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Metformin use linked to birth defects in boys
researchers have found.
The association appears to involve the effects of metformin on the development of sperm during a critical window prior to conception. Female offspring were not affected. Although previous studies have linked diabetes with fertility problems in men, the latest study is the first to show that these problems can result from treatment rather than the disease itself, according to the researchers, whose findings appear in Annals of Internal Medicine.
“This is the first data to suggest that paternal metformin [use] may be associated with birth defects in children. As such, it would be early to begin to alter clinical practice,” Michael Eisenberg, MD, director of male reproductive medicine and surgery, department of urology, Stanford (Calif.) University, who is a coauthor of the study, said in an interview. “However, if it is confirmed in other populations, then it may begin to enter counseling discussions.”
Dr. Eisenberg added that eating a nutritious diet, exercising, and maintaining a healthy body weight “can improve a man’s health and likely his fertility as well.”
For the new study, Dr. Eisenberg and colleagues analyzed records in a registry of all 1.25 million births that occurred in Denmark between 1997 and 2016. The registry included information on birth defects and parental drug prescriptions.
Offspring were considered exposed to a diabetes drug if a father had filled one or more prescriptions for the medications during the 3 months prior to conception, when the fertilizing sperm would have been produced.
The final analysis included 1,116,779 offspring – all singleton births to women without a history of diabetes or essential hypertension – of whom 7,029 were exposed to diabetes drugs via the father, and 3.3% (n = 36,585) had one or more major birth defects.
Among male offspring whose fathers had taken metformin (n = 1,451), there was a 3.4-fold greater incidence of major genitourinary birth defects, according to the researchers. The study failed to find associations between birth defects and the use of insulin. Although a signal did emerge for sulfonylurea-based drugs, it did not reach statistical significance.
The risk associated with metformin did not appear for men who were prescribed the drug in the year before or after sperm development. Nor was it evident in siblings of the boys with birth defects who were not considered to have been exposed to the medication, the researchers reported.
In an editorial accompanying the journal article, Germaine Buck Louis, PhD, a reproductive and perinatal epidemiologist, wrote: “Given the prevalence of metformin use as first-line therapy for type 2 diabetes, corroboration of these findings is urgently needed.”
Dr. Louis, dean of the College of Health and Human Services at George Mason University, Washington, said a key limitation of the research is the lack of data on how well men in the study adhered to their diabetes treatment. Nevertheless, “clinical guidance is needed to help couples planning pregnancy weigh the risks and benefits of paternal metformin use relative to other medications.”
The researchers received funding from the National Institutes of Health and the Centers for Disease Control and Prevention.
A version of this article first appeared on Medscape.com.
researchers have found.
The association appears to involve the effects of metformin on the development of sperm during a critical window prior to conception. Female offspring were not affected. Although previous studies have linked diabetes with fertility problems in men, the latest study is the first to show that these problems can result from treatment rather than the disease itself, according to the researchers, whose findings appear in Annals of Internal Medicine.
“This is the first data to suggest that paternal metformin [use] may be associated with birth defects in children. As such, it would be early to begin to alter clinical practice,” Michael Eisenberg, MD, director of male reproductive medicine and surgery, department of urology, Stanford (Calif.) University, who is a coauthor of the study, said in an interview. “However, if it is confirmed in other populations, then it may begin to enter counseling discussions.”
Dr. Eisenberg added that eating a nutritious diet, exercising, and maintaining a healthy body weight “can improve a man’s health and likely his fertility as well.”
For the new study, Dr. Eisenberg and colleagues analyzed records in a registry of all 1.25 million births that occurred in Denmark between 1997 and 2016. The registry included information on birth defects and parental drug prescriptions.
Offspring were considered exposed to a diabetes drug if a father had filled one or more prescriptions for the medications during the 3 months prior to conception, when the fertilizing sperm would have been produced.
The final analysis included 1,116,779 offspring – all singleton births to women without a history of diabetes or essential hypertension – of whom 7,029 were exposed to diabetes drugs via the father, and 3.3% (n = 36,585) had one or more major birth defects.
Among male offspring whose fathers had taken metformin (n = 1,451), there was a 3.4-fold greater incidence of major genitourinary birth defects, according to the researchers. The study failed to find associations between birth defects and the use of insulin. Although a signal did emerge for sulfonylurea-based drugs, it did not reach statistical significance.
The risk associated with metformin did not appear for men who were prescribed the drug in the year before or after sperm development. Nor was it evident in siblings of the boys with birth defects who were not considered to have been exposed to the medication, the researchers reported.
In an editorial accompanying the journal article, Germaine Buck Louis, PhD, a reproductive and perinatal epidemiologist, wrote: “Given the prevalence of metformin use as first-line therapy for type 2 diabetes, corroboration of these findings is urgently needed.”
Dr. Louis, dean of the College of Health and Human Services at George Mason University, Washington, said a key limitation of the research is the lack of data on how well men in the study adhered to their diabetes treatment. Nevertheless, “clinical guidance is needed to help couples planning pregnancy weigh the risks and benefits of paternal metformin use relative to other medications.”
The researchers received funding from the National Institutes of Health and the Centers for Disease Control and Prevention.
A version of this article first appeared on Medscape.com.
researchers have found.
The association appears to involve the effects of metformin on the development of sperm during a critical window prior to conception. Female offspring were not affected. Although previous studies have linked diabetes with fertility problems in men, the latest study is the first to show that these problems can result from treatment rather than the disease itself, according to the researchers, whose findings appear in Annals of Internal Medicine.
“This is the first data to suggest that paternal metformin [use] may be associated with birth defects in children. As such, it would be early to begin to alter clinical practice,” Michael Eisenberg, MD, director of male reproductive medicine and surgery, department of urology, Stanford (Calif.) University, who is a coauthor of the study, said in an interview. “However, if it is confirmed in other populations, then it may begin to enter counseling discussions.”
Dr. Eisenberg added that eating a nutritious diet, exercising, and maintaining a healthy body weight “can improve a man’s health and likely his fertility as well.”
For the new study, Dr. Eisenberg and colleagues analyzed records in a registry of all 1.25 million births that occurred in Denmark between 1997 and 2016. The registry included information on birth defects and parental drug prescriptions.
Offspring were considered exposed to a diabetes drug if a father had filled one or more prescriptions for the medications during the 3 months prior to conception, when the fertilizing sperm would have been produced.
The final analysis included 1,116,779 offspring – all singleton births to women without a history of diabetes or essential hypertension – of whom 7,029 were exposed to diabetes drugs via the father, and 3.3% (n = 36,585) had one or more major birth defects.
Among male offspring whose fathers had taken metformin (n = 1,451), there was a 3.4-fold greater incidence of major genitourinary birth defects, according to the researchers. The study failed to find associations between birth defects and the use of insulin. Although a signal did emerge for sulfonylurea-based drugs, it did not reach statistical significance.
The risk associated with metformin did not appear for men who were prescribed the drug in the year before or after sperm development. Nor was it evident in siblings of the boys with birth defects who were not considered to have been exposed to the medication, the researchers reported.
In an editorial accompanying the journal article, Germaine Buck Louis, PhD, a reproductive and perinatal epidemiologist, wrote: “Given the prevalence of metformin use as first-line therapy for type 2 diabetes, corroboration of these findings is urgently needed.”
Dr. Louis, dean of the College of Health and Human Services at George Mason University, Washington, said a key limitation of the research is the lack of data on how well men in the study adhered to their diabetes treatment. Nevertheless, “clinical guidance is needed to help couples planning pregnancy weigh the risks and benefits of paternal metformin use relative to other medications.”
The researchers received funding from the National Institutes of Health and the Centers for Disease Control and Prevention.
A version of this article first appeared on Medscape.com.
FROM ANNALS OF INTERNAL MEDICINE
Is this the most controversial issue in early breast cancer treatment?
Is this the most controversial topic in breast oncology? Quite likely: the results of a recent online poll show split votes and no consensus.
The topic is the use of chemotherapy for premenopausal women with early-stage hormone receptor–positive (HR+), human epidermal growth factor receptor 2–negative (HER2-) breast cancer.
, as the other expert countered?
The debate was held during the recent San Antonio Breast Cancer Symposium (SABCS), at which new results were presented that increased the controversy.
The controversy had arisen the previous year over results from the RxPONDER trial.
Five-year follow-up data from RxPONDER showed that adding chemotherapy to endocrine therapy did not improve outcomes over endocrine therapy alone for postmenopausal women with low-risk, node-positive HR+, HER2- breast cancer. This suggests that older women with early-stage breast cancer may safely forgo chemotherapy.
However, the same trial included premenopausal women with the same disease profile, and the results in this subgroup showed that there was benefit from chemotherapy, with a 5-year invasive disease-free survival (IDFS) rate of 94.2%, versus 89.0% for endocrine therapy alone (P = .0004).
The results were immediately controversial.
Some experts suggested the effect was due to the chemotherapy incidentally causing ovarian suppression, not the cytotoxic effect of the drugs on cancer cells. These experts were skeptical about the suggestion that chemotherapy works differently in premenopausal women than it does in postmenopausal women.
Some clinicians feel the lack of clarity creates an opportunity for greater discussion with women when making the treatment decision.
“When I have this conversation with patients, it’s really nuanced,” Stephanie L. Graff, MD, director of breast oncology, Lifespan Cancer Institute, Providence, R.I., told this news organization.
“I would choose chemotherapy for myself, but I’m a chemotherapy doctor, so I’m very comfortable with these medications and their side effects, and I am also very familiar with the slow burn of the side effects of endocrine therapy,” she said.
But for patients who are hearing their options for the first time, the idea of chemotherapy “feels scary,” and there is “a lot of stigma” associated with it, she commented.
Ultimately, she believes in offering patients as much information as possible, inasmuch as “knowledge is power.”
For Dr. Graff, the message from RxPONDER was that, in premenopausal patients with lymph node positive, HR+ breast cancer, “all comers benefited from chemotherapy.”
“And so if the goal is to be maximally aggressive and optimally lower your risk of distant recurrence, which is a life-threatening event, chemotherapy should offered.”
But chemotherapy comes with side effects, so it’s an important conversation to have with patients; RxPONDER showed that the absolute difference in the rate of distant recurrence with chemotherapy was relatively minor, she added.
Debate rages on
The debate at SABCS was moderated by Harold J. Burstein, MD, PhD, from the Dana-Farber Cancer Institute, Boston, who commented that if this was “a compelling question last week in clinic, it has now become red hot.”
At the meeting, held in December 2021, new longer-term data from the SOFT and TEXT clinical trials were presented, showing that ovarian suppression with tamoxifen plus an aromatase inhibitor provides a greater reduction in long-term risk of recurrence than tamoxifen alone.
Moreover, updated results from RxPONDER presented at the same session revealed that chemoendocrine therapy was associated with longer IDFS and distant relapse-free survival than endocrine therapy alone for women with one to three positive lymph nodes and a recurrence score of 25 or lower on the Oncotype DX (Genomic Health) 21-gene breast cancer assay.
Dr. Burstein said the debate over the use of chemotherapy in premenopausal women “is the most interesting question right now in early-stage breast cancer.”
The debate focused on the effect of chemotherapy in these patients – was it all down to ovarian function suppression?
Yes, argued Michael Gnant, MD, from the Medical University of Vienna.
Data from “modern adjuvant chemotherapy trials” suggest that chemo offers a 2%-3% benefit in distant disease-free survival at 5 years for premenopausal women, he noted. But the effect is much larger with ovarian function suppression via endocrine therapy, which provides 5-year disease-free and overall survival benefits of 9%-13%.
Older studies have shown that the benefit with chemotherapy is seen only in women who experience amenorrhea with the cytotoxic drugs, Dr. Gnant noted.
“In short, if you give adjuvant chemotherapy and you induce amenorrhea, then there is going to be a survival difference,” he said. “But if you give adjuvant chemotherapy and there is no amenorrhea, there won’t be an outcome difference.”
The ABSCG-05 trial, which compared endocrine therapy with chemotherapy, showed that “in the presence of optimal endocrine adjuvant treatment, adjuvant chemotherapy doesn’t add anything, because you have already achieved the effect of treatment-induced amenorrhea.”
So Dr. Gnant argued that the effect of chemotherapy in RxPONDER was due to ovarian function suppression.
But the real question is: “What does it mean for clinical practice?”
Dr. Gnant asserted that for the “large group of lower-risk premenopausal patients, tamoxifen will be good enough,” while those at moderate or intermediate risk should receive ovarian function suppression with either tamoxifen or an aromatase inhibitor, with the choice dictated by their adverse effects.
Chemotherapy “is just a graceless method of ovarian function suppression and should only be given to high-risk patients and to patients with endocrine nonresponsive disease,” he argued.
On the other side of the debate, Sibylle Loibl, MD, PhD, from the Centre of Hematology and Oncology, Bethanien, Frankfurt, argued that the effect is not all due to ovarian function suppression and that chemotherapy also has a cytotoxic effect in these patients.
“We need chemotherapy” because “cancer in young women is biologically different,” she asserted.
Dr. Loibl pointed to data currently awaiting publication in the Journal of the National Cancer Institute that suggest that younger women have “higher immune gene expression” that may make them more chemotherapy sensitive, and lower expression of hormone receptor genes, which “could make them less endocrine sensitive.”
She also cited data from a study from her own group that showed that pathologic complete response rates to neoadjuvant chemotherapy were higher in younger women with HR+, HER2- breast cancer, indicating a direct effect of chemotherapy on the disease and that age was an important prognostic factor.
The data on the induction of amenorrhea by chemotherapy is also not as clearcut as it seems, she commented. Chemotherapy does not achieve 100% amenorrhea, and gonadotropin-releasing hormone analogues are unable to suppress ovarian function in 20% of women.
Dr. Loibl concluded that the “chemotherapy effect is there, it is higher in young women with HR+, HER2- breast cancer,” and that the effect has two components.
“There is a direct cytotoxic effect which cannot be neglected, and there is an endocrine effect on the ovarian function suppression,” she argued.
“I think both are needed in young premenopausal patients,” she added.
Audience responses
After the debate, the audience was polled on what effect they thought chemotherapy was having in lower-risk HR+, HER2- breast cancer patients. About two-thirds responded that it was all or mostly due to ovarian function suppression.
However, the next question split the audience. They were presented with a clinical scenario: a 43-year-old woman with a mammographically detected 1.4-cm, intermediate grade, HR+, HER2- breast cancer who also had metastatic disease in one of three sentinel lymph nodes and whose recurrence score was 13.
When asked about the treatment plan they would choose for this patient, the audience was split over whether to opt for chemoendocrine therapy or endocrine therapy alone.
A similar clinical question was posited recently on Twitter, when Angela Toss, MD, PhD, from the University of Modena and Reggio Emilia, Italy, asked respondents which they would chose from among three options.
From the 815 votes that were cast, 46% chose Oncotype DX testing to determine the likely benefit of chemotherapy, 48% chose chemotherapy, and 6% picked ovarian function suppression and an aromatase inhibitor.
In response, Paolo Tarantino, MD, from the Dana-Farber Cancer Institute, commented: “If you had any doubt of which is the most controversial topic in breast oncology, doubt no more. 815 votes, no consensus.”
