research suggests that There may be a very small increase in risk of MS relapse in patients with COVID-19, he said, but pseudorelapses are far more common. As for mortality, he highlighted a 2021 pooled analysis of 18 studies with 5,634 patients that suggested they had a crude death rate of 1.97%, standardized lethality ratio of 1.24, and a 24% increased risk of death.
Dr. Berger is skeptical of these findings, however, in light of overall death rate numbers. Early on in the pandemic, the fatality rate in China was estimated at 2.3%.
He said he’s more convinced by a retrospective 2021 German COVID-19 study that compared 551 patients with MS to 156,973 other patients and found lower rates of ICU admission (17.1% in patients with MS vs. 22.7% in those without it), ventilation (9.8% vs. 14.5%), and in‐hospital mortality (11.1% vs. 19.3%).
Meanwhile, a 2021 systematic review found no increase in mortality among 4,310 patients with MS (3% death rate, 20.7% hospitalization), but the death risk was highest among those on no DMTs and those taking anti-CD20 monoclonal antibodies. The COViMS Registry has reported similar findings regarding the anti-CD20 drugs rituximab and ocrelizumab, Dr. Berger noted, and a pooled study of Italian and French data links the monoclonal antibodies to more severe COVID. A 2021 aggregated study also linked the antibodies to increased risk of hospitalization and ICU admission.
“Anti-CD20 monoclonal antibodies appear to increase the risk of hospitalization and perhaps the acquisition of the virus, ICU admission, maybe death,” he said, with rituximab appearing to pose the most risk, followed by ocrelizumab and ofatumumab. “And it appears that the platform [older] therapies may be associated with lesser mortality.”
As for nondrug factors, Dr. Berger said, studies have linked higher risk to age, male sex, and comorbidities.
COVID-19 vaccines are another area of concern, he said. “The recommendation is to administer vaccination prior to the initiation of the anti-CD20s, alemtuzumab, and cladribine, and wait a period of time. Three months is ideal, maybe a little longer, because it appears that the antibody response seems to be best as your CD19 count starts to return.”
Finally, Dr. Berger noted that “passive vaccination” is now available via Evusheld (tixagevimab and cilgavimab) as a preexposure treatment for people with moderate to severe immune compromise who may not mount an effective immune response to COVID-19 vaccination or those who are allergic.
Dr. Berger reported multiple disclosures.
NATIONAL HARBOR, MD. – While patients with multiple sclerosis (MS) don’t seem to be more likely to be infected with COVID-19, a neurologist told colleagues, the jury is still out over whether they face a higher mortality risk, especially if they take certain disease-modifying therapies (DMTs)
In regard to MS overall, “the data is conflicting, but any increased risk of mortality appears to be slight. And it appears to be chiefly the consequences associated with comorbidities as seen in other populations,” Joseph R. Berger, MD, said at the John F. Kurtzke Memorial Lecture at the annual meeting of the Consortium of Multiple Sclerosis Centers. “If you’re old, if you’re infirm, if you have obesity and cardiovascular disease and underlying pulmonary disease, you’re at risk of dying yourself. It’s not so much the MS,” said Dr. Berger, professor of neurology at the Hospital of the University of Pennsylvania and chief of the multiple sclerosis division at the University of Pennsylvania, Philadelphia.
Dr. Berger had his own COVID-19 story to tell: He couldn’t attend the conference in person because he was quarantining in Portugal since he tested positive. At press time, he was faring well but had reported 4 days of intense back pain.
In regard to MS and COVID-19, Dr. Berger said consistent research suggests that There may be a very small increase in risk of MS relapse in patients with COVID-19, he said, but pseudorelapses are far more common. As for mortality, he highlighted a 2021 pooled analysis of 18 studies with 5,634 patients that suggested they had a crude death rate of 1.97%, standardized lethality ratio of 1.24, and a 24% increased risk of death.
Dr. Berger is skeptical of these findings, however, in light of overall death rate numbers. Early on in the pandemic, the fatality rate in China was estimated at 2.3%.
He said he’s more convinced by a retrospective 2021 German COVID-19 study that compared 551 patients with MS to 156,973 other patients and found lower rates of ICU admission (17.1% in patients with MS vs. 22.7% in those without it), ventilation (9.8% vs. 14.5%), and in‐hospital mortality (11.1% vs. 19.3%).
Meanwhile, a 2021 systematic review found no increase in mortality among 4,310 patients with MS (3% death rate, 20.7% hospitalization), but the death risk was highest among those on no DMTs and those taking anti-CD20 monoclonal antibodies. The COViMS Registry has reported similar findings regarding the anti-CD20 drugs rituximab and ocrelizumab, Dr. Berger noted, and a pooled study of Italian and French data links the monoclonal antibodies to more severe COVID. A 2021 aggregated study also linked the antibodies to increased risk of hospitalization and ICU admission.
“Anti-CD20 monoclonal antibodies appear to increase the risk of hospitalization and perhaps the acquisition of the virus, ICU admission, maybe death,” he said, with rituximab appearing to pose the most risk, followed by ocrelizumab and ofatumumab. “And it appears that the platform [older] therapies may be associated with lesser mortality.”
As for nondrug factors, Dr. Berger said, studies have linked higher risk to age, male sex, and comorbidities.
COVID-19 vaccines are another area of concern, he said. “The recommendation is to administer vaccination prior to the initiation of the anti-CD20s, alemtuzumab, and cladribine, and wait a period of time. Three months is ideal, maybe a little longer, because it appears that the antibody response seems to be best as your CD19 count starts to return.”
Finally, Dr. Berger noted that “passive vaccination” is now available via Evusheld (tixagevimab and cilgavimab) as a preexposure treatment for people with moderate to severe immune compromise who may not mount an effective immune response to COVID-19 vaccination or those who are allergic.
Dr. Berger reported multiple disclosures.
NATIONAL HARBOR, MD. – While patients with multiple sclerosis (MS) don’t seem to be more likely to be infected with COVID-19, a neurologist told colleagues, the jury is still out over whether they face a higher mortality risk, especially if they take certain disease-modifying therapies (DMTs)
In regard to MS overall, “the data is conflicting, but any increased risk of mortality appears to be slight. And it appears to be chiefly the consequences associated with comorbidities as seen in other populations,” Joseph R. Berger, MD, said at the John F. Kurtzke Memorial Lecture at the annual meeting of the Consortium of Multiple Sclerosis Centers. “If you’re old, if you’re infirm, if you have obesity and cardiovascular disease and underlying pulmonary disease, you’re at risk of dying yourself. It’s not so much the MS,” said Dr. Berger, professor of neurology at the Hospital of the University of Pennsylvania and chief of the multiple sclerosis division at the University of Pennsylvania, Philadelphia.
Dr. Berger had his own COVID-19 story to tell: He couldn’t attend the conference in person because he was quarantining in Portugal since he tested positive. At press time, he was faring well but had reported 4 days of intense back pain.
In regard to MS and COVID-19, Dr. Berger said consistent research suggests that There may be a very small increase in risk of MS relapse in patients with COVID-19, he said, but pseudorelapses are far more common. As for mortality, he highlighted a 2021 pooled analysis of 18 studies with 5,634 patients that suggested they had a crude death rate of 1.97%, standardized lethality ratio of 1.24, and a 24% increased risk of death.
Dr. Berger is skeptical of these findings, however, in light of overall death rate numbers. Early on in the pandemic, the fatality rate in China was estimated at 2.3%.
He said he’s more convinced by a retrospective 2021 German COVID-19 study that compared 551 patients with MS to 156,973 other patients and found lower rates of ICU admission (17.1% in patients with MS vs. 22.7% in those without it), ventilation (9.8% vs. 14.5%), and in‐hospital mortality (11.1% vs. 19.3%).
Meanwhile, a 2021 systematic review found no increase in mortality among 4,310 patients with MS (3% death rate, 20.7% hospitalization), but the death risk was highest among those on no DMTs and those taking anti-CD20 monoclonal antibodies. The COViMS Registry has reported similar findings regarding the anti-CD20 drugs rituximab and ocrelizumab, Dr. Berger noted, and a pooled study of Italian and French data links the monoclonal antibodies to more severe COVID. A 2021 aggregated study also linked the antibodies to increased risk of hospitalization and ICU admission.
“Anti-CD20 monoclonal antibodies appear to increase the risk of hospitalization and perhaps the acquisition of the virus, ICU admission, maybe death,” he said, with rituximab appearing to pose the most risk, followed by ocrelizumab and ofatumumab. “And it appears that the platform [older] therapies may be associated with lesser mortality.”