Approached for comment, Eric Winer, MD, director of the Yale Cancer Center, New Haven, Conn., said that the data from RxPONDER “in many ways was helpful, but ... it created about as many questions as it answered, if not more.”
Because the results showed a benefit from chemotherapy for premenopausal women but not for postmenopausal women with breast cancer, Dr. Winer told this news organization that one of the outstanding questions is “whether premenopausal women are fundamentally different from postmenopausal women ... and my answer to that is that is very unlikely.”
Dr. Winer added that the “real tragedy” of this trial was that it did not include women with more than three positive nodes, particularly those who have a low recurrence score, he said.
Clinicians are therefore left either “extrapolating” data from those with fewer nodes or “marching down a path that we’ve taken for years of just giving those people chemotherapy routinely,” even though there may be no benefit, Dr. Winer commented.
Another expert who was approached for comment had a different take on the data. Matteo Lambertini, MD, IRCCS Ospedale Policlinico San Martino, Genoa, Italy, agreed with Loibl’s argument that chemotherapy has a cytotoxic effect in premenopausal women with HR+, HER2- breast cancer in addition to its effect on ovarian function suppression.
He did not agree, however, that there is a question mark over what to do for patients with more than three positive lymph nodes.
Dr. Lambertini said in an interview that he thinks “too much” trust is placed in genomic testing and that there is a “risk of forgetting about all the other factors that we normally use to make our treatment choices.”
A patient with five positive nodes will benefit from chemotherapy, “even if she had a very low recurrence score,” he said, “because there is a very high clinical risk of disease recurrence,” and chemotherapy “is of benefit” in these situations, he asserted.
Dr. Lambertini said that the RxPONDER results – and also studies such as TAILORx, which demonstrated the ability of Oncotype DX to identify which patients with early breast cancer could skip chemotherapy – show that “chemotherapy has a role to play” and that most patients should receive it.
He suggested, however, that “probably the benefit of chemotherapy is smaller” in real life than was seen in these trials, because in the trials, they did not use optimal adjuvant endocrine therapy.
Treating individual patients
When it comes to making treatment decisions for individual patients, Dr. Winer said he has a “conversation with people about what the results of the study showed and what [he believes] that they need.”
For patients whose Oncotype DX score is in the “very low range, I do not recommend chemotherapy,” he said, preferring instead to use endocrine therapy for ovarian function suppression.
For women with a more intermediate score, “I explain that I don’t think we have an answer and that, if they would want to take the most traditional and conservative path, it would be to get chemotherapy.
“But I’m certainly not rigid about my recommendations, and I’m particularly open” to ovarian function suppression for a premenopausal woman with an Onctyope DX score of 20 and two positive nodes who does not have “other adverse features.”
“Ultimately, what pushes me in one direction or another,” Dr. Winer said, aside from number of positive nodes or the size of the tumor, “is the patient’s preferences.”
This was a theme taken up by Kim Sabelko, PhD, vice-president of scientific strategy and programs at Susan G. Komen, Dallas.
The results from RxPONDER and similar studies are “really interesting,” as researchers are “working out how to individualize treatment,” and that it is not a matter of “one size fits all.”
“We need to understand when to use chemotherapy and other drugs, and more importantly, when not to, because we don’t want to overtreat people who don’t necessarily need these drugs,” she commented.
Dr. Sabelko emphasized that treatment decisions “should be shared” between the patient and their doctor, and she noted that there “will be some people who are going to refuse chemotherapy for different reasons.”
These clinical trial results help clinicians to explain the risks and benefits of treatment options, but the treatment decision should be taken “together” with the patient, she emphasized.
Dr. Gnant has relationships with Sandoz, Amge, Daiichi Sankyo, AstraZeneca, Eli Lilly, Nanostring, Novartis, Pierre Fabre, TLC Pharmaceuticals, and Life Brain. Dr. Loibl has relationships with AbbVie, Amgen, AstraZeneca, Bayer, Bristol-Meyers Squibb, Celgene, Daiichi Sankyo, Eirgenix, GSK, Gilead, Lilly, Merck, Novartis, Pfizer, Pierre Fabre, Medscape, Puma, Roche, Samsung, Seagen, VM Scope, and GBG Forschungs.
A version of this article first appeared on Medscape.com.
Is this the most controversial topic in breast oncology? Quite likely: the results of a recent online poll show split votes and no consensus.
The topic is the use of chemotherapy for premenopausal women with early-stage hormone receptor–positive (HR+), human epidermal growth factor receptor 2–negative (HER2-) breast cancer.
, as the other expert countered?
The debate was held during the recent San Antonio Breast Cancer Symposium (SABCS), at which new results were presented that increased the controversy.
The controversy had arisen the previous year over results from the RxPONDER trial.
Five-year follow-up data from RxPONDER showed that adding chemotherapy to endocrine therapy did not improve outcomes over endocrine therapy alone for postmenopausal women with low-risk, node-positive HR+, HER2- breast cancer. This suggests that older women with early-stage breast cancer may safely forgo chemotherapy.
However, the same trial included premenopausal women with the same disease profile, and the results in this subgroup showed that there was benefit from chemotherapy, with a 5-year invasive disease-free survival (IDFS) rate of 94.2%, versus 89.0% for endocrine therapy alone (P = .0004).
The results were immediately controversial.
Some experts suggested the effect was due to the chemotherapy incidentally causing ovarian suppression, not the cytotoxic effect of the drugs on cancer cells. These experts were skeptical about the suggestion that chemotherapy works differently in premenopausal women than it does in postmenopausal women.
Some clinicians feel the lack of clarity creates an opportunity for greater discussion with women when making the treatment decision.
“When I have this conversation with patients, it’s really nuanced,” Stephanie L. Graff, MD, director of breast oncology, Lifespan Cancer Institute, Providence, R.I., told this news organization.
“I would choose chemotherapy for myself, but I’m a chemotherapy doctor, so I’m very comfortable with these medications and their side effects, and I am also very familiar with the slow burn of the side effects of endocrine therapy,” she said.
But for patients who are hearing their options for the first time, the idea of chemotherapy “feels scary,” and there is “a lot of stigma” associated with it, she commented.
Ultimately, she believes in offering patients as much information as possible, inasmuch as “knowledge is power.”
For Dr. Graff, the message from RxPONDER was that, in premenopausal patients with lymph node positive, HR+ breast cancer, “all comers benefited from chemotherapy.”
“And so if the goal is to be maximally aggressive and optimally lower your risk of distant recurrence, which is a life-threatening event, chemotherapy should offered.”
But chemotherapy comes with side effects, so it’s an important conversation to have with patients; RxPONDER showed that the absolute difference in the rate of distant recurrence with chemotherapy was relatively minor, she added.
Debate rages on
The debate at SABCS was moderated by Harold J. Burstein, MD, PhD, from the Dana-Farber Cancer Institute, Boston, who commented that if this was “a compelling question last week in clinic, it has now become red hot.”
At the meeting, held in December 2021, new longer-term data from the SOFT and TEXT clinical trials were presented, showing that ovarian suppression with tamoxifen plus an aromatase inhibitor provides a greater reduction in long-term risk of recurrence than tamoxifen alone.
Moreover, updated results from RxPONDER presented at the same session revealed that chemoendocrine therapy was associated with longer IDFS and distant relapse-free survival than endocrine therapy alone for women with one to three positive lymph nodes and a recurrence score of 25 or lower on the Oncotype DX (Genomic Health) 21-gene breast cancer assay.
Dr. Burstein said the debate over the use of chemotherapy in premenopausal women “is the most interesting question right now in early-stage breast cancer.”
The debate focused on the effect of chemotherapy in these patients – was it all down to ovarian function suppression?
Yes, argued Michael Gnant, MD, from the Medical University of Vienna.
Data from “modern adjuvant chemotherapy trials” suggest that chemo offers a 2%-3% benefit in distant disease-free survival at 5 years for premenopausal women, he noted. But the effect is much larger with ovarian function suppression via endocrine therapy, which provides 5-year disease-free and overall survival benefits of 9%-13%.
Older studies have shown that the benefit with chemotherapy is seen only in women who experience amenorrhea with the cytotoxic drugs, Dr. Gnant noted.
“In short, if you give adjuvant chemotherapy and you induce amenorrhea, then there is going to be a survival difference,” he said. “But if you give adjuvant chemotherapy and there is no amenorrhea, there won’t be an outcome difference.”
The ABSCG-05 trial, which compared endocrine therapy with chemotherapy, showed that “in the presence of optimal endocrine adjuvant treatment, adjuvant chemotherapy doesn’t add anything, because you have already achieved the effect of treatment-induced amenorrhea.”
So Dr. Gnant argued that the effect of chemotherapy in RxPONDER was due to ovarian function suppression.
But the real question is: “What does it mean for clinical practice?”
Dr. Gnant asserted that for the “large group of lower-risk premenopausal patients, tamoxifen will be good enough,” while those at moderate or intermediate risk should receive ovarian function suppression with either tamoxifen or an aromatase inhibitor, with the choice dictated by their adverse effects.
Chemotherapy “is just a graceless method of ovarian function suppression and should only be given to high-risk patients and to patients with endocrine nonresponsive disease,” he argued.
On the other side of the debate, Sibylle Loibl, MD, PhD, from the Centre of Hematology and Oncology, Bethanien, Frankfurt, argued that the effect is not all due to ovarian function suppression and that chemotherapy also has a cytotoxic effect in these patients.
“We need chemotherapy” because “cancer in young women is biologically different,” she asserted.
Dr. Loibl pointed to data currently awaiting publication in the Journal of the National Cancer Institute that suggest that younger women have “higher immune gene expression” that may make them more chemotherapy sensitive, and lower expression of hormone receptor genes, which “could make them less endocrine sensitive.”
She also cited data from a study from her own group that showed that pathologic complete response rates to neoadjuvant chemotherapy were higher in younger women with HR+, HER2- breast cancer, indicating a direct effect of chemotherapy on the disease and that age was an important prognostic factor.
The data on the induction of amenorrhea by chemotherapy is also not as clearcut as it seems, she commented. Chemotherapy does not achieve 100% amenorrhea, and gonadotropin-releasing hormone analogues are unable to suppress ovarian function in 20% of women.
Dr. Loibl concluded that the “chemotherapy effect is there, it is higher in young women with HR+, HER2- breast cancer,” and that the effect has two components.
“There is a direct cytotoxic effect which cannot be neglected, and there is an endocrine effect on the ovarian function suppression,” she argued.
“I think both are needed in young premenopausal patients,” she added.
Audience responses
After the debate, the audience was polled on what effect they thought chemotherapy was having in lower-risk HR+, HER2- breast cancer patients. About two-thirds responded that it was all or mostly due to ovarian function suppression.
However, the next question split the audience. They were presented with a clinical scenario: a 43-year-old woman with a mammographically detected 1.4-cm, intermediate grade, HR+, HER2- breast cancer who also had metastatic disease in one of three sentinel lymph nodes and whose recurrence score was 13.
When asked about the treatment plan they would choose for this patient, the audience was split over whether to opt for chemoendocrine therapy or endocrine therapy alone.
A similar clinical question was posited recently on Twitter, when Angela Toss, MD, PhD, from the University of Modena and Reggio Emilia, Italy, asked respondents which they would chose from among three options.
From the 815 votes that were cast, 46% chose Oncotype DX testing to determine the likely benefit of chemotherapy, 48% chose chemotherapy, and 6% picked ovarian function suppression and an aromatase inhibitor.
In response, Paolo Tarantino, MD, from the Dana-Farber Cancer Institute, commented: “If you had any doubt of which is the most controversial topic in breast oncology, doubt no more. 815 votes, no consensus.”
Approached for comment, Eric Winer, MD, director of the Yale Cancer Center, New Haven, Conn., said that the data from RxPONDER “in many ways was helpful, but ... it created about as many questions as it answered, if not more.”
Because the results showed a benefit from chemotherapy for premenopausal women but not for postmenopausal women with breast cancer, Dr. Winer told this news organization that one of the outstanding questions is “whether premenopausal women are fundamentally different from postmenopausal women ... and my answer to that is that is very unlikely.”
Dr. Winer added that the “real tragedy” of this trial was that it did not include women with more than three positive nodes, particularly those who have a low recurrence score, he said.
Clinicians are therefore left either “extrapolating” data from those with fewer nodes or “marching down a path that we’ve taken for years of just giving those people chemotherapy routinely,” even though there may be no benefit, Dr. Winer commented.
Another expert who was approached for comment had a different take on the data. Matteo Lambertini, MD, IRCCS Ospedale Policlinico San Martino, Genoa, Italy, agreed with Loibl’s argument that chemotherapy has a cytotoxic effect in premenopausal women with HR+, HER2- breast cancer in addition to its effect on ovarian function suppression.
He did not agree, however, that there is a question mark over what to do for patients with more than three positive lymph nodes.
Dr. Lambertini said in an interview that he thinks “too much” trust is placed in genomic testing and that there is a “risk of forgetting about all the other factors that we normally use to make our treatment choices.”
A patient with five positive nodes will benefit from chemotherapy, “even if she had a very low recurrence score,” he said, “because there is a very high clinical risk of disease recurrence,” and chemotherapy “is of benefit” in these situations, he asserted.
Dr. Lambertini said that the RxPONDER results – and also studies such as TAILORx, which demonstrated the ability of Oncotype DX to identify which patients with early breast cancer could skip chemotherapy – show that “chemotherapy has a role to play” and that most patients should receive it.
He suggested, however, that “probably the benefit of chemotherapy is smaller” in real life than was seen in these trials, because in the trials, they did not use optimal adjuvant endocrine therapy.
Treating individual patients
When it comes to making treatment decisions for individual patients, Dr. Winer said he has a “conversation with people about what the results of the study showed and what [he believes] that they need.”
For patients whose Oncotype DX score is in the “very low range, I do not recommend chemotherapy,” he said, preferring instead to use endocrine therapy for ovarian function suppression.
For women with a more intermediate score, “I explain that I don’t think we have an answer and that, if they would want to take the most traditional and conservative path, it would be to get chemotherapy.
“But I’m certainly not rigid about my recommendations, and I’m particularly open” to ovarian function suppression for a premenopausal woman with an Onctyope DX score of 20 and two positive nodes who does not have “other adverse features.”
“Ultimately, what pushes me in one direction or another,” Dr. Winer said, aside from number of positive nodes or the size of the tumor, “is the patient’s preferences.”
This was a theme taken up by Kim Sabelko, PhD, vice-president of scientific strategy and programs at Susan G. Komen, Dallas.
The results from RxPONDER and similar studies are “really interesting,” as researchers are “working out how to individualize treatment,” and that it is not a matter of “one size fits all.”
“We need to understand when to use chemotherapy and other drugs, and more importantly, when not to, because we don’t want to overtreat people who don’t necessarily need these drugs,” she commented.
Dr. Sabelko emphasized that treatment decisions “should be shared” between the patient and their doctor, and she noted that there “will be some people who are going to refuse chemotherapy for different reasons.”
These clinical trial results help clinicians to explain the risks and benefits of treatment options, but the treatment decision should be taken “together” with the patient, she emphasized.
Dr. Gnant has relationships with Sandoz, Amge, Daiichi Sankyo, AstraZeneca, Eli Lilly, Nanostring, Novartis, Pierre Fabre, TLC Pharmaceuticals, and Life Brain. Dr. Loibl has relationships with AbbVie, Amgen, AstraZeneca, Bayer, Bristol-Meyers Squibb, Celgene, Daiichi Sankyo, Eirgenix, GSK, Gilead, Lilly, Merck, Novartis, Pfizer, Pierre Fabre, Medscape, Puma, Roche, Samsung, Seagen, VM Scope, and GBG Forschungs.
A version of this article first appeared on Medscape.com.
Is this the most controversial topic in breast oncology? Quite likely: the results of a recent online poll show split votes and no consensus.
The topic is the use of chemotherapy for premenopausal women with early-stage hormone receptor–positive (HR+), human epidermal growth factor receptor 2–negative (HER2-) breast cancer.
, as the other expert countered?
The debate was held during the recent San Antonio Breast Cancer Symposium (SABCS), at which new results were presented that increased the controversy.
The controversy had arisen the previous year over results from the RxPONDER trial.
Five-year follow-up data from RxPONDER showed that adding chemotherapy to endocrine therapy did not improve outcomes over endocrine therapy alone for postmenopausal women with low-risk, node-positive HR+, HER2- breast cancer. This suggests that older women with early-stage breast cancer may safely forgo chemotherapy.
However, the same trial included premenopausal women with the same disease profile, and the results in this subgroup showed that there was benefit from chemotherapy, with a 5-year invasive disease-free survival (IDFS) rate of 94.2%, versus 89.0% for endocrine therapy alone (P = .0004).
The results were immediately controversial.
Some experts suggested the effect was due to the chemotherapy incidentally causing ovarian suppression, not the cytotoxic effect of the drugs on cancer cells. These experts were skeptical about the suggestion that chemotherapy works differently in premenopausal women than it does in postmenopausal women.
Some clinicians feel the lack of clarity creates an opportunity for greater discussion with women when making the treatment decision.
“When I have this conversation with patients, it’s really nuanced,” Stephanie L. Graff, MD, director of breast oncology, Lifespan Cancer Institute, Providence, R.I., told this news organization.
“I would choose chemotherapy for myself, but I’m a chemotherapy doctor, so I’m very comfortable with these medications and their side effects, and I am also very familiar with the slow burn of the side effects of endocrine therapy,” she said.
But for patients who are hearing their options for the first time, the idea of chemotherapy “feels scary,” and there is “a lot of stigma” associated with it, she commented.
Ultimately, she believes in offering patients as much information as possible, inasmuch as “knowledge is power.”
For Dr. Graff, the message from RxPONDER was that, in premenopausal patients with lymph node positive, HR+ breast cancer, “all comers benefited from chemotherapy.”
“And so if the goal is to be maximally aggressive and optimally lower your risk of distant recurrence, which is a life-threatening event, chemotherapy should offered.”
But chemotherapy comes with side effects, so it’s an important conversation to have with patients; RxPONDER showed that the absolute difference in the rate of distant recurrence with chemotherapy was relatively minor, she added.
Debate rages on
The debate at SABCS was moderated by Harold J. Burstein, MD, PhD, from the Dana-Farber Cancer Institute, Boston, who commented that if this was “a compelling question last week in clinic, it has now become red hot.”
At the meeting, held in December 2021, new longer-term data from the SOFT and TEXT clinical trials were presented, showing that ovarian suppression with tamoxifen plus an aromatase inhibitor provides a greater reduction in long-term risk of recurrence than tamoxifen alone.
Moreover, updated results from RxPONDER presented at the same session revealed that chemoendocrine therapy was associated with longer IDFS and distant relapse-free survival than endocrine therapy alone for women with one to three positive lymph nodes and a recurrence score of 25 or lower on the Oncotype DX (Genomic Health) 21-gene breast cancer assay.
Dr. Burstein said the debate over the use of chemotherapy in premenopausal women “is the most interesting question right now in early-stage breast cancer.”
The debate focused on the effect of chemotherapy in these patients – was it all down to ovarian function suppression?
Yes, argued Michael Gnant, MD, from the Medical University of Vienna.
Data from “modern adjuvant chemotherapy trials” suggest that chemo offers a 2%-3% benefit in distant disease-free survival at 5 years for premenopausal women, he noted. But the effect is much larger with ovarian function suppression via endocrine therapy, which provides 5-year disease-free and overall survival benefits of 9%-13%.
Older studies have shown that the benefit with chemotherapy is seen only in women who experience amenorrhea with the cytotoxic drugs, Dr. Gnant noted.
“In short, if you give adjuvant chemotherapy and you induce amenorrhea, then there is going to be a survival difference,” he said. “But if you give adjuvant chemotherapy and there is no amenorrhea, there won’t be an outcome difference.”
The ABSCG-05 trial, which compared endocrine therapy with chemotherapy, showed that “in the presence of optimal endocrine adjuvant treatment, adjuvant chemotherapy doesn’t add anything, because you have already achieved the effect of treatment-induced amenorrhea.”
So Dr. Gnant argued that the effect of chemotherapy in RxPONDER was due to ovarian function suppression.
But the real question is: “What does it mean for clinical practice?”
Dr. Gnant asserted that for the “large group of lower-risk premenopausal patients, tamoxifen will be good enough,” while those at moderate or intermediate risk should receive ovarian function suppression with either tamoxifen or an aromatase inhibitor, with the choice dictated by their adverse effects.
Chemotherapy “is just a graceless method of ovarian function suppression and should only be given to high-risk patients and to patients with endocrine nonresponsive disease,” he argued.
On the other side of the debate, Sibylle Loibl, MD, PhD, from the Centre of Hematology and Oncology, Bethanien, Frankfurt, argued that the effect is not all due to ovarian function suppression and that chemotherapy also has a cytotoxic effect in these patients.
“We need chemotherapy” because “cancer in young women is biologically different,” she asserted.
Dr. Loibl pointed to data currently awaiting publication in the Journal of the National Cancer Institute that suggest that younger women have “higher immune gene expression” that may make them more chemotherapy sensitive, and lower expression of hormone receptor genes, which “could make them less endocrine sensitive.”
She also cited data from a study from her own group that showed that pathologic complete response rates to neoadjuvant chemotherapy were higher in younger women with HR+, HER2- breast cancer, indicating a direct effect of chemotherapy on the disease and that age was an important prognostic factor.
The data on the induction of amenorrhea by chemotherapy is also not as clearcut as it seems, she commented. Chemotherapy does not achieve 100% amenorrhea, and gonadotropin-releasing hormone analogues are unable to suppress ovarian function in 20% of women.
Dr. Loibl concluded that the “chemotherapy effect is there, it is higher in young women with HR+, HER2- breast cancer,” and that the effect has two components.
“There is a direct cytotoxic effect which cannot be neglected, and there is an endocrine effect on the ovarian function suppression,” she argued.
“I think both are needed in young premenopausal patients,” she added.
Audience responses
After the debate, the audience was polled on what effect they thought chemotherapy was having in lower-risk HR+, HER2- breast cancer patients. About two-thirds responded that it was all or mostly due to ovarian function suppression.
However, the next question split the audience. They were presented with a clinical scenario: a 43-year-old woman with a mammographically detected 1.4-cm, intermediate grade, HR+, HER2- breast cancer who also had metastatic disease in one of three sentinel lymph nodes and whose recurrence score was 13.
When asked about the treatment plan they would choose for this patient, the audience was split over whether to opt for chemoendocrine therapy or endocrine therapy alone.
A similar clinical question was posited recently on Twitter, when Angela Toss, MD, PhD, from the University of Modena and Reggio Emilia, Italy, asked respondents which they would chose from among three options.
From the 815 votes that were cast, 46% chose Oncotype DX testing to determine the likely benefit of chemotherapy, 48% chose chemotherapy, and 6% picked ovarian function suppression and an aromatase inhibitor.
In response, Paolo Tarantino, MD, from the Dana-Farber Cancer Institute, commented: “If you had any doubt of which is the most controversial topic in breast oncology, doubt no more. 815 votes, no consensus.”
Approached for comment, Eric Winer, MD, director of the Yale Cancer Center, New Haven, Conn., said that the data from RxPONDER “in many ways was helpful, but ... it created about as many questions as it answered, if not more.”
Because the results showed a benefit from chemotherapy for premenopausal women but not for postmenopausal women with breast cancer, Dr. Winer told this news organization that one of the outstanding questions is “whether premenopausal women are fundamentally different from postmenopausal women ... and my answer to that is that is very unlikely.”
Dr. Winer added that the “real tragedy” of this trial was that it did not include women with more than three positive nodes, particularly those who have a low recurrence score, he said.
Clinicians are therefore left either “extrapolating” data from those with fewer nodes or “marching down a path that we’ve taken for years of just giving those people chemotherapy routinely,” even though there may be no benefit, Dr. Winer commented.
Another expert who was approached for comment had a different take on the data. Matteo Lambertini, MD, IRCCS Ospedale Policlinico San Martino, Genoa, Italy, agreed with Loibl’s argument that chemotherapy has a cytotoxic effect in premenopausal women with HR+, HER2- breast cancer in addition to its effect on ovarian function suppression.
He did not agree, however, that there is a question mark over what to do for patients with more than three positive lymph nodes.
Dr. Lambertini said in an interview that he thinks “too much” trust is placed in genomic testing and that there is a “risk of forgetting about all the other factors that we normally use to make our treatment choices.”
A patient with five positive nodes will benefit from chemotherapy, “even if she had a very low recurrence score,” he said, “because there is a very high clinical risk of disease recurrence,” and chemotherapy “is of benefit” in these situations, he asserted.
Dr. Lambertini said that the RxPONDER results – and also studies such as TAILORx, which demonstrated the ability of Oncotype DX to identify which patients with early breast cancer could skip chemotherapy – show that “chemotherapy has a role to play” and that most patients should receive it.
He suggested, however, that “probably the benefit of chemotherapy is smaller” in real life than was seen in these trials, because in the trials, they did not use optimal adjuvant endocrine therapy.
Treating individual patients
When it comes to making treatment decisions for individual patients, Dr. Winer said he has a “conversation with people about what the results of the study showed and what [he believes] that they need.”
For patients whose Oncotype DX score is in the “very low range, I do not recommend chemotherapy,” he said, preferring instead to use endocrine therapy for ovarian function suppression.
For women with a more intermediate score, “I explain that I don’t think we have an answer and that, if they would want to take the most traditional and conservative path, it would be to get chemotherapy.
“But I’m certainly not rigid about my recommendations, and I’m particularly open” to ovarian function suppression for a premenopausal woman with an Onctyope DX score of 20 and two positive nodes who does not have “other adverse features.”
“Ultimately, what pushes me in one direction or another,” Dr. Winer said, aside from number of positive nodes or the size of the tumor, “is the patient’s preferences.”
This was a theme taken up by Kim Sabelko, PhD, vice-president of scientific strategy and programs at Susan G. Komen, Dallas.
The results from RxPONDER and similar studies are “really interesting,” as researchers are “working out how to individualize treatment,” and that it is not a matter of “one size fits all.”
“We need to understand when to use chemotherapy and other drugs, and more importantly, when not to, because we don’t want to overtreat people who don’t necessarily need these drugs,” she commented.
Dr. Sabelko emphasized that treatment decisions “should be shared” between the patient and their doctor, and she noted that there “will be some people who are going to refuse chemotherapy for different reasons.”
These clinical trial results help clinicians to explain the risks and benefits of treatment options, but the treatment decision should be taken “together” with the patient, she emphasized.
Dr. Gnant has relationships with Sandoz, Amge, Daiichi Sankyo, AstraZeneca, Eli Lilly, Nanostring, Novartis, Pierre Fabre, TLC Pharmaceuticals, and Life Brain. Dr. Loibl has relationships with AbbVie, Amgen, AstraZeneca, Bayer, Bristol-Meyers Squibb, Celgene, Daiichi Sankyo, Eirgenix, GSK, Gilead, Lilly, Merck, Novartis, Pfizer, Pierre Fabre, Medscape, Puma, Roche, Samsung, Seagen, VM Scope, and GBG Forschungs.
A version of this article first appeared on Medscape.com.
New trial data show hair growth in more alopecia areata patients
BOSTON – according to updated results from two phase 3 trials presented at the annual meeting of the American Academy of Dermatology.
The results indicate improved response rates and hair growth among trial participants, said Brett King, MD, PhD, an associate professor of dermatology at Yale University, New Haven, Conn. He is the lead author of the analyses and presented the research.
Dr. King presented 36-week results from the clinical trials at the 2021 annual meeting of the European Academy of Dermatology and Venereology. The same results were also published March 26, 2022, in the New England Journal of Medicine.
“Every bit of data we’ve had is hugely important,” Dr. King said in an interview. “Every time we add 16 weeks of data across hundreds of patients, we are making a huge step forward toward the goal of [Food and Drug Administration approval for a medication for alopecia areata.”
All patients enrolled in the two trials, called BRAVE-AA1 and BRAVE-AA2, had severe alopecia areata, defined as a Severity of Alopecia Tool (SALT) score of at least 50, meaning 50% or less scalp coverage. The score ranges from 0 (no hair loss) to 100 (complete hair loss). The primary endpoint was a SALT score of 20 or less (80% scalp hair coverage).
The researchers pooled data from both clinical trials, with a combined enrollment of 1,200, for the 52-week results presented at the meeting. The placebo group stopped at 36 weeks, and these patients were randomly reassigned to either the 4-mg or 2-mg once-daily baricitinib treatment groups.
At baseline, patients enrolled in the trial had a mean SALT score of 85.5. After 52 weeks, 39.0% of patients who received 4 mg of baricitinib had at least 80% scalp coverage. Of this group, nearly three out of four (74.1%) had at least 90% scalp coverage, or a SALT score of 10 or less.
In patients who received 2 mg of baricitinib, 22.6% had a SALT score of 20 or less 20 (at least 80% scalp hair coverage) at 52 weeks, and two-thirds of that group (67.5%) had at least 90% scalp hair coverage at 52 weeks.
Comparatively, at 36 weeks, 35.2% of participants in BRAVE-AA1 and 32.5% of participants in BRAVE-AA2 receiving 4 mg of baricitinib had at least 80% scalp coverage. In the group taking the lower dose, 21.7% and 17.3% of patients in the BRAVE-AA1 and BRAVE-AA2 trials, respectively, had achieved at least 80% scalp coverage at 36 weeks. (These percentages differ slightly from the NEJM article because of a different analysis of missing data, Dr. King said. For comparison of both 36- and 52-week results, the percentages from the EADV are used above.)
The results indicate that 5% more patients reached the primary endpoint in the additional 16 weeks of the trial, Dr. King said.
Alopecia areata is an autoimmune condition where immune cells attack hair follicles, causing the hair to fall out, and is associated with emotional and psychological distress. Any hair follicle can be attacked, but they are rarely destroyed, so hair can regrow.
"Many underestimate the impact of this autoimmune hair loss condition," Adam Friedman, MD, professor and chair of dermatology at George Washington University, Washington, told this news organization. He was not involved with the trial. "The burden of the disease, which certainly is an emotional but also a physical one, definitely needs to be addressed with indicated FDA-approved drugs," he noted, which is the goal of these trials.