As for nondrug factors, Dr. Berger said, studies have linked higher risk to age, male sex, and comorbidities.
COVID-19 vaccines are another area of concern, he said. “The recommendation is to administer vaccination prior to the initiation of the anti-CD20s, alemtuzumab, and cladribine, and wait a period of time. Three months is ideal, maybe a little longer, because it appears that the antibody response seems to be best as your CD19 count starts to return.”
Finally, Dr. Berger noted that “passive vaccination” is now available via Evusheld (tixagevimab and cilgavimab) as a preexposure treatment for people with moderate to severe immune compromise who may not mount an effective immune response to COVID-19 vaccination or those who are allergic.
Dr. Berger reported multiple disclosures.
AT CMSC 2022
Pseudocirrhosis in breast cancer may signal liver metastases
CHICAGO – Pseudocirrhosis appears radiographically similar to cirrhosis, but lacks its classic pathologic features.
The study is the largest cohort of patients with pseudocirrhosis studied to date. “It provides important clinical information about the natural history of this condition to help oncologists better understand which patients develop this condition and what complications are most common. Interestingly, we found that patients who developed ascites had a worse overall survival than patients who did not develop ascites, which was not previously reported,” said Laura Huppert, MD, who presented the findings during a poster session at the annual meeting of the American Society of Clinical Oncology.
Pseudocirrhosis is commonly found in patients with metastatic breast cancer and can lead to ascites and varices, among other complications. “These problems can be quite debilitating and even life-threatening for our patients. In order to better diagnose and treat our patients with pseudocirrhosis, we first wanted to understand the natural history of this condition, including which patients develop it, what treatments they have received, and what complications are most frequent,” said Dr. Huppert, MD, who is a hematology/oncology fellow at the University of California, San Francisco.
The study was retrospective, making it impossible to determine causality. “It is possible that the biology of HR+ disease predisposes patients to the development of pseudocirrhosis through mechanisms that are not yet elucidated. Alternatively, this may be due to the fact that patients with HR+ disease tend to have longer survival and are on systemic therapy for longer periods of time, allowing more time for pseudocirrhosis to develop in response to systemic therapy,” Dr. Huppert said.
In future work, Dr. Huppert plans to examine a control arm of patients with liver disease who do not develop pseudocirrhosis to gain a better understanding of factors that might cause the condition. She also hopes to work with hepatologists to determine if new antifibrosis agents might be applicable to pseudocirrhosis. “There may be interesting things we can learn from other disease states and apply to this condition,” she said.
The researchers analyzed data from 120 patients with pseudocirrhosis. 82.5% of patients were HR+/HER2–, 11.7% were HR+/HER2+, 2.5% were HR–/HER2+, and 3.3% were triple negative. Liver metastases were present in all patients, and 82.5% had more than 15 liver lesions.
A total of 92.5% of patients had previously undergone chemotherapy before pseudocirrhosis was identified, and the median time to diagnosis of pseudocirrhosis after diagnosis of liver metastases was 18.7 months. 50% of patients with pseudocirrhosis had stable or responding disease. After pseudocirrhosis diagnosis, patients underwent a median of 1.0 additional lines of therapy, and the median overall survival following pseudocirrhosis diagnosis was 7.9 months. A total of 80.8% of patients went on to be diagnosed with ascites, 17.5% with esophageal varices, 21.7% with splenomegaly, 10.0% with gastrointestinal bleeding, and 9.2% with hepatic encephalopathy.
Patients with radiographic evidence of ascites survived an average of 42.8 months after metastatic breast cancer diagnosis, while those without ascites survived an average of 76.2 months (P < .001).
Specialty care was rare: Just 7.5% of patients received a GI/hepatology consultation.
Dr. Huppert has no relevant financial disclosures.
CHICAGO – Pseudocirrhosis appears radiographically similar to cirrhosis, but lacks its classic pathologic features.
The study is the largest cohort of patients with pseudocirrhosis studied to date. “It provides important clinical information about the natural history of this condition to help oncologists better understand which patients develop this condition and what complications are most common. Interestingly, we found that patients who developed ascites had a worse overall survival than patients who did not develop ascites, which was not previously reported,” said Laura Huppert, MD, who presented the findings during a poster session at the annual meeting of the American Society of Clinical Oncology.
Pseudocirrhosis is commonly found in patients with metastatic breast cancer and can lead to ascites and varices, among other complications. “These problems can be quite debilitating and even life-threatening for our patients. In order to better diagnose and treat our patients with pseudocirrhosis, we first wanted to understand the natural history of this condition, including which patients develop it, what treatments they have received, and what complications are most frequent,” said Dr. Huppert, MD, who is a hematology/oncology fellow at the University of California, San Francisco.
The study was retrospective, making it impossible to determine causality. “It is possible that the biology of HR+ disease predisposes patients to the development of pseudocirrhosis through mechanisms that are not yet elucidated. Alternatively, this may be due to the fact that patients with HR+ disease tend to have longer survival and are on systemic therapy for longer periods of time, allowing more time for pseudocirrhosis to develop in response to systemic therapy,” Dr. Huppert said.
In future work, Dr. Huppert plans to examine a control arm of patients with liver disease who do not develop pseudocirrhosis to gain a better understanding of factors that might cause the condition. She also hopes to work with hepatologists to determine if new antifibrosis agents might be applicable to pseudocirrhosis. “There may be interesting things we can learn from other disease states and apply to this condition,” she said.
The researchers analyzed data from 120 patients with pseudocirrhosis. 82.5% of patients were HR+/HER2–, 11.7% were HR+/HER2+, 2.5% were HR–/HER2+, and 3.3% were triple negative. Liver metastases were present in all patients, and 82.5% had more than 15 liver lesions.
A total of 92.5% of patients had previously undergone chemotherapy before pseudocirrhosis was identified, and the median time to diagnosis of pseudocirrhosis after diagnosis of liver metastases was 18.7 months. 50% of patients with pseudocirrhosis had stable or responding disease. After pseudocirrhosis diagnosis, patients underwent a median of 1.0 additional lines of therapy, and the median overall survival following pseudocirrhosis diagnosis was 7.9 months. A total of 80.8% of patients went on to be diagnosed with ascites, 17.5% with esophageal varices, 21.7% with splenomegaly, 10.0% with gastrointestinal bleeding, and 9.2% with hepatic encephalopathy.
Patients with radiographic evidence of ascites survived an average of 42.8 months after metastatic breast cancer diagnosis, while those without ascites survived an average of 76.2 months (P < .001).
Specialty care was rare: Just 7.5% of patients received a GI/hepatology consultation.
Dr. Huppert has no relevant financial disclosures.
CHICAGO – Pseudocirrhosis appears radiographically similar to cirrhosis, but lacks its classic pathologic features.
The study is the largest cohort of patients with pseudocirrhosis studied to date. “It provides important clinical information about the natural history of this condition to help oncologists better understand which patients develop this condition and what complications are most common. Interestingly, we found that patients who developed ascites had a worse overall survival than patients who did not develop ascites, which was not previously reported,” said Laura Huppert, MD, who presented the findings during a poster session at the annual meeting of the American Society of Clinical Oncology.
Pseudocirrhosis is commonly found in patients with metastatic breast cancer and can lead to ascites and varices, among other complications. “These problems can be quite debilitating and even life-threatening for our patients. In order to better diagnose and treat our patients with pseudocirrhosis, we first wanted to understand the natural history of this condition, including which patients develop it, what treatments they have received, and what complications are most frequent,” said Dr. Huppert, MD, who is a hematology/oncology fellow at the University of California, San Francisco.
The study was retrospective, making it impossible to determine causality. “It is possible that the biology of HR+ disease predisposes patients to the development of pseudocirrhosis through mechanisms that are not yet elucidated. Alternatively, this may be due to the fact that patients with HR+ disease tend to have longer survival and are on systemic therapy for longer periods of time, allowing more time for pseudocirrhosis to develop in response to systemic therapy,” Dr. Huppert said.
In future work, Dr. Huppert plans to examine a control arm of patients with liver disease who do not develop pseudocirrhosis to gain a better understanding of factors that might cause the condition. She also hopes to work with hepatologists to determine if new antifibrosis agents might be applicable to pseudocirrhosis. “There may be interesting things we can learn from other disease states and apply to this condition,” she said.
The researchers analyzed data from 120 patients with pseudocirrhosis. 82.5% of patients were HR+/HER2–, 11.7% were HR+/HER2+, 2.5% were HR–/HER2+, and 3.3% were triple negative. Liver metastases were present in all patients, and 82.5% had more than 15 liver lesions.
A total of 92.5% of patients had previously undergone chemotherapy before pseudocirrhosis was identified, and the median time to diagnosis of pseudocirrhosis after diagnosis of liver metastases was 18.7 months. 50% of patients with pseudocirrhosis had stable or responding disease. After pseudocirrhosis diagnosis, patients underwent a median of 1.0 additional lines of therapy, and the median overall survival following pseudocirrhosis diagnosis was 7.9 months. A total of 80.8% of patients went on to be diagnosed with ascites, 17.5% with esophageal varices, 21.7% with splenomegaly, 10.0% with gastrointestinal bleeding, and 9.2% with hepatic encephalopathy.
Patients with radiographic evidence of ascites survived an average of 42.8 months after metastatic breast cancer diagnosis, while those without ascites survived an average of 76.2 months (P < .001).
Specialty care was rare: Just 7.5% of patients received a GI/hepatology consultation.
Dr. Huppert has no relevant financial disclosures.
AT ASCO 2022
Excess weight may ward off infection in breast cancer treatment
– a potentially deadly outcome that can occur as a result of chemotherapy treatment.
The study was presented at the annual meeting of the American Society of Clinical Oncology.
It is known that body mass index can affect breast cancer risk and prognosis, but it is not known if BMI can affect how well endocrine therapy works in a given patient. In the PALLAS clinical trial, Georg Pfeiler, MD, Medical University of Vienna, and colleagues, conducted an analysis of 5,698 patients with early hormone receptor–positive breast cancer receiving endocrine therapy with or without palbociclib. Dr. Pfeiler found that women who are overweight or obese had significantly less frequent and less severe cases of neutropenia. With fewer or less severe cases of neutropenia, there were also fewer interruptions in palbociclib treatment.
“One explanation for the lower discontinuation rates may be that the distributional volume of the drug is higher in overweight and obese patients leading to lower serum drug concentrations. It could also be influenced by differences in pharmacokinetics with respect to hyperinsulinemia,” said Dr. Pfeiler, who leads the Oncological Breast Outpatient Clinic and Bone Health Outpatient Clinic at the Medical University of Vienna.
The PALLAS trial compared the combination of palbociclib and adjuvant endocrine therapy with endocrine therapy alone in 5,698 women with early breast cancer. Patients were categorized according to BMI as underweight (BMI < 18.5 kg/m2), normal weight (BMI 18.5-24.9), overweight (BMI, 25-29.9), and obese (> 30). The investigators analyzed differences in adverse events, time to early discontinuation of palbociclib, and in time to invasive disease-free survival.
At baseline, of 5,698 patients, 68 (1.2%) were underweight, 2,082 (36.5%) were of normal weight, 1,818 (31.9%) were overweight, and, 1,730 (30.4%) were obese. In patients treated with palbociclib, neutropenia was the primary toxicity leading to treatment discontinuation with rates of 21.1% in normal-weight patients, 14.0% of overweight patients, and 5.9% of obese patients, respectively.
Significantly different rates of all-grade neutropenia were observed in normal weight, overweight, and obese participants with regard to total (88.5%, 85.7% and 74.7%), as well as grade 3 (64.1%, 62.0% and 43.9%) and grade 4 neutropenia (7.0%, 3.6% and 2.0%), respectively. The lower frequency and severity of neutropenia observed in overweight and obese patients was associated with a significantly lower treatment discontinuation rate over time when compared with normal-weight patients (overweight vs. normal weight: HR, 0.73; 95% CI 0.63-0.84; P < .0001, and obese vs. normal weight: HR, 0.65; 95% CI, 0.56-0.75; P < .0001). There was, however, despite these observations, no statistically significant improvement in invasive disease survival with the addition of palbociclib to endocrine therapy in any weight category (normal weight: HR, 0.84; 95% CI 0.63-1.12; overweight: HR, 1.10; 95% CI 0.82-1.49; and obese: HR, 0.95; 95% CI, 0.69-1.30).
“This is an early analysis, and should be interpreted with caution, especially with regard to disease outcomes. The findings may reduce concerns over hematologic side effects in the overweight and obese. In the future there may be an important impact if it turns out after longer-term follow-up that palbociclib has been underdosed in the overweight and obese. We may need BMI-adapted dose management,” said Dr. Pfeiler, who is currently working on a longer-term follow-up study of the PALLAS group.
The analysis found no significant correlation between weight and occurrence of invasive disease events.
Dr. Pfeiler disclosed honoraria and grants from Pfizer. The study was funded by Alliance Foundation Trials.
– a potentially deadly outcome that can occur as a result of chemotherapy treatment.
The study was presented at the annual meeting of the American Society of Clinical Oncology.
It is known that body mass index can affect breast cancer risk and prognosis, but it is not known if BMI can affect how well endocrine therapy works in a given patient. In the PALLAS clinical trial, Georg Pfeiler, MD, Medical University of Vienna, and colleagues, conducted an analysis of 5,698 patients with early hormone receptor–positive breast cancer receiving endocrine therapy with or without palbociclib. Dr. Pfeiler found that women who are overweight or obese had significantly less frequent and less severe cases of neutropenia. With fewer or less severe cases of neutropenia, there were also fewer interruptions in palbociclib treatment.
“One explanation for the lower discontinuation rates may be that the distributional volume of the drug is higher in overweight and obese patients leading to lower serum drug concentrations. It could also be influenced by differences in pharmacokinetics with respect to hyperinsulinemia,” said Dr. Pfeiler, who leads the Oncological Breast Outpatient Clinic and Bone Health Outpatient Clinic at the Medical University of Vienna.
The PALLAS trial compared the combination of palbociclib and adjuvant endocrine therapy with endocrine therapy alone in 5,698 women with early breast cancer. Patients were categorized according to BMI as underweight (BMI < 18.5 kg/m2), normal weight (BMI 18.5-24.9), overweight (BMI, 25-29.9), and obese (> 30). The investigators analyzed differences in adverse events, time to early discontinuation of palbociclib, and in time to invasive disease-free survival.
At baseline, of 5,698 patients, 68 (1.2%) were underweight, 2,082 (36.5%) were of normal weight, 1,818 (31.9%) were overweight, and, 1,730 (30.4%) were obese. In patients treated with palbociclib, neutropenia was the primary toxicity leading to treatment discontinuation with rates of 21.1% in normal-weight patients, 14.0% of overweight patients, and 5.9% of obese patients, respectively.
Significantly different rates of all-grade neutropenia were observed in normal weight, overweight, and obese participants with regard to total (88.5%, 85.7% and 74.7%), as well as grade 3 (64.1%, 62.0% and 43.9%) and grade 4 neutropenia (7.0%, 3.6% and 2.0%), respectively. The lower frequency and severity of neutropenia observed in overweight and obese patients was associated with a significantly lower treatment discontinuation rate over time when compared with normal-weight patients (overweight vs. normal weight: HR, 0.73; 95% CI 0.63-0.84; P < .0001, and obese vs. normal weight: HR, 0.65; 95% CI, 0.56-0.75; P < .0001). There was, however, despite these observations, no statistically significant improvement in invasive disease survival with the addition of palbociclib to endocrine therapy in any weight category (normal weight: HR, 0.84; 95% CI 0.63-1.12; overweight: HR, 1.10; 95% CI 0.82-1.49; and obese: HR, 0.95; 95% CI, 0.69-1.30).
“This is an early analysis, and should be interpreted with caution, especially with regard to disease outcomes. The findings may reduce concerns over hematologic side effects in the overweight and obese. In the future there may be an important impact if it turns out after longer-term follow-up that palbociclib has been underdosed in the overweight and obese. We may need BMI-adapted dose management,” said Dr. Pfeiler, who is currently working on a longer-term follow-up study of the PALLAS group.
The analysis found no significant correlation between weight and occurrence of invasive disease events.
Dr. Pfeiler disclosed honoraria and grants from Pfizer. The study was funded by Alliance Foundation Trials.
– a potentially deadly outcome that can occur as a result of chemotherapy treatment.
The study was presented at the annual meeting of the American Society of Clinical Oncology.
It is known that body mass index can affect breast cancer risk and prognosis, but it is not known if BMI can affect how well endocrine therapy works in a given patient. In the PALLAS clinical trial, Georg Pfeiler, MD, Medical University of Vienna, and colleagues, conducted an analysis of 5,698 patients with early hormone receptor–positive breast cancer receiving endocrine therapy with or without palbociclib. Dr. Pfeiler found that women who are overweight or obese had significantly less frequent and less severe cases of neutropenia. With fewer or less severe cases of neutropenia, there were also fewer interruptions in palbociclib treatment.