The BRAVE-AA1 and BRAVE-AA2 trials focused on scalp hair regrowth.
Eyebrow and eyelash growth, secondary outcomes, also improved between 36 and 52 weeks in both groups, calculated using the proportion of participants who had achieved full regrowth or regrowth with minimal gaps. At 36 weeks, about 31%-35% of patients who received 4 mg of baricitinib regrew eyebrow and eyelash hair. By 52 weeks, more than two out of five patients regrew eyebrow (44.1%) and eyelash (45.3%) hair.
“It’s a fantastic achievement and a major step forward in alopecia areata, especially for patients with the most severe and refractory cases,” said Arash Mostaghimi, MD, MPH, the director of inpatient dermatology at Brigham and Women’s Hospital in Boston, Massachusetts. Dr. Mostaghimi is on the advisory board for Eli Lilly, which manufactures baricitinib, and Brigham and Women’s was one of the clinical sites of the trial.
While dermatologists have been aware of how JAK inhibitors can affect hair regrowth in alopecia patients, they have been using these drugs off label, Dr. Friedman said. Therefore, these drugs are expensive and more difficult to access. These trials provide "data that proves the efficacy and safety of [baricitinib] under the umbrella of the FDA portal," he added, which will hopefully lead to an approved indication for alopecia areata, so it can be more accessible to patients.
Adverse events at 52 weeks were consistent with data from 36 weeks, which found that none of these adverse events occurred in more than 10% of participants. The most common adverse events were headache, acne, and increases in muscle-related blood markers. The most common infections reported were pneumonia, herpes zoster, and urinary tract infection.
In February 2022, the FDA granted priority review for baricitinib for the treatment of severe alopecia areata. Lilly expects a regulatory decision by the end of 2022, they said in a press release.
Lilly provided funding for the BRAVE-AA1 and BRAVE-AA2 trials. Dr. King reported financial relationships with Aclaris, Arena Pharmaceuticals, Bristol-Myers Squibb, Concert Pharmaceutics, Dermavant, Lilly, Pfizer, Regeneron, Sanofi Genzyme, and Viela Bio. Dr. Mostaghimi has reported serving on an advisory board for Lilly. Dr. Friedman reported no relevant financial relationships.
A version of this article first appeared on Medscape.com.
*This article was updated on 3/28/2022 to include Dr. Friedman's comments, and on 3/31/2022 to correct the statement regarding adverse events reported in the study
BOSTON – according to updated results from two phase 3 trials presented at the annual meeting of the American Academy of Dermatology.
The results indicate improved response rates and hair growth among trial participants, said Brett King, MD, PhD, an associate professor of dermatology at Yale University, New Haven, Conn. He is the lead author of the analyses and presented the research.
Dr. King presented 36-week results from the clinical trials at the 2021 annual meeting of the European Academy of Dermatology and Venereology. The same results were also published March 26, 2022, in the New England Journal of Medicine.
“Every bit of data we’ve had is hugely important,” Dr. King said in an interview. “Every time we add 16 weeks of data across hundreds of patients, we are making a huge step forward toward the goal of [Food and Drug Administration approval for a medication for alopecia areata.”
All patients enrolled in the two trials, called BRAVE-AA1 and BRAVE-AA2, had severe alopecia areata, defined as a Severity of Alopecia Tool (SALT) score of at least 50, meaning 50% or less scalp coverage. The score ranges from 0 (no hair loss) to 100 (complete hair loss). The primary endpoint was a SALT score of 20 or less (80% scalp hair coverage).
The researchers pooled data from both clinical trials, with a combined enrollment of 1,200, for the 52-week results presented at the meeting. The placebo group stopped at 36 weeks, and these patients were randomly reassigned to either the 4-mg or 2-mg once-daily baricitinib treatment groups.
At baseline, patients enrolled in the trial had a mean SALT score of 85.5. After 52 weeks, 39.0% of patients who received 4 mg of baricitinib had at least 80% scalp coverage. Of this group, nearly three out of four (74.1%) had at least 90% scalp coverage, or a SALT score of 10 or less.
In patients who received 2 mg of baricitinib, 22.6% had a SALT score of 20 or less 20 (at least 80% scalp hair coverage) at 52 weeks, and two-thirds of that group (67.5%) had at least 90% scalp hair coverage at 52 weeks.
Comparatively, at 36 weeks, 35.2% of participants in BRAVE-AA1 and 32.5% of participants in BRAVE-AA2 receiving 4 mg of baricitinib had at least 80% scalp coverage. In the group taking the lower dose, 21.7% and 17.3% of patients in the BRAVE-AA1 and BRAVE-AA2 trials, respectively, had achieved at least 80% scalp coverage at 36 weeks. (These percentages differ slightly from the NEJM article because of a different analysis of missing data, Dr. King said. For comparison of both 36- and 52-week results, the percentages from the EADV are used above.)
The results indicate that 5% more patients reached the primary endpoint in the additional 16 weeks of the trial, Dr. King said.
Alopecia areata is an autoimmune condition where immune cells attack hair follicles, causing the hair to fall out, and is associated with emotional and psychological distress. Any hair follicle can be attacked, but they are rarely destroyed, so hair can regrow.
"Many underestimate the impact of this autoimmune hair loss condition," Adam Friedman, MD, professor and chair of dermatology at George Washington University, Washington, told this news organization. He was not involved with the trial. "The burden of the disease, which certainly is an emotional but also a physical one, definitely needs to be addressed with indicated FDA-approved drugs," he noted, which is the goal of these trials.
The BRAVE-AA1 and BRAVE-AA2 trials focused on scalp hair regrowth.
Eyebrow and eyelash growth, secondary outcomes, also improved between 36 and 52 weeks in both groups, calculated using the proportion of participants who had achieved full regrowth or regrowth with minimal gaps. At 36 weeks, about 31%-35% of patients who received 4 mg of baricitinib regrew eyebrow and eyelash hair. By 52 weeks, more than two out of five patients regrew eyebrow (44.1%) and eyelash (45.3%) hair.
“It’s a fantastic achievement and a major step forward in alopecia areata, especially for patients with the most severe and refractory cases,” said Arash Mostaghimi, MD, MPH, the director of inpatient dermatology at Brigham and Women’s Hospital in Boston, Massachusetts. Dr. Mostaghimi is on the advisory board for Eli Lilly, which manufactures baricitinib, and Brigham and Women’s was one of the clinical sites of the trial.
While dermatologists have been aware of how JAK inhibitors can affect hair regrowth in alopecia patients, they have been using these drugs off label, Dr. Friedman said. Therefore, these drugs are expensive and more difficult to access. These trials provide "data that proves the efficacy and safety of [baricitinib] under the umbrella of the FDA portal," he added, which will hopefully lead to an approved indication for alopecia areata, so it can be more accessible to patients.
Adverse events at 52 weeks were consistent with data from 36 weeks, which found that none of these adverse events occurred in more than 10% of participants. The most common adverse events were headache, acne, and increases in muscle-related blood markers. The most common infections reported were pneumonia, herpes zoster, and urinary tract infection.
In February 2022, the FDA granted priority review for baricitinib for the treatment of severe alopecia areata. Lilly expects a regulatory decision by the end of 2022, they said in a press release.
Lilly provided funding for the BRAVE-AA1 and BRAVE-AA2 trials. Dr. King reported financial relationships with Aclaris, Arena Pharmaceuticals, Bristol-Myers Squibb, Concert Pharmaceutics, Dermavant, Lilly, Pfizer, Regeneron, Sanofi Genzyme, and Viela Bio. Dr. Mostaghimi has reported serving on an advisory board for Lilly. Dr. Friedman reported no relevant financial relationships.
A version of this article first appeared on Medscape.com.
*This article was updated on 3/28/2022 to include Dr. Friedman's comments, and on 3/31/2022 to correct the statement regarding adverse events reported in the study
BOSTON – according to updated results from two phase 3 trials presented at the annual meeting of the American Academy of Dermatology.
The results indicate improved response rates and hair growth among trial participants, said Brett King, MD, PhD, an associate professor of dermatology at Yale University, New Haven, Conn. He is the lead author of the analyses and presented the research.
Dr. King presented 36-week results from the clinical trials at the 2021 annual meeting of the European Academy of Dermatology and Venereology. The same results were also published March 26, 2022, in the New England Journal of Medicine.
“Every bit of data we’ve had is hugely important,” Dr. King said in an interview. “Every time we add 16 weeks of data across hundreds of patients, we are making a huge step forward toward the goal of [Food and Drug Administration approval for a medication for alopecia areata.”
All patients enrolled in the two trials, called BRAVE-AA1 and BRAVE-AA2, had severe alopecia areata, defined as a Severity of Alopecia Tool (SALT) score of at least 50, meaning 50% or less scalp coverage. The score ranges from 0 (no hair loss) to 100 (complete hair loss). The primary endpoint was a SALT score of 20 or less (80% scalp hair coverage).
The researchers pooled data from both clinical trials, with a combined enrollment of 1,200, for the 52-week results presented at the meeting. The placebo group stopped at 36 weeks, and these patients were randomly reassigned to either the 4-mg or 2-mg once-daily baricitinib treatment groups.
At baseline, patients enrolled in the trial had a mean SALT score of 85.5. After 52 weeks, 39.0% of patients who received 4 mg of baricitinib had at least 80% scalp coverage. Of this group, nearly three out of four (74.1%) had at least 90% scalp coverage, or a SALT score of 10 or less.
In patients who received 2 mg of baricitinib, 22.6% had a SALT score of 20 or less 20 (at least 80% scalp hair coverage) at 52 weeks, and two-thirds of that group (67.5%) had at least 90% scalp hair coverage at 52 weeks.
Comparatively, at 36 weeks, 35.2% of participants in BRAVE-AA1 and 32.5% of participants in BRAVE-AA2 receiving 4 mg of baricitinib had at least 80% scalp coverage. In the group taking the lower dose, 21.7% and 17.3% of patients in the BRAVE-AA1 and BRAVE-AA2 trials, respectively, had achieved at least 80% scalp coverage at 36 weeks. (These percentages differ slightly from the NEJM article because of a different analysis of missing data, Dr. King said. For comparison of both 36- and 52-week results, the percentages from the EADV are used above.)
The results indicate that 5% more patients reached the primary endpoint in the additional 16 weeks of the trial, Dr. King said.
Alopecia areata is an autoimmune condition where immune cells attack hair follicles, causing the hair to fall out, and is associated with emotional and psychological distress. Any hair follicle can be attacked, but they are rarely destroyed, so hair can regrow.
"Many underestimate the impact of this autoimmune hair loss condition," Adam Friedman, MD, professor and chair of dermatology at George Washington University, Washington, told this news organization. He was not involved with the trial. "The burden of the disease, which certainly is an emotional but also a physical one, definitely needs to be addressed with indicated FDA-approved drugs," he noted, which is the goal of these trials.
The BRAVE-AA1 and BRAVE-AA2 trials focused on scalp hair regrowth.
Eyebrow and eyelash growth, secondary outcomes, also improved between 36 and 52 weeks in both groups, calculated using the proportion of participants who had achieved full regrowth or regrowth with minimal gaps. At 36 weeks, about 31%-35% of patients who received 4 mg of baricitinib regrew eyebrow and eyelash hair. By 52 weeks, more than two out of five patients regrew eyebrow (44.1%) and eyelash (45.3%) hair.
“It’s a fantastic achievement and a major step forward in alopecia areata, especially for patients with the most severe and refractory cases,” said Arash Mostaghimi, MD, MPH, the director of inpatient dermatology at Brigham and Women’s Hospital in Boston, Massachusetts. Dr. Mostaghimi is on the advisory board for Eli Lilly, which manufactures baricitinib, and Brigham and Women’s was one of the clinical sites of the trial.
While dermatologists have been aware of how JAK inhibitors can affect hair regrowth in alopecia patients, they have been using these drugs off label, Dr. Friedman said. Therefore, these drugs are expensive and more difficult to access. These trials provide "data that proves the efficacy and safety of [baricitinib] under the umbrella of the FDA portal," he added, which will hopefully lead to an approved indication for alopecia areata, so it can be more accessible to patients.
Adverse events at 52 weeks were consistent with data from 36 weeks, which found that none of these adverse events occurred in more than 10% of participants. The most common adverse events were headache, acne, and increases in muscle-related blood markers. The most common infections reported were pneumonia, herpes zoster, and urinary tract infection.
In February 2022, the FDA granted priority review for baricitinib for the treatment of severe alopecia areata. Lilly expects a regulatory decision by the end of 2022, they said in a press release.
Lilly provided funding for the BRAVE-AA1 and BRAVE-AA2 trials. Dr. King reported financial relationships with Aclaris, Arena Pharmaceuticals, Bristol-Myers Squibb, Concert Pharmaceutics, Dermavant, Lilly, Pfizer, Regeneron, Sanofi Genzyme, and Viela Bio. Dr. Mostaghimi has reported serving on an advisory board for Lilly. Dr. Friedman reported no relevant financial relationships.
A version of this article first appeared on Medscape.com.
*This article was updated on 3/28/2022 to include Dr. Friedman's comments, and on 3/31/2022 to correct the statement regarding adverse events reported in the study
AT AAD 2022
Immunotherapy treatment shows promise for resectable liver cancer
(HCC), according to findings from an open-label phase 2 clinical trial published in The Lancet Gastroenterology and Hepatolgy.
The study compared the anti-PD1 antibody nivolumab (Opdivo, Bristol Myers Squibb) alone and nivolumab plus the anti-CTLA-4 antibody ipilimumab (Yervoy, Bristol Myers Squibb) among patients with resectable disease at a single center in Sweden. The treatments were found to be “safe and feasible in patients with resectable hepatocellular carcinoma,” wrote researchers who were led by Ahmed O. Kaseb, MD, a medical oncologist with MD Anderson Cancer Center, Houston.
The rate of 5-year tumor recurrence following HCC resection can be as high as 70%, and there are no approved neoadjuvant or adjuvant therapies.
Immune checkpoint therapy has not been well studied in early-stage HCC, but it is used in advanced HCC.
The combination of PDL1 blockade with atezolizumab and VEGF blockade with bevacizumab, is currently a first-line treatment for advanced HCC. “Checkpoint inhibitors targeting PD1 and PDL1 and CTLA4 are active, tolerable, and clinically beneficial against advanced HCC,” according to researchers writing in a Nature Reviews article published in April 2021.
There are other promising immunotherapies under study for HCC, such as additional checkpoint inhibitors, adoptive cell transfer, vaccination, and virotherapy.
Small study of 27 patients
The Lancet study included 27 patients (64 years mean age, 19 patients were male). Twenty-three percent of patients on nivolumab alone had a partial pathological response at week 6, while none in the combination group had a response. Among 20 patients who underwent surgery, 3 of 9 (33%) and 3 of 11 (27%) in the combination group experienced a major pathological response. Two patients in the nivolumab and three patients in the combination group achieved a complete pathological response.