“One explanation for the lower discontinuation rates may be that the distributional volume of the drug is higher in overweight and obese patients leading to lower serum drug concentrations. It could also be influenced by differences in pharmacokinetics with respect to hyperinsulinemia,” said Dr. Pfeiler, who leads the Oncological Breast Outpatient Clinic and Bone Health Outpatient Clinic at the Medical University of Vienna.
The PALLAS trial compared the combination of palbociclib and adjuvant endocrine therapy with endocrine therapy alone in 5,698 women with early breast cancer. Patients were categorized according to BMI as underweight (BMI < 18.5 kg/m2), normal weight (BMI 18.5-24.9), overweight (BMI, 25-29.9), and obese (> 30). The investigators analyzed differences in adverse events, time to early discontinuation of palbociclib, and in time to invasive disease-free survival.
At baseline, of 5,698 patients, 68 (1.2%) were underweight, 2,082 (36.5%) were of normal weight, 1,818 (31.9%) were overweight, and, 1,730 (30.4%) were obese. In patients treated with palbociclib, neutropenia was the primary toxicity leading to treatment discontinuation with rates of 21.1% in normal-weight patients, 14.0% of overweight patients, and 5.9% of obese patients, respectively.
Significantly different rates of all-grade neutropenia were observed in normal weight, overweight, and obese participants with regard to total (88.5%, 85.7% and 74.7%), as well as grade 3 (64.1%, 62.0% and 43.9%) and grade 4 neutropenia (7.0%, 3.6% and 2.0%), respectively. The lower frequency and severity of neutropenia observed in overweight and obese patients was associated with a significantly lower treatment discontinuation rate over time when compared with normal-weight patients (overweight vs. normal weight: HR, 0.73; 95% CI 0.63-0.84; P < .0001, and obese vs. normal weight: HR, 0.65; 95% CI, 0.56-0.75; P < .0001). There was, however, despite these observations, no statistically significant improvement in invasive disease survival with the addition of palbociclib to endocrine therapy in any weight category (normal weight: HR, 0.84; 95% CI 0.63-1.12; overweight: HR, 1.10; 95% CI 0.82-1.49; and obese: HR, 0.95; 95% CI, 0.69-1.30).
“This is an early analysis, and should be interpreted with caution, especially with regard to disease outcomes. The findings may reduce concerns over hematologic side effects in the overweight and obese. In the future there may be an important impact if it turns out after longer-term follow-up that palbociclib has been underdosed in the overweight and obese. We may need BMI-adapted dose management,” said Dr. Pfeiler, who is currently working on a longer-term follow-up study of the PALLAS group.
The analysis found no significant correlation between weight and occurrence of invasive disease events.
Dr. Pfeiler disclosed honoraria and grants from Pfizer. The study was funded by Alliance Foundation Trials.
FROM ASCO 2022
Women with HER2+ metastatic breast cancer are living longer
When a patient first presents to a doctor with signs and symptoms of having breast cancer that has metastasized to other parts of the body, the prospects of long-term survival are dim. But now, a new study presented at the annual meeting of the American Society of Clinical Oncology suggests that women with metastatic HER2+ breast cancer are generally living longer, compared with women treated in previous years.
Between 2010 and 2018, the overall survival for 5,576 women (99% women) with HER2+ metastatic breast cancer enrolled in this study improved 5.6% each year of the study. The study also showed a 6.4% improvement in breast cancer–specific death rates year over year.
“These highlights coincide with significant therapeutic advances for HER2+ metastatic breast cancer over the past decade. We need to continue our research efforts to identify better treatments for our patients so we can continue to improve the prognosis of these patients,” said study author Jose Pablo Leone, MD, a medical oncologist with Dana-Farber Cancer Institute, Boston.
The study, which is based on an evaluation of data from the Surveillance, Epidemiology and End Results database, found factors associated with shorter survival included older age, Black race, lower income, and the presence of visceral or brain metastases. Long-term survival of more than 5 years was associated with younger age, White race, and higher income, but also having fewer metastatic sites and estrogen receptor (ER)/progesterone receptor (PR) positivity.
“We also found specific factors that were only associated with shorter overall survival, such as the presence of metastases in the brain, liver, or lung. The lack of metastasis in these sites was not associated with longer overall survival. In contrast, a lower number of metastatic sites, regardless of the location of those sites were associated with longer overall survival but not short-term survival,” Dr. Leone said.
A total of 63.3% of patients in the study survived less than 2 years while 37.8% lived 5 years or more, and 26.8% lived longer than 8 years. Factors associated with less than 2 years in overall survival were older age (odds ratio, 3.76), Black race (OR 1.5), nonductal nonlobular (OR, 4.64), brain metastases (OR, 2.95), liver metastases (OR, 1.98), lung metastases (OR, 1.56), ER/PR negativity (OR, 1.74), and lower income (OR, 1.62). Factors associated with longer survival of 5 years or more included younger age (OR, 2.85), White race (OR, 1.7), fewer metastatic organ sites (OR, 2.6), ER/PR positivity (OR, 1.27), and higher income (OR, 3.31).
Dr. Leone said that, while involvement of specific visceral sites (brain, liver, lung) was associated with shorter overall survival, the odds of living longer than 5 years was not associated with those sites. In contrast, the number of sites was associated with longer overall survival, but not shorter overall survival regardless of location. “While fewer number of metastatic sites were associated with higher odds of overall survival greater than 5 years, the number of metastatic sites was not associated with the odds of overall survival of being less than 2 years,” he said.
A limitation of the study included the retrospective nature of the study. “Treatment data are unavailable, so we cannot quantify the impact of various treatments on the odds of survival,” Dr. Leone said.
This study was not funded.
When a patient first presents to a doctor with signs and symptoms of having breast cancer that has metastasized to other parts of the body, the prospects of long-term survival are dim. But now, a new study presented at the annual meeting of the American Society of Clinical Oncology suggests that women with metastatic HER2+ breast cancer are generally living longer, compared with women treated in previous years.
Between 2010 and 2018, the overall survival for 5,576 women (99% women) with HER2+ metastatic breast cancer enrolled in this study improved 5.6% each year of the study. The study also showed a 6.4% improvement in breast cancer–specific death rates year over year.
“These highlights coincide with significant therapeutic advances for HER2+ metastatic breast cancer over the past decade. We need to continue our research efforts to identify better treatments for our patients so we can continue to improve the prognosis of these patients,” said study author Jose Pablo Leone, MD, a medical oncologist with Dana-Farber Cancer Institute, Boston.
The study, which is based on an evaluation of data from the Surveillance, Epidemiology and End Results database, found factors associated with shorter survival included older age, Black race, lower income, and the presence of visceral or brain metastases. Long-term survival of more than 5 years was associated with younger age, White race, and higher income, but also having fewer metastatic sites and estrogen receptor (ER)/progesterone receptor (PR) positivity.
“We also found specific factors that were only associated with shorter overall survival, such as the presence of metastases in the brain, liver, or lung. The lack of metastasis in these sites was not associated with longer overall survival. In contrast, a lower number of metastatic sites, regardless of the location of those sites were associated with longer overall survival but not short-term survival,” Dr. Leone said.
A total of 63.3% of patients in the study survived less than 2 years while 37.8% lived 5 years or more, and 26.8% lived longer than 8 years. Factors associated with less than 2 years in overall survival were older age (odds ratio, 3.76), Black race (OR 1.5), nonductal nonlobular (OR, 4.64), brain metastases (OR, 2.95), liver metastases (OR, 1.98), lung metastases (OR, 1.56), ER/PR negativity (OR, 1.74), and lower income (OR, 1.62). Factors associated with longer survival of 5 years or more included younger age (OR, 2.85), White race (OR, 1.7), fewer metastatic organ sites (OR, 2.6), ER/PR positivity (OR, 1.27), and higher income (OR, 3.31).
Dr. Leone said that, while involvement of specific visceral sites (brain, liver, lung) was associated with shorter overall survival, the odds of living longer than 5 years was not associated with those sites. In contrast, the number of sites was associated with longer overall survival, but not shorter overall survival regardless of location. “While fewer number of metastatic sites were associated with higher odds of overall survival greater than 5 years, the number of metastatic sites was not associated with the odds of overall survival of being less than 2 years,” he said.
A limitation of the study included the retrospective nature of the study. “Treatment data are unavailable, so we cannot quantify the impact of various treatments on the odds of survival,” Dr. Leone said.
This study was not funded.
When a patient first presents to a doctor with signs and symptoms of having breast cancer that has metastasized to other parts of the body, the prospects of long-term survival are dim. But now, a new study presented at the annual meeting of the American Society of Clinical Oncology suggests that women with metastatic HER2+ breast cancer are generally living longer, compared with women treated in previous years.
Between 2010 and 2018, the overall survival for 5,576 women (99% women) with HER2+ metastatic breast cancer enrolled in this study improved 5.6% each year of the study. The study also showed a 6.4% improvement in breast cancer–specific death rates year over year.
“These highlights coincide with significant therapeutic advances for HER2+ metastatic breast cancer over the past decade. We need to continue our research efforts to identify better treatments for our patients so we can continue to improve the prognosis of these patients,” said study author Jose Pablo Leone, MD, a medical oncologist with Dana-Farber Cancer Institute, Boston.
The study, which is based on an evaluation of data from the Surveillance, Epidemiology and End Results database, found factors associated with shorter survival included older age, Black race, lower income, and the presence of visceral or brain metastases. Long-term survival of more than 5 years was associated with younger age, White race, and higher income, but also having fewer metastatic sites and estrogen receptor (ER)/progesterone receptor (PR) positivity.
“We also found specific factors that were only associated with shorter overall survival, such as the presence of metastases in the brain, liver, or lung. The lack of metastasis in these sites was not associated with longer overall survival. In contrast, a lower number of metastatic sites, regardless of the location of those sites were associated with longer overall survival but not short-term survival,” Dr. Leone said.
A total of 63.3% of patients in the study survived less than 2 years while 37.8% lived 5 years or more, and 26.8% lived longer than 8 years. Factors associated with less than 2 years in overall survival were older age (odds ratio, 3.76), Black race (OR 1.5), nonductal nonlobular (OR, 4.64), brain metastases (OR, 2.95), liver metastases (OR, 1.98), lung metastases (OR, 1.56), ER/PR negativity (OR, 1.74), and lower income (OR, 1.62). Factors associated with longer survival of 5 years or more included younger age (OR, 2.85), White race (OR, 1.7), fewer metastatic organ sites (OR, 2.6), ER/PR positivity (OR, 1.27), and higher income (OR, 3.31).
Dr. Leone said that, while involvement of specific visceral sites (brain, liver, lung) was associated with shorter overall survival, the odds of living longer than 5 years was not associated with those sites. In contrast, the number of sites was associated with longer overall survival, but not shorter overall survival regardless of location. “While fewer number of metastatic sites were associated with higher odds of overall survival greater than 5 years, the number of metastatic sites was not associated with the odds of overall survival of being less than 2 years,” he said.
A limitation of the study included the retrospective nature of the study. “Treatment data are unavailable, so we cannot quantify the impact of various treatments on the odds of survival,” Dr. Leone said.
This study was not funded.
FROM ASCO 2022
Panitumumab beats bevacizumab in left-sided mCRC
A suspicion from retrospective data has now been confirmed by a prospective clinical trial: Adding panitumumab (Vectibix) to standard chemotherapy in left-sided RAS wild-type metastatic colorectal cancer (mCRC) is more effective than adding bevacizumab (Avastin).
Patients treated with panitumumab alongside chemotherapy saw a 16% improvement in overall survival versus those given bevacizumab after a median follow-up of over 5 years.
The overall survival benefit rose to 18% in those with left-sided tumors.
However, there was no difference in overall survival between the two treatment groups in the small subgroup of patients with right-sided primary tumors.
These findings come from the PARADIGM trial conducted in Japan.
The results were presented during a plenary session at the annual meeting of the American Society of Clinical Oncology.
“If gene testing shows that a tumor is RAS wild-type, the choice of initial treatment with panitumumab plus mFOLFOX6 chemotherapy is superior ... for those people with left-sided tumors,” said lead researcher Takayuki Yoshino, MD, PhD, department of gastrointestinal oncology, National Cancer Center Hospital East, Chiba, Japan, in an ASCO press release.
“It has long been believed that the sequence of metastatic colorectal cancer treatment does not matter as long as patients had access to the drugs at some point, which has now been disproven,” he noted.
Dr. Yoshino added in a press conference about the trial that the results establish “a standard first-line combination regimen for patients with RAS wild-type, left-sided mCRC.”
commented Cathy Eng, MD, ASCO Expert in gastrointestinal cancers.
The findings “emphasize the importance of taking into account sidedness, as well as including comprehensive biomarker testing,” she said.
Dr. Eng underlined that this is especially the case for RAS gene status testing, “which is critical for all colorectal cancer patients at the time of diagnosis of metastatic disease.”
These results are of particular relevance in the United States, where the choice between an anti-EGFR or anti-VEGF antibody for the treatment of mCRC has been an area of “controversy” because of the lack of supporting data.
Panitumumab is a human monoclonal antibody that targets EGFR. It was approved in 2006 for use in mCRC by the U.S. Food and Drug Administration and also approved in 2014 for use in combination with FOLFOX for the first-line treatment of patients with wild-type KRAS (exon 2 in codons 12 or 13) mCRC, having previously been shown to be equally effective as cetuximab (another EGFR inhibitor) in this population.
In contrast, bevacizumab is a monoclonal antibody that targets the VEGF receptor. It was approved by the FDA for use in mCRC in 2004 in combination with intravenous 5-fluorouracil–based chemotherapy.
Dr. Yoshino explained that around 36% of patients with CRC have metastatic tumors at diagnosis and that adding an anti-EGFR or anti-VEGF antibody to chemotherapy improves overall survival in these patients by up to 30 months.
There has been “accumulating” evidence from retrospective studies suggesting that patients with RAS wild-type mCRC whose primary tumor is on the left side, which accounts for approximately 35% of mCRC cases, have a longer survival benefit with an anti-EGFR antibody, he commented.
Despite this, both antibody types continue to be used in these patients, he added.
PARADIGM was the first prospective trial to compare the two antibody types. Patients were randomized to receive either panitumumab or bevacizumab plus the combination chemotherapy regimen modified FOLFOX6 (mFOLFOX6).
The trial involved 823 Japanese patients with previously untreated wild-type mCRC with unresectable disease. Most patients had left-sided primary tumors (312 of 400 patients in the panitumumab group, and 292 of 402 patients in the bevacizumab group).
After a median follow-up of 61 months, panitumumab was associated with a significant improvement in overall survival in the overall study population, at a hazard ratio of 0.84 (P = .030, with the boundary of significance set at P < .05).
In addition, panitumumab was associated with a significant improvement in overall survival in the large subgroup of patients with left-sided primary tumors, at 37.9 versus 34.3 months, or a hazard ratio of 0.82 (P = .031).
However, there was no significant difference in overall survival between the two treatment groups in the smaller subgroup of patients with right-sided tumors, at a hazard ratio of 1.09.
Median progression-free survival was no different between the panitumumab and bevacizumab groups, at 13.7 versus 13.2 months in patients with a left-sided tumor and 12.9 versus 12.0 months in the overall cohort.
There was, however, a difference in response rates in left-sided patients between those receiving the two antibodies, at 80.2% with panitumumab versus 68.6% with bevacizumab, and in curative resection rates, at 18.3% and 11.6%, respectively.
These results demonstrate the “superiority of first-line panitumumab versus bevacizumab in combination with mFOLFOX6 in the left-sided and overall populations,” Dr. Yoshino concluded.
He also highlighted that the team has undertaken a large-scale biomarker analysis of pre- and posttreatment plasma and tissue samples from patients in the PARADIGM study to identify potential biomarkers of treatment response.
At the plenary session, discussant for this abstract Chiara Cremolini, MD, PhD, professor of medical oncology, Pisa (Italy) University Hospital, commented that “location matters” when it comes to mCRC tumors.
Dr. Cremolini pointed out that the separation of the survival curves at 28 months suggests that the 40% of patients with left-sided tumors who survived only up until that time point receive an equal benefit from panitumumab and bevacizumab.
In contrast, the remainder who survived for longer showed better outcomes with panitumumab.
Overall, she said, in her opinion and based on the findings from other studies, the current results support the use of panitumumab plus mFOLFOX6 as first-line therapy in patients with microsatellite stable RAS wild-type and with BRAF wild-type left-sided mCRC.
Dr. Cremolini emphasized that patients should be warned that, if they opt for doublet chemotherapy plus bevacizumab, they could face a median 3.6-month loss in overall survival, as well as poorer treatment activity.
However, patients with high microsatellite instability should receive immunotherapy up front, she added, while those with BRAF mutations should be given FOLFOX upfront plus bevacizumab, followed by encorafenib plus cetuximab in the case of progression.
Dr. Cremolini ended by noting that there has, as yet, been no prospective comparison of doublet chemotherapy plus an anti-EGFR antibody with triplet chemotherapy plus bevacizumab in this population.