Disease progression occurred in 7 of 12 patients who were evaluated in the nivolumab group, and 4 of 13 patients in the combination group. Estimated median time to disease progression in the nivolumab group was 9.4 months (95% confidence interval, 1.47 to not estimable) and 19.53 months (95% CI, 2.33 to not estimable) in the combination group. Two-year progression-free survival was estimated to be 42% (95% CI, 21%-81%) in the nivolumab group and 26% (95% CI, 8%-78%, no significant difference) in the combination group.
Among 20 patients who underwent surgery, 6 patients had experienced a major pathological response. None of the 6 patients had a recurrence after a median follow-up of 26.8 months, versus 7 recurrences among 14 patients without a pathological response (log-rank P = .049).
Seventy-seven percent of patients in the nivolumab group experienced at least one adverse event (23% grade 3-4), as did 86% in the combination group (43% grade 3-4, difference nonsignificant). No patients delayed or canceled surgery because of adverse events.
Patients who had a major pathological response on the combination treatment had higher levels of immune infiltration versus baseline values. Those who had complete pathological responses in the nivolumab group had high infiltration at baseline. Those results imply some optimism for further study. “These data suggest that, with the immune-priming ability of anti–CTLA-4 treatment, nivolumab plus ipilimumab was able to generate a major pathological response even in tumours that had low immune infiltration at baseline,” the authors wrote.
The study was limited by its open-label nature and small sample size, and it was conducted at a single center.
The study was funded by Bristol Myers Squibb and the National Institutes of Health. Dr. Kaseb reports consulting, advisory roles or stock ownership, or both with Bristol-Myers Squibb.
(HCC), according to findings from an open-label phase 2 clinical trial published in The Lancet Gastroenterology and Hepatolgy.
The study compared the anti-PD1 antibody nivolumab (Opdivo, Bristol Myers Squibb) alone and nivolumab plus the anti-CTLA-4 antibody ipilimumab (Yervoy, Bristol Myers Squibb) among patients with resectable disease at a single center in Sweden. The treatments were found to be “safe and feasible in patients with resectable hepatocellular carcinoma,” wrote researchers who were led by Ahmed O. Kaseb, MD, a medical oncologist with MD Anderson Cancer Center, Houston.
The rate of 5-year tumor recurrence following HCC resection can be as high as 70%, and there are no approved neoadjuvant or adjuvant therapies.
Immune checkpoint therapy has not been well studied in early-stage HCC, but it is used in advanced HCC.
The combination of PDL1 blockade with atezolizumab and VEGF blockade with bevacizumab, is currently a first-line treatment for advanced HCC. “Checkpoint inhibitors targeting PD1 and PDL1 and CTLA4 are active, tolerable, and clinically beneficial against advanced HCC,” according to researchers writing in a Nature Reviews article published in April 2021.
There are other promising immunotherapies under study for HCC, such as additional checkpoint inhibitors, adoptive cell transfer, vaccination, and virotherapy.
Small study of 27 patients
The Lancet study included 27 patients (64 years mean age, 19 patients were male). Twenty-three percent of patients on nivolumab alone had a partial pathological response at week 6, while none in the combination group had a response. Among 20 patients who underwent surgery, 3 of 9 (33%) and 3 of 11 (27%) in the combination group experienced a major pathological response. Two patients in the nivolumab and three patients in the combination group achieved a complete pathological response.
Disease progression occurred in 7 of 12 patients who were evaluated in the nivolumab group, and 4 of 13 patients in the combination group. Estimated median time to disease progression in the nivolumab group was 9.4 months (95% confidence interval, 1.47 to not estimable) and 19.53 months (95% CI, 2.33 to not estimable) in the combination group. Two-year progression-free survival was estimated to be 42% (95% CI, 21%-81%) in the nivolumab group and 26% (95% CI, 8%-78%, no significant difference) in the combination group.
Among 20 patients who underwent surgery, 6 patients had experienced a major pathological response. None of the 6 patients had a recurrence after a median follow-up of 26.8 months, versus 7 recurrences among 14 patients without a pathological response (log-rank P = .049).
Seventy-seven percent of patients in the nivolumab group experienced at least one adverse event (23% grade 3-4), as did 86% in the combination group (43% grade 3-4, difference nonsignificant). No patients delayed or canceled surgery because of adverse events.
Patients who had a major pathological response on the combination treatment had higher levels of immune infiltration versus baseline values. Those who had complete pathological responses in the nivolumab group had high infiltration at baseline. Those results imply some optimism for further study. “These data suggest that, with the immune-priming ability of anti–CTLA-4 treatment, nivolumab plus ipilimumab was able to generate a major pathological response even in tumours that had low immune infiltration at baseline,” the authors wrote.
The study was limited by its open-label nature and small sample size, and it was conducted at a single center.
The study was funded by Bristol Myers Squibb and the National Institutes of Health. Dr. Kaseb reports consulting, advisory roles or stock ownership, or both with Bristol-Myers Squibb.
(HCC), according to findings from an open-label phase 2 clinical trial published in The Lancet Gastroenterology and Hepatolgy.
The study compared the anti-PD1 antibody nivolumab (Opdivo, Bristol Myers Squibb) alone and nivolumab plus the anti-CTLA-4 antibody ipilimumab (Yervoy, Bristol Myers Squibb) among patients with resectable disease at a single center in Sweden. The treatments were found to be “safe and feasible in patients with resectable hepatocellular carcinoma,” wrote researchers who were led by Ahmed O. Kaseb, MD, a medical oncologist with MD Anderson Cancer Center, Houston.
The rate of 5-year tumor recurrence following HCC resection can be as high as 70%, and there are no approved neoadjuvant or adjuvant therapies.
Immune checkpoint therapy has not been well studied in early-stage HCC, but it is used in advanced HCC.
The combination of PDL1 blockade with atezolizumab and VEGF blockade with bevacizumab, is currently a first-line treatment for advanced HCC. “Checkpoint inhibitors targeting PD1 and PDL1 and CTLA4 are active, tolerable, and clinically beneficial against advanced HCC,” according to researchers writing in a Nature Reviews article published in April 2021.
There are other promising immunotherapies under study for HCC, such as additional checkpoint inhibitors, adoptive cell transfer, vaccination, and virotherapy.
Small study of 27 patients
The Lancet study included 27 patients (64 years mean age, 19 patients were male). Twenty-three percent of patients on nivolumab alone had a partial pathological response at week 6, while none in the combination group had a response. Among 20 patients who underwent surgery, 3 of 9 (33%) and 3 of 11 (27%) in the combination group experienced a major pathological response. Two patients in the nivolumab and three patients in the combination group achieved a complete pathological response.
Disease progression occurred in 7 of 12 patients who were evaluated in the nivolumab group, and 4 of 13 patients in the combination group. Estimated median time to disease progression in the nivolumab group was 9.4 months (95% confidence interval, 1.47 to not estimable) and 19.53 months (95% CI, 2.33 to not estimable) in the combination group. Two-year progression-free survival was estimated to be 42% (95% CI, 21%-81%) in the nivolumab group and 26% (95% CI, 8%-78%, no significant difference) in the combination group.
Among 20 patients who underwent surgery, 6 patients had experienced a major pathological response. None of the 6 patients had a recurrence after a median follow-up of 26.8 months, versus 7 recurrences among 14 patients without a pathological response (log-rank P = .049).
Seventy-seven percent of patients in the nivolumab group experienced at least one adverse event (23% grade 3-4), as did 86% in the combination group (43% grade 3-4, difference nonsignificant). No patients delayed or canceled surgery because of adverse events.
Patients who had a major pathological response on the combination treatment had higher levels of immune infiltration versus baseline values. Those who had complete pathological responses in the nivolumab group had high infiltration at baseline. Those results imply some optimism for further study. “These data suggest that, with the immune-priming ability of anti–CTLA-4 treatment, nivolumab plus ipilimumab was able to generate a major pathological response even in tumours that had low immune infiltration at baseline,” the authors wrote.
The study was limited by its open-label nature and small sample size, and it was conducted at a single center.
The study was funded by Bristol Myers Squibb and the National Institutes of Health. Dr. Kaseb reports consulting, advisory roles or stock ownership, or both with Bristol-Myers Squibb.
FROM THE LANCET GASTROENTEROLOGY & HEPATOLOGY
Pfizer recalls BP drugs because of potential carcinogen
Pfizer is voluntarily recalling some antihypertensive medications because of unacceptable levels of a potential carcinogen, the company announced.
The affected products are quinapril HCI/hydrochlorothiazide (Accuretic) tablets that Pfizer distributes, and two authorized generics, quinapril plus hydrochlorothiazide and quinapril HCI/hydrochlorothiazide, distributed by Greenstone. The drugs have been withdrawn because of the presence of nitrosamine, N-nitroso-quinapril.
“Although long-term ingestion of N-nitroso-quinapril may be associated with a potential increased cancer risk in humans, there is no immediate risk to patients taking this medication,” Pfizer said in a news release.
The tablets are indicated for the treatment of hypertension. Patients currently taking the products are asked to consult with their doctor about alternative treatment options.
To date, there have been no reports of adverse events related to the recall, the company said.
In all, Pfizer is recalling six lots of Accuretic tablets (two at 10 mg/12.5 mg, three at 20 mg/12.5 mg, and one at 20 mg/25 mg), one lot of quinapril plus hydrochlorothiazide 20-mg/25-mg tablets, and four lots of quinapril HCl/ hydrochlorothiazide tablets (three at 20 mg/12.5 mg and one at 20 mg/25 mg)
The recalled tablets were sold in 90-count bottles distributed in the United States and Puerto Rico between November 2019 and March 2022. Product codes and lot numbers of the recalled medications are listed on the Pfizer website.
Patients who are taking this product should consult with their health care provider or pharmacy to determine if they have the affected product. Those with the affected tablets should contact claims management firm Sedgwick by phone at 888-843-0247 Monday through Friday from 8 a.m. to 5 p.m. ET for instructions on how to return their product and obtain reimbursement.
Health care providers with medical questions regarding the recall can contact Pfizer by telephone at 800-438-1985, option 3, Monday through Friday 8 a.m. to 9 p.m. ET.
Providers should report adverse reactions or quality problems they experience using these tablets to Pfizer either by telephone at 800-438-1985, option 1, by regular mail or by fax, or to the Food and Drug Administration’s MedWatch program.
A version of this article first appeared on Medscape.com.
Pfizer is voluntarily recalling some antihypertensive medications because of unacceptable levels of a potential carcinogen, the company announced.
The affected products are quinapril HCI/hydrochlorothiazide (Accuretic) tablets that Pfizer distributes, and two authorized generics, quinapril plus hydrochlorothiazide and quinapril HCI/hydrochlorothiazide, distributed by Greenstone. The drugs have been withdrawn because of the presence of nitrosamine, N-nitroso-quinapril.
“Although long-term ingestion of N-nitroso-quinapril may be associated with a potential increased cancer risk in humans, there is no immediate risk to patients taking this medication,” Pfizer said in a news release.
The tablets are indicated for the treatment of hypertension. Patients currently taking the products are asked to consult with their doctor about alternative treatment options.
To date, there have been no reports of adverse events related to the recall, the company said.
In all, Pfizer is recalling six lots of Accuretic tablets (two at 10 mg/12.5 mg, three at 20 mg/12.5 mg, and one at 20 mg/25 mg), one lot of quinapril plus hydrochlorothiazide 20-mg/25-mg tablets, and four lots of quinapril HCl/ hydrochlorothiazide tablets (three at 20 mg/12.5 mg and one at 20 mg/25 mg)
The recalled tablets were sold in 90-count bottles distributed in the United States and Puerto Rico between November 2019 and March 2022. Product codes and lot numbers of the recalled medications are listed on the Pfizer website.
Patients who are taking this product should consult with their health care provider or pharmacy to determine if they have the affected product. Those with the affected tablets should contact claims management firm Sedgwick by phone at 888-843-0247 Monday through Friday from 8 a.m. to 5 p.m. ET for instructions on how to return their product and obtain reimbursement.
Health care providers with medical questions regarding the recall can contact Pfizer by telephone at 800-438-1985, option 3, Monday through Friday 8 a.m. to 9 p.m. ET.
Providers should report adverse reactions or quality problems they experience using these tablets to Pfizer either by telephone at 800-438-1985, option 1, by regular mail or by fax, or to the Food and Drug Administration’s MedWatch program.
A version of this article first appeared on Medscape.com.
Pfizer is voluntarily recalling some antihypertensive medications because of unacceptable levels of a potential carcinogen, the company announced.
The affected products are quinapril HCI/hydrochlorothiazide (Accuretic) tablets that Pfizer distributes, and two authorized generics, quinapril plus hydrochlorothiazide and quinapril HCI/hydrochlorothiazide, distributed by Greenstone. The drugs have been withdrawn because of the presence of nitrosamine, N-nitroso-quinapril.
“Although long-term ingestion of N-nitroso-quinapril may be associated with a potential increased cancer risk in humans, there is no immediate risk to patients taking this medication,” Pfizer said in a news release.
The tablets are indicated for the treatment of hypertension. Patients currently taking the products are asked to consult with their doctor about alternative treatment options.
To date, there have been no reports of adverse events related to the recall, the company said.
In all, Pfizer is recalling six lots of Accuretic tablets (two at 10 mg/12.5 mg, three at 20 mg/12.5 mg, and one at 20 mg/25 mg), one lot of quinapril plus hydrochlorothiazide 20-mg/25-mg tablets, and four lots of quinapril HCl/ hydrochlorothiazide tablets (three at 20 mg/12.5 mg and one at 20 mg/25 mg)
The recalled tablets were sold in 90-count bottles distributed in the United States and Puerto Rico between November 2019 and March 2022. Product codes and lot numbers of the recalled medications are listed on the Pfizer website.
Patients who are taking this product should consult with their health care provider or pharmacy to determine if they have the affected product. Those with the affected tablets should contact claims management firm Sedgwick by phone at 888-843-0247 Monday through Friday from 8 a.m. to 5 p.m. ET for instructions on how to return their product and obtain reimbursement.
Health care providers with medical questions regarding the recall can contact Pfizer by telephone at 800-438-1985, option 3, Monday through Friday 8 a.m. to 9 p.m. ET.
Providers should report adverse reactions or quality problems they experience using these tablets to Pfizer either by telephone at 800-438-1985, option 1, by regular mail or by fax, or to the Food and Drug Administration’s MedWatch program.
A version of this article first appeared on Medscape.com.
FDA approves new immunotherapy combo for metastatic melanoma
in adults and children 12 years or older, according to the drug’s manufacturer, Bristol-Myers Squibb.
Approval was based on the company’s RELATIVITY-047 trial, which found a median progression-free survival (PFS) of 10.1 months among 355 patients randomly assigned to the combination therapy compared with 4.6 months among 359 patients who received nivolumab alone (hazard ratio, 0.75; P = .0055).
In the combination therapy group, 18.9% of patients reported a grade 3/4 drug-related adverse event, compared with 9.7% in the nivolumab group; 14.6% of patients in the combination group had drug-related adverse events leading to discontinuation versus 6.7% of those receiving monotherapy, the company noted in a press release.
Relatlimab is the company’s third immune checkpoint inhibitor to reach the U.S. market, joining the PD-1 inhibitor nivolumab and the CTLA-4 blocker ipilimumab. Relatlimab targets LAG-3, a cell-surface receptor found on activated CD4+ T cells.