The study was funded by Takeda. Dr. Yoshino has reported relationships with Bayer Yakuhin, Chugai Pharmaceutical, Merck, and MSD. Dr. Eng has reported relationships with Bayer Health, Gilead/Forty Seven, GlaxoSmithKline, Hookipa Biotech, Mirati Therapeutics, Natera, Pfizer, Elevar, Fruquitinib, Merck, and Pfizer.
A version of this article first appeared on Medscape.com.
A suspicion from retrospective data has now been confirmed by a prospective clinical trial: Adding panitumumab (Vectibix) to standard chemotherapy in left-sided RAS wild-type metastatic colorectal cancer (mCRC) is more effective than adding bevacizumab (Avastin).
Patients treated with panitumumab alongside chemotherapy saw a 16% improvement in overall survival versus those given bevacizumab after a median follow-up of over 5 years.
The overall survival benefit rose to 18% in those with left-sided tumors.
However, there was no difference in overall survival between the two treatment groups in the small subgroup of patients with right-sided primary tumors.
These findings come from the PARADIGM trial conducted in Japan.
The results were presented during a plenary session at the annual meeting of the American Society of Clinical Oncology.
“If gene testing shows that a tumor is RAS wild-type, the choice of initial treatment with panitumumab plus mFOLFOX6 chemotherapy is superior ... for those people with left-sided tumors,” said lead researcher Takayuki Yoshino, MD, PhD, department of gastrointestinal oncology, National Cancer Center Hospital East, Chiba, Japan, in an ASCO press release.
“It has long been believed that the sequence of metastatic colorectal cancer treatment does not matter as long as patients had access to the drugs at some point, which has now been disproven,” he noted.
Dr. Yoshino added in a press conference about the trial that the results establish “a standard first-line combination regimen for patients with RAS wild-type, left-sided mCRC.”
commented Cathy Eng, MD, ASCO Expert in gastrointestinal cancers.
The findings “emphasize the importance of taking into account sidedness, as well as including comprehensive biomarker testing,” she said.
Dr. Eng underlined that this is especially the case for RAS gene status testing, “which is critical for all colorectal cancer patients at the time of diagnosis of metastatic disease.”
These results are of particular relevance in the United States, where the choice between an anti-EGFR or anti-VEGF antibody for the treatment of mCRC has been an area of “controversy” because of the lack of supporting data.
Panitumumab is a human monoclonal antibody that targets EGFR. It was approved in 2006 for use in mCRC by the U.S. Food and Drug Administration and also approved in 2014 for use in combination with FOLFOX for the first-line treatment of patients with wild-type KRAS (exon 2 in codons 12 or 13) mCRC, having previously been shown to be equally effective as cetuximab (another EGFR inhibitor) in this population.
In contrast, bevacizumab is a monoclonal antibody that targets the VEGF receptor. It was approved by the FDA for use in mCRC in 2004 in combination with intravenous 5-fluorouracil–based chemotherapy.
Dr. Yoshino explained that around 36% of patients with CRC have metastatic tumors at diagnosis and that adding an anti-EGFR or anti-VEGF antibody to chemotherapy improves overall survival in these patients by up to 30 months.
There has been “accumulating” evidence from retrospective studies suggesting that patients with RAS wild-type mCRC whose primary tumor is on the left side, which accounts for approximately 35% of mCRC cases, have a longer survival benefit with an anti-EGFR antibody, he commented.
Despite this, both antibody types continue to be used in these patients, he added.
PARADIGM was the first prospective trial to compare the two antibody types. Patients were randomized to receive either panitumumab or bevacizumab plus the combination chemotherapy regimen modified FOLFOX6 (mFOLFOX6).
The trial involved 823 Japanese patients with previously untreated wild-type mCRC with unresectable disease. Most patients had left-sided primary tumors (312 of 400 patients in the panitumumab group, and 292 of 402 patients in the bevacizumab group).
After a median follow-up of 61 months, panitumumab was associated with a significant improvement in overall survival in the overall study population, at a hazard ratio of 0.84 (P = .030, with the boundary of significance set at P < .05).
In addition, panitumumab was associated with a significant improvement in overall survival in the large subgroup of patients with left-sided primary tumors, at 37.9 versus 34.3 months, or a hazard ratio of 0.82 (P = .031).
However, there was no significant difference in overall survival between the two treatment groups in the smaller subgroup of patients with right-sided tumors, at a hazard ratio of 1.09.
Median progression-free survival was no different between the panitumumab and bevacizumab groups, at 13.7 versus 13.2 months in patients with a left-sided tumor and 12.9 versus 12.0 months in the overall cohort.
There was, however, a difference in response rates in left-sided patients between those receiving the two antibodies, at 80.2% with panitumumab versus 68.6% with bevacizumab, and in curative resection rates, at 18.3% and 11.6%, respectively.
These results demonstrate the “superiority of first-line panitumumab versus bevacizumab in combination with mFOLFOX6 in the left-sided and overall populations,” Dr. Yoshino concluded.
He also highlighted that the team has undertaken a large-scale biomarker analysis of pre- and posttreatment plasma and tissue samples from patients in the PARADIGM study to identify potential biomarkers of treatment response.
At the plenary session, discussant for this abstract Chiara Cremolini, MD, PhD, professor of medical oncology, Pisa (Italy) University Hospital, commented that “location matters” when it comes to mCRC tumors.
Dr. Cremolini pointed out that the separation of the survival curves at 28 months suggests that the 40% of patients with left-sided tumors who survived only up until that time point receive an equal benefit from panitumumab and bevacizumab.
In contrast, the remainder who survived for longer showed better outcomes with panitumumab.
Overall, she said, in her opinion and based on the findings from other studies, the current results support the use of panitumumab plus mFOLFOX6 as first-line therapy in patients with microsatellite stable RAS wild-type and with BRAF wild-type left-sided mCRC.
Dr. Cremolini emphasized that patients should be warned that, if they opt for doublet chemotherapy plus bevacizumab, they could face a median 3.6-month loss in overall survival, as well as poorer treatment activity.
However, patients with high microsatellite instability should receive immunotherapy up front, she added, while those with BRAF mutations should be given FOLFOX upfront plus bevacizumab, followed by encorafenib plus cetuximab in the case of progression.
Dr. Cremolini ended by noting that there has, as yet, been no prospective comparison of doublet chemotherapy plus an anti-EGFR antibody with triplet chemotherapy plus bevacizumab in this population.
The study was funded by Takeda. Dr. Yoshino has reported relationships with Bayer Yakuhin, Chugai Pharmaceutical, Merck, and MSD. Dr. Eng has reported relationships with Bayer Health, Gilead/Forty Seven, GlaxoSmithKline, Hookipa Biotech, Mirati Therapeutics, Natera, Pfizer, Elevar, Fruquitinib, Merck, and Pfizer.
A version of this article first appeared on Medscape.com.
A suspicion from retrospective data has now been confirmed by a prospective clinical trial: Adding panitumumab (Vectibix) to standard chemotherapy in left-sided RAS wild-type metastatic colorectal cancer (mCRC) is more effective than adding bevacizumab (Avastin).
Patients treated with panitumumab alongside chemotherapy saw a 16% improvement in overall survival versus those given bevacizumab after a median follow-up of over 5 years.
The overall survival benefit rose to 18% in those with left-sided tumors.
However, there was no difference in overall survival between the two treatment groups in the small subgroup of patients with right-sided primary tumors.
These findings come from the PARADIGM trial conducted in Japan.
The results were presented during a plenary session at the annual meeting of the American Society of Clinical Oncology.
“If gene testing shows that a tumor is RAS wild-type, the choice of initial treatment with panitumumab plus mFOLFOX6 chemotherapy is superior ... for those people with left-sided tumors,” said lead researcher Takayuki Yoshino, MD, PhD, department of gastrointestinal oncology, National Cancer Center Hospital East, Chiba, Japan, in an ASCO press release.
“It has long been believed that the sequence of metastatic colorectal cancer treatment does not matter as long as patients had access to the drugs at some point, which has now been disproven,” he noted.
Dr. Yoshino added in a press conference about the trial that the results establish “a standard first-line combination regimen for patients with RAS wild-type, left-sided mCRC.”
commented Cathy Eng, MD, ASCO Expert in gastrointestinal cancers.
The findings “emphasize the importance of taking into account sidedness, as well as including comprehensive biomarker testing,” she said.
Dr. Eng underlined that this is especially the case for RAS gene status testing, “which is critical for all colorectal cancer patients at the time of diagnosis of metastatic disease.”
These results are of particular relevance in the United States, where the choice between an anti-EGFR or anti-VEGF antibody for the treatment of mCRC has been an area of “controversy” because of the lack of supporting data.
Panitumumab is a human monoclonal antibody that targets EGFR. It was approved in 2006 for use in mCRC by the U.S. Food and Drug Administration and also approved in 2014 for use in combination with FOLFOX for the first-line treatment of patients with wild-type KRAS (exon 2 in codons 12 or 13) mCRC, having previously been shown to be equally effective as cetuximab (another EGFR inhibitor) in this population.
In contrast, bevacizumab is a monoclonal antibody that targets the VEGF receptor. It was approved by the FDA for use in mCRC in 2004 in combination with intravenous 5-fluorouracil–based chemotherapy.
Dr. Yoshino explained that around 36% of patients with CRC have metastatic tumors at diagnosis and that adding an anti-EGFR or anti-VEGF antibody to chemotherapy improves overall survival in these patients by up to 30 months.
There has been “accumulating” evidence from retrospective studies suggesting that patients with RAS wild-type mCRC whose primary tumor is on the left side, which accounts for approximately 35% of mCRC cases, have a longer survival benefit with an anti-EGFR antibody, he commented.
Despite this, both antibody types continue to be used in these patients, he added.
PARADIGM was the first prospective trial to compare the two antibody types. Patients were randomized to receive either panitumumab or bevacizumab plus the combination chemotherapy regimen modified FOLFOX6 (mFOLFOX6).
The trial involved 823 Japanese patients with previously untreated wild-type mCRC with unresectable disease. Most patients had left-sided primary tumors (312 of 400 patients in the panitumumab group, and 292 of 402 patients in the bevacizumab group).
After a median follow-up of 61 months, panitumumab was associated with a significant improvement in overall survival in the overall study population, at a hazard ratio of 0.84 (P = .030, with the boundary of significance set at P < .05).
In addition, panitumumab was associated with a significant improvement in overall survival in the large subgroup of patients with left-sided primary tumors, at 37.9 versus 34.3 months, or a hazard ratio of 0.82 (P = .031).
However, there was no significant difference in overall survival between the two treatment groups in the smaller subgroup of patients with right-sided tumors, at a hazard ratio of 1.09.
Median progression-free survival was no different between the panitumumab and bevacizumab groups, at 13.7 versus 13.2 months in patients with a left-sided tumor and 12.9 versus 12.0 months in the overall cohort.
There was, however, a difference in response rates in left-sided patients between those receiving the two antibodies, at 80.2% with panitumumab versus 68.6% with bevacizumab, and in curative resection rates, at 18.3% and 11.6%, respectively.
These results demonstrate the “superiority of first-line panitumumab versus bevacizumab in combination with mFOLFOX6 in the left-sided and overall populations,” Dr. Yoshino concluded.
He also highlighted that the team has undertaken a large-scale biomarker analysis of pre- and posttreatment plasma and tissue samples from patients in the PARADIGM study to identify potential biomarkers of treatment response.
At the plenary session, discussant for this abstract Chiara Cremolini, MD, PhD, professor of medical oncology, Pisa (Italy) University Hospital, commented that “location matters” when it comes to mCRC tumors.
Dr. Cremolini pointed out that the separation of the survival curves at 28 months suggests that the 40% of patients with left-sided tumors who survived only up until that time point receive an equal benefit from panitumumab and bevacizumab.
In contrast, the remainder who survived for longer showed better outcomes with panitumumab.
Overall, she said, in her opinion and based on the findings from other studies, the current results support the use of panitumumab plus mFOLFOX6 as first-line therapy in patients with microsatellite stable RAS wild-type and with BRAF wild-type left-sided mCRC.
Dr. Cremolini emphasized that patients should be warned that, if they opt for doublet chemotherapy plus bevacizumab, they could face a median 3.6-month loss in overall survival, as well as poorer treatment activity.
However, patients with high microsatellite instability should receive immunotherapy up front, she added, while those with BRAF mutations should be given FOLFOX upfront plus bevacizumab, followed by encorafenib plus cetuximab in the case of progression.
Dr. Cremolini ended by noting that there has, as yet, been no prospective comparison of doublet chemotherapy plus an anti-EGFR antibody with triplet chemotherapy plus bevacizumab in this population.
The study was funded by Takeda. Dr. Yoshino has reported relationships with Bayer Yakuhin, Chugai Pharmaceutical, Merck, and MSD. Dr. Eng has reported relationships with Bayer Health, Gilead/Forty Seven, GlaxoSmithKline, Hookipa Biotech, Mirati Therapeutics, Natera, Pfizer, Elevar, Fruquitinib, Merck, and Pfizer.
A version of this article first appeared on Medscape.com.
FROM ASCO 2022
Non-White subjects are sparse in DMT trials for MS
NATIONAL HARBOR, MD. -- Over 25 years of clinical research, phase 3 trials of approved disease-modifying therapies (DMTs) for multiple sclerosis (MS) were overwhelmingly made up of White subjects, a new analysis finds, and many studies failed to report percentages of non-White subjects at all. Researchers also found that the websites of multiple major drug manufacturers don’t include any trial data about how medications may affect people of different races and ethnicities.
It’s clear that “non-White participants are significantly underreported and unrepresented,” said study corresponding author and Dell Medical School/The University of Texas at Austin neurologist Leorah Freeman, MD, PhD, in an interview.
The study was presented at the annual meeting of the Consortium of Multiple Sclerosis Centers and published in Neurology.
“The lack of diversity in MS research is something that has been sporadically discussed in the past. By conducting this systematic review of MS phase 3 trials, we wanted to put numbers on this issue and review the evidence systematically,” Dr. Freeman said. “By doing so, we hoped to raise awareness about the problem of underreporting and underrepresentation of non-White participants in trials so that we, as a community involved in MS research, can start having the difficult conversations needed for change to occur.”
25 years of clinical research
The researchers reviewed 44 phase 3 studies from 1995-2020 that represented 45 trials. “We wanted to capture data from the very first global trials being conducted for the approval of MS DMTs, and the first was published in 1995,” Dr. Freeman said. “We were interested in understanding the impact of trial globalization over a long period of time on diversity of enrollment.”
The studies include trials of mainstays of MS treatment such as interferon, glatiramer acetate, teriflunomide, dimethyl fumarate, diroximel fumarate, fingolimod, natalizumab, and others.
The researchers found that 17 (37.8%) of the trials did not report race or ethnicity, 14 (31.1%) reported race and ethnicity as proportion of White participants only, and 14 (31.1%) reported 2 or more races/ethnicities.
Of the 28 trials with racial breakdowns, the median percentage of White participants was 93.8% (range 78.5-99.6% across 28 studies), 1.9% for Black participants (range 0.1-8.1% across 14 studies), and 0.5% for Asian participants (range 0.1-14.5% across 11 studies).
The studies often failed to account for non-White subjects even though “Black people, in particular, have been shown to have a more severe disease course,” Dr. Freeman said.
A 2022 study of more than 2.6 million Southern California adults finds that prevalence of MS was similar among White and Black people at about 230 per 100,000. “Taken together with previous studies, these findings indicate that the burden of MS in the United States Black community has long been underrecognized,” the researchers wrote.
According to Dr. Freeman, it’s unclear why the studies were so dominated by White subjects. “Lack of awareness about the importance of this information likely explains why this information often goes unreported.”
She highlighted the TOWER (teriflunomide) and DEFINE and CONFIRM (dimethyl fumarate) studies as positive examples. “We noted the inclusion of trial sites in Asia and consequently a higher representation of Asian people with MS in those trials. We felt these studies were examples of how trial globalization can support better representation of underrepresented groups.”
And she noted that the ongoing CHIMES trial is examining the use of ocrelizumab in Black and Hispanic people with MS. “This study was designed in partnership with MS patients and advocacy groups to bridge gaps in clinical trial participation in these communities,” she said. “Innovative strategies were developed to increase participation of Black and Hispanic patients in this trial.”
What should happen next?
Going forward, Dr. Freeman said, “MS researchers, DMT manufacturers, sponsors, and publishers need to set better standards for racial and ethnic representation and reporting in trial publications.”
In an interview, epidemiologist Luisa N. Borrell, DDS, PhD, a professor who studies race and medicine at City University of New York, said the new study is valid and useful. She noted that it reflects the findings of a 2022 analysis of more than 20,500 clinical trials in the U.S. from 2000-2020: Only 43% reported racial/ethnic breakdowns, and the subjects were much more White than the population at large.
Possible reasons for the disparity include distrust among possible participants and lack of health literacy, she said, which are both “modifiable issues.”