Nivolumab plus ipilimumab is currently the standard of care for previously untreated metastatic or inoperable melanoma. Both combinations produce similar PFS, but the incidence of grade 3/4 adverse events is higher with ipilimumab, according to a Jan. 6, 2022, editorial in the New England Journal of Medicine.
Musculoskeletal pain, fatigue, rash, pruritus, and diarrhea were the most common adverse reactions with combination nivolumab/relatlimab, occurring in 20% or more of RELATIVITY-047 trial participants.
Adrenal insufficiency, anemia, colitis, pneumonia, and myocardial infarction were the most frequent serious adverse reactions, but each occurred in less than 2% of patients. There were three fatal adverse events in the trial caused by hemophagocytic lymphohistiocytosis, acute lung edema, and pneumonitis.
The approved dosage is 480 mg nivolumab and 160 mg relatlimab administered intravenously every 4 weeks.
A version of this article first appeared on Medscape.com.
in adults and children 12 years or older, according to the drug’s manufacturer, Bristol-Myers Squibb.
Approval was based on the company’s RELATIVITY-047 trial, which found a median progression-free survival (PFS) of 10.1 months among 355 patients randomly assigned to the combination therapy compared with 4.6 months among 359 patients who received nivolumab alone (hazard ratio, 0.75; P = .0055).
In the combination therapy group, 18.9% of patients reported a grade 3/4 drug-related adverse event, compared with 9.7% in the nivolumab group; 14.6% of patients in the combination group had drug-related adverse events leading to discontinuation versus 6.7% of those receiving monotherapy, the company noted in a press release.
Relatlimab is the company’s third immune checkpoint inhibitor to reach the U.S. market, joining the PD-1 inhibitor nivolumab and the CTLA-4 blocker ipilimumab. Relatlimab targets LAG-3, a cell-surface receptor found on activated CD4+ T cells.
Nivolumab plus ipilimumab is currently the standard of care for previously untreated metastatic or inoperable melanoma. Both combinations produce similar PFS, but the incidence of grade 3/4 adverse events is higher with ipilimumab, according to a Jan. 6, 2022, editorial in the New England Journal of Medicine.
Musculoskeletal pain, fatigue, rash, pruritus, and diarrhea were the most common adverse reactions with combination nivolumab/relatlimab, occurring in 20% or more of RELATIVITY-047 trial participants.
Adrenal insufficiency, anemia, colitis, pneumonia, and myocardial infarction were the most frequent serious adverse reactions, but each occurred in less than 2% of patients. There were three fatal adverse events in the trial caused by hemophagocytic lymphohistiocytosis, acute lung edema, and pneumonitis.
The approved dosage is 480 mg nivolumab and 160 mg relatlimab administered intravenously every 4 weeks.
A version of this article first appeared on Medscape.com.
in adults and children 12 years or older, according to the drug’s manufacturer, Bristol-Myers Squibb.
Approval was based on the company’s RELATIVITY-047 trial, which found a median progression-free survival (PFS) of 10.1 months among 355 patients randomly assigned to the combination therapy compared with 4.6 months among 359 patients who received nivolumab alone (hazard ratio, 0.75; P = .0055).
In the combination therapy group, 18.9% of patients reported a grade 3/4 drug-related adverse event, compared with 9.7% in the nivolumab group; 14.6% of patients in the combination group had drug-related adverse events leading to discontinuation versus 6.7% of those receiving monotherapy, the company noted in a press release.
Relatlimab is the company’s third immune checkpoint inhibitor to reach the U.S. market, joining the PD-1 inhibitor nivolumab and the CTLA-4 blocker ipilimumab. Relatlimab targets LAG-3, a cell-surface receptor found on activated CD4+ T cells.
Nivolumab plus ipilimumab is currently the standard of care for previously untreated metastatic or inoperable melanoma. Both combinations produce similar PFS, but the incidence of grade 3/4 adverse events is higher with ipilimumab, according to a Jan. 6, 2022, editorial in the New England Journal of Medicine.
Musculoskeletal pain, fatigue, rash, pruritus, and diarrhea were the most common adverse reactions with combination nivolumab/relatlimab, occurring in 20% or more of RELATIVITY-047 trial participants.
Adrenal insufficiency, anemia, colitis, pneumonia, and myocardial infarction were the most frequent serious adverse reactions, but each occurred in less than 2% of patients. There were three fatal adverse events in the trial caused by hemophagocytic lymphohistiocytosis, acute lung edema, and pneumonitis.
The approved dosage is 480 mg nivolumab and 160 mg relatlimab administered intravenously every 4 weeks.
A version of this article first appeared on Medscape.com.
First-line CAR T-cell therapy could help cure some lymphomas
Results of the phase 2 ZUMA-12 trial suggest that axicabtagene ciloleucel (axi-cel), a chimeric antigen receptor (CAR) T-cell therapy approved to treat certain types of lymphoma, also shows promise as a treatment for another group of lymphoma patients – those with high-risk large B-cell lymphoma (LBCL) who failed two rounds of standard chemoimmunotherapy. In fact, a study author said, first-line treatment with this therapy could help usher some patients toward a cure.
The results appeared March 21, 2022, in Nature Medicine.
“The high efficacy with manageable safety profile suggest that further evaluation of axi-cel in first-line setting in patients with high-risk LBCL is warranted in a randomized, phase 3 trial comparing it to standard chemoimmunotherapy,” study lead author Sattva S. Neelapu, MD, of the University of Texas MD Anderson Cancer Center, Houston, said in an interview.
According to Dr. Neelapu, “patients with high-risk LBCL include those with high-intermediate or high International Prognostic Index score and those with certain molecular subtypes such as double- or triple-hit lymphoma. These patients have lower response rates and lower progression-free and overall survival with standard chemoimmunotherapy.”
Treatment of these patients can be especially challenging because they are underrepresented in clinical research, hematologist Michael Dickinson, MBBS, of the Peter MacCallum Cancer Center in Melbourne, said in an interview. “They often have disease that requires urgent treatment, so there is no time to recruit them into trials. A feature of ZUMA-12 is that it allowed patients to be recruited after short exposure to chemotherapy, which means that higher-risk patients could successfully be recruited into the trial.”
Axi-cel is already Food and Drug Administration approved for treatment of relapsed or refractory LBCL after 2 or more lines of systemic therapy plus relapsed or refractory follicular lymphoma, also after two or more lines of systemic therapy, Dr. Neelapu said.
For this study, researchers administered the treatment to 40 subjects with high-risk disease from 2019-2020 (median age, 61 years; 68% male; 95% at disease stage III or IV).
The researchers reported that 78% of 37 patients in the primary efficacy analysis reached complete response rate (95% confidence interval, 62-90); the median time to first complete response rate was 30 days (range, 27-207). About 89% of these subjects reached the secondary endpoint of objective response rate (95% CI, 75-97); the median time to first objective response was 29 days (range, 27-207).
At a median follow-up of 15.9 months, 73% were still in objective response.
“This is quite remarkable,” Dr. Neelapu said. “The durability of more than 70% is far higher than what would be expected with standard chemoimmunotherapy in these patients – under 40% durability with standard chemoimmunotherapy. Also, axi-cel induces durable responses in about 40% of patients in second- and third-line setting. However, when used as part of first-line therapy in this study, durable responses were observed in more than 70% of patients, suggesting that the efficacy of axi-cel may be much higher when used in first-line setting.”
Dr. Neelapu added: “Although the follow-up is short, it is highly likely that the majority of the patients with ongoing response beyond 1 year will likely be cured of their lymphoma.”
As for side effects, no treatment-related grade 5 events occurred, but 18 patients (45%) experienced serious adverse events. Grade 3 or higher cytokine release syndrome occurred in three patients (8%) and nine experienced neurologic events (23%).
“The majority of the higher-grade adverse events observed were due to cytopenias, which were expected due to the conditioning therapy,” Dr. Neelapu said. “Such cytopenias would also have been expected if these patients had received standard chemoimmunotherapy.”
Six patients (15%) died, 4 of progressive disease after going forward to other therapies.
As for cost, Dr. Neelapu said it should be similar to that of axi-cel as an FDA-approved third-line therapy. Axi-cel is highly expensive. Research has suggested that CAR T-cell therapy can boost costs beyond standard chemotherapy by $350,000-$490,000 with gains of 2-8 years of life (J Med Econ. Jan-Dec 2021;24[1]:458-68).
The study was funded by Kite. The authors reported various disclosures.
Results of the phase 2 ZUMA-12 trial suggest that axicabtagene ciloleucel (axi-cel), a chimeric antigen receptor (CAR) T-cell therapy approved to treat certain types of lymphoma, also shows promise as a treatment for another group of lymphoma patients – those with high-risk large B-cell lymphoma (LBCL) who failed two rounds of standard chemoimmunotherapy. In fact, a study author said, first-line treatment with this therapy could help usher some patients toward a cure.
The results appeared March 21, 2022, in Nature Medicine.
“The high efficacy with manageable safety profile suggest that further evaluation of axi-cel in first-line setting in patients with high-risk LBCL is warranted in a randomized, phase 3 trial comparing it to standard chemoimmunotherapy,” study lead author Sattva S. Neelapu, MD, of the University of Texas MD Anderson Cancer Center, Houston, said in an interview.
According to Dr. Neelapu, “patients with high-risk LBCL include those with high-intermediate or high International Prognostic Index score and those with certain molecular subtypes such as double- or triple-hit lymphoma. These patients have lower response rates and lower progression-free and overall survival with standard chemoimmunotherapy.”
Treatment of these patients can be especially challenging because they are underrepresented in clinical research, hematologist Michael Dickinson, MBBS, of the Peter MacCallum Cancer Center in Melbourne, said in an interview. “They often have disease that requires urgent treatment, so there is no time to recruit them into trials. A feature of ZUMA-12 is that it allowed patients to be recruited after short exposure to chemotherapy, which means that higher-risk patients could successfully be recruited into the trial.”
Axi-cel is already Food and Drug Administration approved for treatment of relapsed or refractory LBCL after 2 or more lines of systemic therapy plus relapsed or refractory follicular lymphoma, also after two or more lines of systemic therapy, Dr. Neelapu said.
For this study, researchers administered the treatment to 40 subjects with high-risk disease from 2019-2020 (median age, 61 years; 68% male; 95% at disease stage III or IV).
The researchers reported that 78% of 37 patients in the primary efficacy analysis reached complete response rate (95% confidence interval, 62-90); the median time to first complete response rate was 30 days (range, 27-207). About 89% of these subjects reached the secondary endpoint of objective response rate (95% CI, 75-97); the median time to first objective response was 29 days (range, 27-207).
At a median follow-up of 15.9 months, 73% were still in objective response.
“This is quite remarkable,” Dr. Neelapu said. “The durability of more than 70% is far higher than what would be expected with standard chemoimmunotherapy in these patients – under 40% durability with standard chemoimmunotherapy. Also, axi-cel induces durable responses in about 40% of patients in second- and third-line setting. However, when used as part of first-line therapy in this study, durable responses were observed in more than 70% of patients, suggesting that the efficacy of axi-cel may be much higher when used in first-line setting.”
Dr. Neelapu added: “Although the follow-up is short, it is highly likely that the majority of the patients with ongoing response beyond 1 year will likely be cured of their lymphoma.”
As for side effects, no treatment-related grade 5 events occurred, but 18 patients (45%) experienced serious adverse events. Grade 3 or higher cytokine release syndrome occurred in three patients (8%) and nine experienced neurologic events (23%).
“The majority of the higher-grade adverse events observed were due to cytopenias, which were expected due to the conditioning therapy,” Dr. Neelapu said. “Such cytopenias would also have been expected if these patients had received standard chemoimmunotherapy.”
Six patients (15%) died, 4 of progressive disease after going forward to other therapies.
As for cost, Dr. Neelapu said it should be similar to that of axi-cel as an FDA-approved third-line therapy. Axi-cel is highly expensive. Research has suggested that CAR T-cell therapy can boost costs beyond standard chemotherapy by $350,000-$490,000 with gains of 2-8 years of life (J Med Econ. Jan-Dec 2021;24[1]:458-68).
The study was funded by Kite. The authors reported various disclosures.
Results of the phase 2 ZUMA-12 trial suggest that axicabtagene ciloleucel (axi-cel), a chimeric antigen receptor (CAR) T-cell therapy approved to treat certain types of lymphoma, also shows promise as a treatment for another group of lymphoma patients – those with high-risk large B-cell lymphoma (LBCL) who failed two rounds of standard chemoimmunotherapy. In fact, a study author said, first-line treatment with this therapy could help usher some patients toward a cure.
The results appeared March 21, 2022, in Nature Medicine.
“The high efficacy with manageable safety profile suggest that further evaluation of axi-cel in first-line setting in patients with high-risk LBCL is warranted in a randomized, phase 3 trial comparing it to standard chemoimmunotherapy,” study lead author Sattva S. Neelapu, MD, of the University of Texas MD Anderson Cancer Center, Houston, said in an interview.
According to Dr. Neelapu, “patients with high-risk LBCL include those with high-intermediate or high International Prognostic Index score and those with certain molecular subtypes such as double- or triple-hit lymphoma. These patients have lower response rates and lower progression-free and overall survival with standard chemoimmunotherapy.”
Treatment of these patients can be especially challenging because they are underrepresented in clinical research, hematologist Michael Dickinson, MBBS, of the Peter MacCallum Cancer Center in Melbourne, said in an interview. “They often have disease that requires urgent treatment, so there is no time to recruit them into trials. A feature of ZUMA-12 is that it allowed patients to be recruited after short exposure to chemotherapy, which means that higher-risk patients could successfully be recruited into the trial.”
Axi-cel is already Food and Drug Administration approved for treatment of relapsed or refractory LBCL after 2 or more lines of systemic therapy plus relapsed or refractory follicular lymphoma, also after two or more lines of systemic therapy, Dr. Neelapu said.
For this study, researchers administered the treatment to 40 subjects with high-risk disease from 2019-2020 (median age, 61 years; 68% male; 95% at disease stage III or IV).
The researchers reported that 78% of 37 patients in the primary efficacy analysis reached complete response rate (95% confidence interval, 62-90); the median time to first complete response rate was 30 days (range, 27-207). About 89% of these subjects reached the secondary endpoint of objective response rate (95% CI, 75-97); the median time to first objective response was 29 days (range, 27-207).
At a median follow-up of 15.9 months, 73% were still in objective response.
“This is quite remarkable,” Dr. Neelapu said. “The durability of more than 70% is far higher than what would be expected with standard chemoimmunotherapy in these patients – under 40% durability with standard chemoimmunotherapy. Also, axi-cel induces durable responses in about 40% of patients in second- and third-line setting. However, when used as part of first-line therapy in this study, durable responses were observed in more than 70% of patients, suggesting that the efficacy of axi-cel may be much higher when used in first-line setting.”
Dr. Neelapu added: “Although the follow-up is short, it is highly likely that the majority of the patients with ongoing response beyond 1 year will likely be cured of their lymphoma.”