Dr. Borrell added: “Clinical trials should aim to recruit populations affected by the outcome of interest. That would allow for the intervention to effectively treat those who need it the most. Moreover, the lack of diversity of trials brings issues of generalizability and transportability of the findings.”
No funding is reported. Dr. Freeman and some of the other study authors report various disclosures.
NATIONAL HARBOR, MD. -- Over 25 years of clinical research, phase 3 trials of approved disease-modifying therapies (DMTs) for multiple sclerosis (MS) were overwhelmingly made up of White subjects, a new analysis finds, and many studies failed to report percentages of non-White subjects at all. Researchers also found that the websites of multiple major drug manufacturers don’t include any trial data about how medications may affect people of different races and ethnicities.
It’s clear that “non-White participants are significantly underreported and unrepresented,” said study corresponding author and Dell Medical School/The University of Texas at Austin neurologist Leorah Freeman, MD, PhD, in an interview.
The study was presented at the annual meeting of the Consortium of Multiple Sclerosis Centers and published in Neurology.
“The lack of diversity in MS research is something that has been sporadically discussed in the past. By conducting this systematic review of MS phase 3 trials, we wanted to put numbers on this issue and review the evidence systematically,” Dr. Freeman said. “By doing so, we hoped to raise awareness about the problem of underreporting and underrepresentation of non-White participants in trials so that we, as a community involved in MS research, can start having the difficult conversations needed for change to occur.”
25 years of clinical research
The researchers reviewed 44 phase 3 studies from 1995-2020 that represented 45 trials. “We wanted to capture data from the very first global trials being conducted for the approval of MS DMTs, and the first was published in 1995,” Dr. Freeman said. “We were interested in understanding the impact of trial globalization over a long period of time on diversity of enrollment.”
The studies include trials of mainstays of MS treatment such as interferon, glatiramer acetate, teriflunomide, dimethyl fumarate, diroximel fumarate, fingolimod, natalizumab, and others.
The researchers found that 17 (37.8%) of the trials did not report race or ethnicity, 14 (31.1%) reported race and ethnicity as proportion of White participants only, and 14 (31.1%) reported 2 or more races/ethnicities.
Of the 28 trials with racial breakdowns, the median percentage of White participants was 93.8% (range 78.5-99.6% across 28 studies), 1.9% for Black participants (range 0.1-8.1% across 14 studies), and 0.5% for Asian participants (range 0.1-14.5% across 11 studies).
The studies often failed to account for non-White subjects even though “Black people, in particular, have been shown to have a more severe disease course,” Dr. Freeman said.
A 2022 study of more than 2.6 million Southern California adults finds that prevalence of MS was similar among White and Black people at about 230 per 100,000. “Taken together with previous studies, these findings indicate that the burden of MS in the United States Black community has long been underrecognized,” the researchers wrote.
According to Dr. Freeman, it’s unclear why the studies were so dominated by White subjects. “Lack of awareness about the importance of this information likely explains why this information often goes unreported.”
She highlighted the TOWER (teriflunomide) and DEFINE and CONFIRM (dimethyl fumarate) studies as positive examples. “We noted the inclusion of trial sites in Asia and consequently a higher representation of Asian people with MS in those trials. We felt these studies were examples of how trial globalization can support better representation of underrepresented groups.”
And she noted that the ongoing CHIMES trial is examining the use of ocrelizumab in Black and Hispanic people with MS. “This study was designed in partnership with MS patients and advocacy groups to bridge gaps in clinical trial participation in these communities,” she said. “Innovative strategies were developed to increase participation of Black and Hispanic patients in this trial.”
What should happen next?
Going forward, Dr. Freeman said, “MS researchers, DMT manufacturers, sponsors, and publishers need to set better standards for racial and ethnic representation and reporting in trial publications.”
In an interview, epidemiologist Luisa N. Borrell, DDS, PhD, a professor who studies race and medicine at City University of New York, said the new study is valid and useful. She noted that it reflects the findings of a 2022 analysis of more than 20,500 clinical trials in the U.S. from 2000-2020: Only 43% reported racial/ethnic breakdowns, and the subjects were much more White than the population at large.
Possible reasons for the disparity include distrust among possible participants and lack of health literacy, she said, which are both “modifiable issues.”
Dr. Borrell added: “Clinical trials should aim to recruit populations affected by the outcome of interest. That would allow for the intervention to effectively treat those who need it the most. Moreover, the lack of diversity of trials brings issues of generalizability and transportability of the findings.”
No funding is reported. Dr. Freeman and some of the other study authors report various disclosures.
NATIONAL HARBOR, MD. -- Over 25 years of clinical research, phase 3 trials of approved disease-modifying therapies (DMTs) for multiple sclerosis (MS) were overwhelmingly made up of White subjects, a new analysis finds, and many studies failed to report percentages of non-White subjects at all. Researchers also found that the websites of multiple major drug manufacturers don’t include any trial data about how medications may affect people of different races and ethnicities.
It’s clear that “non-White participants are significantly underreported and unrepresented,” said study corresponding author and Dell Medical School/The University of Texas at Austin neurologist Leorah Freeman, MD, PhD, in an interview.
The study was presented at the annual meeting of the Consortium of Multiple Sclerosis Centers and published in Neurology.
“The lack of diversity in MS research is something that has been sporadically discussed in the past. By conducting this systematic review of MS phase 3 trials, we wanted to put numbers on this issue and review the evidence systematically,” Dr. Freeman said. “By doing so, we hoped to raise awareness about the problem of underreporting and underrepresentation of non-White participants in trials so that we, as a community involved in MS research, can start having the difficult conversations needed for change to occur.”
25 years of clinical research
The researchers reviewed 44 phase 3 studies from 1995-2020 that represented 45 trials. “We wanted to capture data from the very first global trials being conducted for the approval of MS DMTs, and the first was published in 1995,” Dr. Freeman said. “We were interested in understanding the impact of trial globalization over a long period of time on diversity of enrollment.”
The studies include trials of mainstays of MS treatment such as interferon, glatiramer acetate, teriflunomide, dimethyl fumarate, diroximel fumarate, fingolimod, natalizumab, and others.
The researchers found that 17 (37.8%) of the trials did not report race or ethnicity, 14 (31.1%) reported race and ethnicity as proportion of White participants only, and 14 (31.1%) reported 2 or more races/ethnicities.
Of the 28 trials with racial breakdowns, the median percentage of White participants was 93.8% (range 78.5-99.6% across 28 studies), 1.9% for Black participants (range 0.1-8.1% across 14 studies), and 0.5% for Asian participants (range 0.1-14.5% across 11 studies).
The studies often failed to account for non-White subjects even though “Black people, in particular, have been shown to have a more severe disease course,” Dr. Freeman said.
A 2022 study of more than 2.6 million Southern California adults finds that prevalence of MS was similar among White and Black people at about 230 per 100,000. “Taken together with previous studies, these findings indicate that the burden of MS in the United States Black community has long been underrecognized,” the researchers wrote.
According to Dr. Freeman, it’s unclear why the studies were so dominated by White subjects. “Lack of awareness about the importance of this information likely explains why this information often goes unreported.”
She highlighted the TOWER (teriflunomide) and DEFINE and CONFIRM (dimethyl fumarate) studies as positive examples. “We noted the inclusion of trial sites in Asia and consequently a higher representation of Asian people with MS in those trials. We felt these studies were examples of how trial globalization can support better representation of underrepresented groups.”
And she noted that the ongoing CHIMES trial is examining the use of ocrelizumab in Black and Hispanic people with MS. “This study was designed in partnership with MS patients and advocacy groups to bridge gaps in clinical trial participation in these communities,” she said. “Innovative strategies were developed to increase participation of Black and Hispanic patients in this trial.”
What should happen next?
Going forward, Dr. Freeman said, “MS researchers, DMT manufacturers, sponsors, and publishers need to set better standards for racial and ethnic representation and reporting in trial publications.”
In an interview, epidemiologist Luisa N. Borrell, DDS, PhD, a professor who studies race and medicine at City University of New York, said the new study is valid and useful. She noted that it reflects the findings of a 2022 analysis of more than 20,500 clinical trials in the U.S. from 2000-2020: Only 43% reported racial/ethnic breakdowns, and the subjects were much more White than the population at large.
Possible reasons for the disparity include distrust among possible participants and lack of health literacy, she said, which are both “modifiable issues.”
Dr. Borrell added: “Clinical trials should aim to recruit populations affected by the outcome of interest. That would allow for the intervention to effectively treat those who need it the most. Moreover, the lack of diversity of trials brings issues of generalizability and transportability of the findings.”
No funding is reported. Dr. Freeman and some of the other study authors report various disclosures.
AT CMSC 2022