As for side effects, no treatment-related grade 5 events occurred, but 18 patients (45%) experienced serious adverse events. Grade 3 or higher cytokine release syndrome occurred in three patients (8%) and nine experienced neurologic events (23%).
“The majority of the higher-grade adverse events observed were due to cytopenias, which were expected due to the conditioning therapy,” Dr. Neelapu said. “Such cytopenias would also have been expected if these patients had received standard chemoimmunotherapy.”
Six patients (15%) died, 4 of progressive disease after going forward to other therapies.
As for cost, Dr. Neelapu said it should be similar to that of axi-cel as an FDA-approved third-line therapy. Axi-cel is highly expensive. Research has suggested that CAR T-cell therapy can boost costs beyond standard chemotherapy by $350,000-$490,000 with gains of 2-8 years of life (J Med Econ. Jan-Dec 2021;24[1]:458-68).
The study was funded by Kite. The authors reported various disclosures.
FROM NATURE MEDICINE
Adverse skin effects of cancer immunotherapy reviewed
Immune checkpoint inhibitors (ICIs) have unquestionably revolutionized the care of patients with malignant melanoma, non-small cell lung cancer, and other types of cancer.
, according to members of a European Academy of Dermatology and Venereology (EADV) task force.
“The desirable, immune-mediated oncologic response is often achieved at the cost of immune-related adverse events (irAEs) that may potentially affect any organ system,” they write in a position statement on the management of ICI-derived dermatologic adverse events.
Recommendations from the EADV “Dermatology for Cancer Patients” task force have been published in the Journal of the European Academy of Dermatology and Venereology.
Task force members developed the recommendations based on clinical experience from published data and came up with specific recommendations for treating cutaneous toxicities associated with dermatologic immune-related adverse events (dirAEs) that occur in patients receiving immunotherapy with an ICI.
ICIs include the cytotoxic T-lymphocyte–associated antigen 4 (CTLA-4) inhibitor ipilimumab (Yervoy, Bristol Myers Squibb), and inhibitors of programmed death protein 1 (PD-1) and its ligand (PD-L1), including nivolumab (Opdivo, Bristol Myers Squibb), pembrolizumab (Keytruda, Merck), and other agents.
“The basic principle of management is that the interventions should be tailored to serve the equilibrium between patients’ relief from the symptoms and signs of skin toxicity and the preservation of an unimpeded oncologic treatment,” they write.
The recommendations are in line with those included in a 2021 update of the American Society of Clinical Oncology (ASCO) guidelines on the management of irAEs in patients treated with ICIs across the whole range of organ systems, said Milan J. Anadkat, MD, professor of dermatology and director of dermatology clinical trials at Washington University School of Medicine, St. Louis. Dr. Anadkat was a coauthor of the ASCO guideline update.
Although the European recommendations focus only on dermatologic side effects of ICIs in patients with cancer, “that doesn’t diminish their importance. They do a good job of summarizing how to approach and how to manage it depending on the severity of the toxicities and the various types of toxicities,” he told this news organization.
Having a paper focused exclusively on the dermatologic side effects of ICIs allows the inclusion of photographs that can help clinicians identify specific conditions that may require referral to a dermatologist, he said.
Both Dr. Anadkat and the authors of the European recommendations noted that dermatologic irAEs are more common with CTLA-4 inhibition than with PD-1/PD-L1 inhibition.
“It has to do with where the target is,” Dr. Anadkat said. “CTLA-4 inhibition works on a central aspect of the immune system, so it’s a much less specific site, whereas PD-1 affects an interaction at the site of the tumor cell itself, so it’s a little more specific.”
Pruritus
ICI-induced pruritus can occur without apparent skin changes, they write, noting that in a recent study of patients with dirAEs, about one-third had isolated pruritus.
The task force members cite a meta-analysis indicating a pruritus incidence of 13.2% for patients treated with nivolumab and 20.2% for patients treated with pembrolizumab but respective grade 3 pruritus rates of only 0.5% and 2.3%. The reported incidence of pruritus with ipilimumab was 47% in a different study.
Recommended treatments include topical moisturizers with or without medium-to-high potency corticosteroids for grade 1 reactions, non-sedating histamines and/or GABA agonists such as pregabalin, or gabapentin for grade 2 pruritus, and suspension of ICIs until pruritus improves in patients with grade 3 pruritus.
Maculopapular rash
Maculopapular or eczema-like rashes may occur in up to 68% of patients who receive a CTLA-4 inhibitor and up to 20% of those who receive a PD1/PD-L1 inhibitor, the authors note. Rashes commonly appear within 3-6 weeks of initiating therapy.
“The clinical presentation is nonspecific and consists of a rapid onset of multiple minimally scaly, erythematous macules and papules, congregating into plaques. Lesions are mostly located on trunk and extensor surfaces of the extremities and the face is generally spared,” they write.
Maculopapular rashes are typically accompanied by itching but could be asymptomatic, they noted.
Mild (grade 1) rashes may respond to moisturizers and topical potent or super-potent corticosteroids. Patients with grade 2 rash should also receive oral antihistamines. Systemic corticosteroids may be considered for patients with grade 3 rashes but only after other dirAEs that may require specific management, such as psoriasis, are ruled out.
Psoriasis-like rash
The most common form of psoriasis seen in patients treated with ICIs is psoriasis vulgaris with plaques, but other clinical variants are also seen, the authors note.
“Topical agents (corticosteroids, Vitamin D analogues) are prescribed in Grades 1/2 and supplementary” to systemic treatment for patients with grade 3 or recalcitrant lesions, they write. “If skin-directed therapies fail to provide symptomatic control,” systemic treatment and narrow band UVB phototherapy “should be considered,” they add.
Evidence regarding the use of systemic therapies to treat psoriasis-like rash associated with ICIs is sparse. Acitretin can be safely used in patients with cancer. Low-dose methotrexate is also safe to use except in patients with non-melanoma skin cancers. Cyclosporine, however, should be avoided because of the potential for tumor-promoting effects, they emphasized.
The recommendations also cover treatment of lichen planus-like and vitiligo-like rashes, as well as hair and nail changes, autoimmune bullous disorders, and oral mucosal dirAEs.
In addition, the recommendations cover severe cutaneous adverse reactions as well as serious, potentially life-threatening dirAEs, including Stevens-Johnson syndrome/TEN, acute generalized exanthematous pustulosis (AGEP), and drug reaction with eosinophilia and systemic symptoms/drug-induced hypersensitivity syndrome (DRESS/DIHS).
“The dose of corticosteroids may be adapted to the severity of DRESS. The therapeutic benefit of systemic corticosteroids in the management of SJS/TEN remains controversial, and some authors favor treatment with cyclosporine. However, the use of corticosteroids in this context of ICI treatment appears reasonable and should be proposed. Short courses of steroids seem also effective in AGEP,” the task force members write.
The recommendations did not have outside funding. Of the 19 authors, 6 disclosed relationships with various pharmaceutical companies, including AbbVie, Leo Pharma, Boehringer Ingelheim, Bristol Myers Squibb, and/or Janssen. Dr. Anadkat disclosed previous relationships with Merck, Bristol Myers Squibb, and current relationships with others.
A version of this article first appeared on Medscape.com.
Immune checkpoint inhibitors (ICIs) have unquestionably revolutionized the care of patients with malignant melanoma, non-small cell lung cancer, and other types of cancer.
, according to members of a European Academy of Dermatology and Venereology (EADV) task force.
“The desirable, immune-mediated oncologic response is often achieved at the cost of immune-related adverse events (irAEs) that may potentially affect any organ system,” they write in a position statement on the management of ICI-derived dermatologic adverse events.
Recommendations from the EADV “Dermatology for Cancer Patients” task force have been published in the Journal of the European Academy of Dermatology and Venereology.
Task force members developed the recommendations based on clinical experience from published data and came up with specific recommendations for treating cutaneous toxicities associated with dermatologic immune-related adverse events (dirAEs) that occur in patients receiving immunotherapy with an ICI.
ICIs include the cytotoxic T-lymphocyte–associated antigen 4 (CTLA-4) inhibitor ipilimumab (Yervoy, Bristol Myers Squibb), and inhibitors of programmed death protein 1 (PD-1) and its ligand (PD-L1), including nivolumab (Opdivo, Bristol Myers Squibb), pembrolizumab (Keytruda, Merck), and other agents.
“The basic principle of management is that the interventions should be tailored to serve the equilibrium between patients’ relief from the symptoms and signs of skin toxicity and the preservation of an unimpeded oncologic treatment,” they write.
The recommendations are in line with those included in a 2021 update of the American Society of Clinical Oncology (ASCO) guidelines on the management of irAEs in patients treated with ICIs across the whole range of organ systems, said Milan J. Anadkat, MD, professor of dermatology and director of dermatology clinical trials at Washington University School of Medicine, St. Louis. Dr. Anadkat was a coauthor of the ASCO guideline update.
Although the European recommendations focus only on dermatologic side effects of ICIs in patients with cancer, “that doesn’t diminish their importance. They do a good job of summarizing how to approach and how to manage it depending on the severity of the toxicities and the various types of toxicities,” he told this news organization.
Having a paper focused exclusively on the dermatologic side effects of ICIs allows the inclusion of photographs that can help clinicians identify specific conditions that may require referral to a dermatologist, he said.
Both Dr. Anadkat and the authors of the European recommendations noted that dermatologic irAEs are more common with CTLA-4 inhibition than with PD-1/PD-L1 inhibition.
“It has to do with where the target is,” Dr. Anadkat said. “CTLA-4 inhibition works on a central aspect of the immune system, so it’s a much less specific site, whereas PD-1 affects an interaction at the site of the tumor cell itself, so it’s a little more specific.”
Pruritus
ICI-induced pruritus can occur without apparent skin changes, they write, noting that in a recent study of patients with dirAEs, about one-third had isolated pruritus.
The task force members cite a meta-analysis indicating a pruritus incidence of 13.2% for patients treated with nivolumab and 20.2% for patients treated with pembrolizumab but respective grade 3 pruritus rates of only 0.5% and 2.3%. The reported incidence of pruritus with ipilimumab was 47% in a different study.
Recommended treatments include topical moisturizers with or without medium-to-high potency corticosteroids for grade 1 reactions, non-sedating histamines and/or GABA agonists such as pregabalin, or gabapentin for grade 2 pruritus, and suspension of ICIs until pruritus improves in patients with grade 3 pruritus.
Maculopapular rash
Maculopapular or eczema-like rashes may occur in up to 68% of patients who receive a CTLA-4 inhibitor and up to 20% of those who receive a PD1/PD-L1 inhibitor, the authors note. Rashes commonly appear within 3-6 weeks of initiating therapy.
“The clinical presentation is nonspecific and consists of a rapid onset of multiple minimally scaly, erythematous macules and papules, congregating into plaques. Lesions are mostly located on trunk and extensor surfaces of the extremities and the face is generally spared,” they write.
Maculopapular rashes are typically accompanied by itching but could be asymptomatic, they noted.
Mild (grade 1) rashes may respond to moisturizers and topical potent or super-potent corticosteroids. Patients with grade 2 rash should also receive oral antihistamines. Systemic corticosteroids may be considered for patients with grade 3 rashes but only after other dirAEs that may require specific management, such as psoriasis, are ruled out.
Psoriasis-like rash
The most common form of psoriasis seen in patients treated with ICIs is psoriasis vulgaris with plaques, but other clinical variants are also seen, the authors note.
“Topical agents (corticosteroids, Vitamin D analogues) are prescribed in Grades 1/2 and supplementary” to systemic treatment for patients with grade 3 or recalcitrant lesions, they write. “If skin-directed therapies fail to provide symptomatic control,” systemic treatment and narrow band UVB phototherapy “should be considered,” they add.
Evidence regarding the use of systemic therapies to treat psoriasis-like rash associated with ICIs is sparse. Acitretin can be safely used in patients with cancer. Low-dose methotrexate is also safe to use except in patients with non-melanoma skin cancers. Cyclosporine, however, should be avoided because of the potential for tumor-promoting effects, they emphasized.
The recommendations also cover treatment of lichen planus-like and vitiligo-like rashes, as well as hair and nail changes, autoimmune bullous disorders, and oral mucosal dirAEs.
In addition, the recommendations cover severe cutaneous adverse reactions as well as serious, potentially life-threatening dirAEs, including Stevens-Johnson syndrome/TEN, acute generalized exanthematous pustulosis (AGEP), and drug reaction with eosinophilia and systemic symptoms/drug-induced hypersensitivity syndrome (DRESS/DIHS).
“The dose of corticosteroids may be adapted to the severity of DRESS. The therapeutic benefit of systemic corticosteroids in the management of SJS/TEN remains controversial, and some authors favor treatment with cyclosporine. However, the use of corticosteroids in this context of ICI treatment appears reasonable and should be proposed. Short courses of steroids seem also effective in AGEP,” the task force members write.
The recommendations did not have outside funding. Of the 19 authors, 6 disclosed relationships with various pharmaceutical companies, including AbbVie, Leo Pharma, Boehringer Ingelheim, Bristol Myers Squibb, and/or Janssen. Dr. Anadkat disclosed previous relationships with Merck, Bristol Myers Squibb, and current relationships with others.
A version of this article first appeared on Medscape.com.
Immune checkpoint inhibitors (ICIs) have unquestionably revolutionized the care of patients with malignant melanoma, non-small cell lung cancer, and other types of cancer.
, according to members of a European Academy of Dermatology and Venereology (EADV) task force.
“The desirable, immune-mediated oncologic response is often achieved at the cost of immune-related adverse events (irAEs) that may potentially affect any organ system,” they write in a position statement on the management of ICI-derived dermatologic adverse events.
Recommendations from the EADV “Dermatology for Cancer Patients” task force have been published in the Journal of the European Academy of Dermatology and Venereology.
Task force members developed the recommendations based on clinical experience from published data and came up with specific recommendations for treating cutaneous toxicities associated with dermatologic immune-related adverse events (dirAEs) that occur in patients receiving immunotherapy with an ICI.
ICIs include the cytotoxic T-lymphocyte–associated antigen 4 (CTLA-4) inhibitor ipilimumab (Yervoy, Bristol Myers Squibb), and inhibitors of programmed death protein 1 (PD-1) and its ligand (PD-L1), including nivolumab (Opdivo, Bristol Myers Squibb), pembrolizumab (Keytruda, Merck), and other agents.
“The basic principle of management is that the interventions should be tailored to serve the equilibrium between patients’ relief from the symptoms and signs of skin toxicity and the preservation of an unimpeded oncologic treatment,” they write.
The recommendations are in line with those included in a 2021 update of the American Society of Clinical Oncology (ASCO) guidelines on the management of irAEs in patients treated with ICIs across the whole range of organ systems, said Milan J. Anadkat, MD, professor of dermatology and director of dermatology clinical trials at Washington University School of Medicine, St. Louis. Dr. Anadkat was a coauthor of the ASCO guideline update.
Although the European recommendations focus only on dermatologic side effects of ICIs in patients with cancer, “that doesn’t diminish their importance. They do a good job of summarizing how to approach and how to manage it depending on the severity of the toxicities and the various types of toxicities,” he told this news organization.
Having a paper focused exclusively on the dermatologic side effects of ICIs allows the inclusion of photographs that can help clinicians identify specific conditions that may require referral to a dermatologist, he said.
Both Dr. Anadkat and the authors of the European recommendations noted that dermatologic irAEs are more common with CTLA-4 inhibition than with PD-1/PD-L1 inhibition.
“It has to do with where the target is,” Dr. Anadkat said. “CTLA-4 inhibition works on a central aspect of the immune system, so it’s a much less specific site, whereas PD-1 affects an interaction at the site of the tumor cell itself, so it’s a little more specific.”
Pruritus
ICI-induced pruritus can occur without apparent skin changes, they write, noting that in a recent study of patients with dirAEs, about one-third had isolated pruritus.
The task force members cite a meta-analysis indicating a pruritus incidence of 13.2% for patients treated with nivolumab and 20.2% for patients treated with pembrolizumab but respective grade 3 pruritus rates of only 0.5% and 2.3%. The reported incidence of pruritus with ipilimumab was 47% in a different study.
Recommended treatments include topical moisturizers with or without medium-to-high potency corticosteroids for grade 1 reactions, non-sedating histamines and/or GABA agonists such as pregabalin, or gabapentin for grade 2 pruritus, and suspension of ICIs until pruritus improves in patients with grade 3 pruritus.
Maculopapular rash
Maculopapular or eczema-like rashes may occur in up to 68% of patients who receive a CTLA-4 inhibitor and up to 20% of those who receive a PD1/PD-L1 inhibitor, the authors note. Rashes commonly appear within 3-6 weeks of initiating therapy.
“The clinical presentation is nonspecific and consists of a rapid onset of multiple minimally scaly, erythematous macules and papules, congregating into plaques. Lesions are mostly located on trunk and extensor surfaces of the extremities and the face is generally spared,” they write.
Maculopapular rashes are typically accompanied by itching but could be asymptomatic, they noted.
Mild (grade 1) rashes may respond to moisturizers and topical potent or super-potent corticosteroids. Patients with grade 2 rash should also receive oral antihistamines. Systemic corticosteroids may be considered for patients with grade 3 rashes but only after other dirAEs that may require specific management, such as psoriasis, are ruled out.
Psoriasis-like rash
The most common form of psoriasis seen in patients treated with ICIs is psoriasis vulgaris with plaques, but other clinical variants are also seen, the authors note.
“Topical agents (corticosteroids, Vitamin D analogues) are prescribed in Grades 1/2 and supplementary” to systemic treatment for patients with grade 3 or recalcitrant lesions, they write. “If skin-directed therapies fail to provide symptomatic control,” systemic treatment and narrow band UVB phototherapy “should be considered,” they add.
Evidence regarding the use of systemic therapies to treat psoriasis-like rash associated with ICIs is sparse. Acitretin can be safely used in patients with cancer. Low-dose methotrexate is also safe to use except in patients with non-melanoma skin cancers. Cyclosporine, however, should be avoided because of the potential for tumor-promoting effects, they emphasized.
The recommendations also cover treatment of lichen planus-like and vitiligo-like rashes, as well as hair and nail changes, autoimmune bullous disorders, and oral mucosal dirAEs.
In addition, the recommendations cover severe cutaneous adverse reactions as well as serious, potentially life-threatening dirAEs, including Stevens-Johnson syndrome/TEN, acute generalized exanthematous pustulosis (AGEP), and drug reaction with eosinophilia and systemic symptoms/drug-induced hypersensitivity syndrome (DRESS/DIHS).
“The dose of corticosteroids may be adapted to the severity of DRESS. The therapeutic benefit of systemic corticosteroids in the management of SJS/TEN remains controversial, and some authors favor treatment with cyclosporine. However, the use of corticosteroids in this context of ICI treatment appears reasonable and should be proposed. Short courses of steroids seem also effective in AGEP,” the task force members write.
The recommendations did not have outside funding. Of the 19 authors, 6 disclosed relationships with various pharmaceutical companies, including AbbVie, Leo Pharma, Boehringer Ingelheim, Bristol Myers Squibb, and/or Janssen. Dr. Anadkat disclosed previous relationships with Merck, Bristol Myers Squibb, and current relationships with others.
A version of this article first appeared on Medscape.com.
Empagliflozin scores topline win in EMPA-KIDNEY trial
Researchers running the EMPA-KIDNEY trial that’s been testing the safety and efficacy of the SGLT2 inhibitor empagliflozin (Jardiance) in about 6,600 patients with chronic kidney disease (CKD) announced on March 16 that they had stopped the trial early because of positive efficacy that met the study’s prespecified threshold for early termination.
EMPA-KIDNEY is the third major trial of an agent from the sodium-glucose cotransport 2 (SGLT2) inhibitor class tested in patients with CKD to be stopped early because of positive results that met a prespecified termination rule.
In 2020, the DAPA-CKD trial of dapagliflozin (Farxiga) stopped early, after a median follow-up of 2.4 years, because of positive efficacy results. In 2019, the same thing happened in the CREDENCE trial of canagliflozin (Invokana), with the unexpected halt coming after a median follow-up of 2.62 years.
The announcement about EMPA-KIDNEY did not include information on median follow-up, but enrollment into the trial ran from May 2019 to April 2021, which means that the longest that enrolled patients could have been in the study was about 2.85 years.
The primary efficacy endpoint in EMPA-KIDNEY was a composite of a sustained decline in estimated glomerular filtration rate (eGFR) to less than 10 mL/min/1.73 m2, renal death, a sustained decline of at least 40% in eGFR from baseline, or cardiovascular death. The announcement of the trial’s early termination provided no details on the efficacy results.
EMPA-KIDNEY enrolled a wider range of patients
EMPA-KIDNEY expands the scope of types of patients with CKD now shown to benefit from treatment with an SGLT2 inhibitor. CREDENCE tested canagliflozin only in patients with type 2 diabetes and diabetic nephropathy, and in DAPA-CKD, two-thirds of enrolled patients had type 2 diabetes, and all had CKD. In EMPA-KIDNEY, 46% of the 6,609 enrolled patients had diabetes (including a very small number with type 1 diabetes).
Another departure from prior studies of an SGLT2 inhibitor for patients selected primarily for having CKD was that in EMPA-KIDNEY, 20% of patients did not have albuminuria, and for 34%, eGFR at entry was less than 30 mL/min/1.73 m2, with all enrolled patients required to have an eGFR at entry of greater than or equal to 20 mL/min/1.73 m2. Average eGFR in EMPA-KIDNEY was about 38 mL/min/1.73 m2. To be included in the trial, patients were not required to have albuminuria, except those whose eGFR was greater than or equal to 45 mL/min/1.73 m2.
In DAPA-CKD, the minimum eGFR at entry had to be greater than or equal to 25 mL/min/1.73 m2, and roughly 14% of enrolled patients had an eGFR of less than 30 mL/min/1.73 m2. The average eGFR in DAPA-CKD was about 43 mL/min/1.73 m2. In addition, all patients had at least microalbuminuria, with a minimum urinary albumin-to-creatinine ratio of 200. In CREDENCE, the minimum eGFR for enrollment was 30 mL/min/1.73 m2, and the average eGFR was about 56 mL/min/1.73 m2. All patients in CREDENCE had to have macroalbuminuria, with a urinary albumin-to-creatinine ratio of more than 300.
According to the researchers who designed EMPA-KIDNEY, the trial enrollment criteria aimed to include adults with CKD “who are frequently seen in practice but were under-represented in previous SGLT2 inhibitor trials.”
Indications for empagliflozin are expanding
The success of empagliflozin in EMPA-KIDNEY follows its positive results in both the EMPEROR-Reduced and EMPEROR-Preserved trials, which collectively proved the efficacy of the agent for patients with heart failure regardless of their left ventricular ejection fraction and regardless of whether they also had diabetes.
These results led the U.S. Food and Drug Administration to recently expand the labeled indication for empagliflozin to all patients with heart failure. Empagliflozin also has labeled indications for glycemic control in patients with type 2 diabetes and to reduce the risk of cardiovascular death in adults with type 2 diabetes and established cardiovascular disease.
As of today, empagliflozin has no labeled indication for treating patients with CKD. Dapagliflozin received that indication in April 2021, and canagliflozin received an indication for treating patients with type 2 diabetes, diabetic nephropathy, and albuminuria in September 2019.
EMPA-KIDNEY is sponsored by Boehringer Ingelheim and Lilly, the two companies that jointly market empagliflozin (Jardiance).
A version of this article first appeared on Medscape.com.
Researchers running the EMPA-KIDNEY trial that’s been testing the safety and efficacy of the SGLT2 inhibitor empagliflozin (Jardiance) in about 6,600 patients with chronic kidney disease (CKD) announced on March 16 that they had stopped the trial early because of positive efficacy that met the study’s prespecified threshold for early termination.
EMPA-KIDNEY is the third major trial of an agent from the sodium-glucose cotransport 2 (SGLT2) inhibitor class tested in patients with CKD to be stopped early because of positive results that met a prespecified termination rule.
In 2020, the DAPA-CKD trial of dapagliflozin (Farxiga) stopped early, after a median follow-up of 2.4 years, because of positive efficacy results. In 2019, the same thing happened in the CREDENCE trial of canagliflozin (Invokana), with the unexpected halt coming after a median follow-up of 2.62 years.
The announcement about EMPA-KIDNEY did not include information on median follow-up, but enrollment into the trial ran from May 2019 to April 2021, which means that the longest that enrolled patients could have been in the study was about 2.85 years.
The primary efficacy endpoint in EMPA-KIDNEY was a composite of a sustained decline in estimated glomerular filtration rate (eGFR) to less than 10 mL/min/1.73 m2, renal death, a sustained decline of at least 40% in eGFR from baseline, or cardiovascular death. The announcement of the trial’s early termination provided no details on the efficacy results.
EMPA-KIDNEY enrolled a wider range of patients
EMPA-KIDNEY expands the scope of types of patients with CKD now shown to benefit from treatment with an SGLT2 inhibitor. CREDENCE tested canagliflozin only in patients with type 2 diabetes and diabetic nephropathy, and in DAPA-CKD, two-thirds of enrolled patients had type 2 diabetes, and all had CKD. In EMPA-KIDNEY, 46% of the 6,609 enrolled patients had diabetes (including a very small number with type 1 diabetes).
Another departure from prior studies of an SGLT2 inhibitor for patients selected primarily for having CKD was that in EMPA-KIDNEY, 20% of patients did not have albuminuria, and for 34%, eGFR at entry was less than 30 mL/min/1.73 m2, with all enrolled patients required to have an eGFR at entry of greater than or equal to 20 mL/min/1.73 m2. Average eGFR in EMPA-KIDNEY was about 38 mL/min/1.73 m2. To be included in the trial, patients were not required to have albuminuria, except those whose eGFR was greater than or equal to 45 mL/min/1.73 m2.
In DAPA-CKD, the minimum eGFR at entry had to be greater than or equal to 25 mL/min/1.73 m2, and roughly 14% of enrolled patients had an eGFR of less than 30 mL/min/1.73 m2. The average eGFR in DAPA-CKD was about 43 mL/min/1.73 m2. In addition, all patients had at least microalbuminuria, with a minimum urinary albumin-to-creatinine ratio of 200. In CREDENCE, the minimum eGFR for enrollment was 30 mL/min/1.73 m2, and the average eGFR was about 56 mL/min/1.73 m2. All patients in CREDENCE had to have macroalbuminuria, with a urinary albumin-to-creatinine ratio of more than 300.
According to the researchers who designed EMPA-KIDNEY, the trial enrollment criteria aimed to include adults with CKD “who are frequently seen in practice but were under-represented in previous SGLT2 inhibitor trials.”
Indications for empagliflozin are expanding
The success of empagliflozin in EMPA-KIDNEY follows its positive results in both the EMPEROR-Reduced and EMPEROR-Preserved trials, which collectively proved the efficacy of the agent for patients with heart failure regardless of their left ventricular ejection fraction and regardless of whether they also had diabetes.
These results led the U.S. Food and Drug Administration to recently expand the labeled indication for empagliflozin to all patients with heart failure. Empagliflozin also has labeled indications for glycemic control in patients with type 2 diabetes and to reduce the risk of cardiovascular death in adults with type 2 diabetes and established cardiovascular disease.
As of today, empagliflozin has no labeled indication for treating patients with CKD. Dapagliflozin received that indication in April 2021, and canagliflozin received an indication for treating patients with type 2 diabetes, diabetic nephropathy, and albuminuria in September 2019.
EMPA-KIDNEY is sponsored by Boehringer Ingelheim and Lilly, the two companies that jointly market empagliflozin (Jardiance).
A version of this article first appeared on Medscape.com.
Researchers running the EMPA-KIDNEY trial that’s been testing the safety and efficacy of the SGLT2 inhibitor empagliflozin (Jardiance) in about 6,600 patients with chronic kidney disease (CKD) announced on March 16 that they had stopped the trial early because of positive efficacy that met the study’s prespecified threshold for early termination.
EMPA-KIDNEY is the third major trial of an agent from the sodium-glucose cotransport 2 (SGLT2) inhibitor class tested in patients with CKD to be stopped early because of positive results that met a prespecified termination rule.
In 2020, the DAPA-CKD trial of dapagliflozin (Farxiga) stopped early, after a median follow-up of 2.4 years, because of positive efficacy results. In 2019, the same thing happened in the CREDENCE trial of canagliflozin (Invokana), with the unexpected halt coming after a median follow-up of 2.62 years.
The announcement about EMPA-KIDNEY did not include information on median follow-up, but enrollment into the trial ran from May 2019 to April 2021, which means that the longest that enrolled patients could have been in the study was about 2.85 years.
The primary efficacy endpoint in EMPA-KIDNEY was a composite of a sustained decline in estimated glomerular filtration rate (eGFR) to less than 10 mL/min/1.73 m2, renal death, a sustained decline of at least 40% in eGFR from baseline, or cardiovascular death. The announcement of the trial’s early termination provided no details on the efficacy results.
EMPA-KIDNEY enrolled a wider range of patients
EMPA-KIDNEY expands the scope of types of patients with CKD now shown to benefit from treatment with an SGLT2 inhibitor. CREDENCE tested canagliflozin only in patients with type 2 diabetes and diabetic nephropathy, and in DAPA-CKD, two-thirds of enrolled patients had type 2 diabetes, and all had CKD. In EMPA-KIDNEY, 46% of the 6,609 enrolled patients had diabetes (including a very small number with type 1 diabetes).
Another departure from prior studies of an SGLT2 inhibitor for patients selected primarily for having CKD was that in EMPA-KIDNEY, 20% of patients did not have albuminuria, and for 34%, eGFR at entry was less than 30 mL/min/1.73 m2, with all enrolled patients required to have an eGFR at entry of greater than or equal to 20 mL/min/1.73 m2. Average eGFR in EMPA-KIDNEY was about 38 mL/min/1.73 m2. To be included in the trial, patients were not required to have albuminuria, except those whose eGFR was greater than or equal to 45 mL/min/1.73 m2.
In DAPA-CKD, the minimum eGFR at entry had to be greater than or equal to 25 mL/min/1.73 m2, and roughly 14% of enrolled patients had an eGFR of less than 30 mL/min/1.73 m2. The average eGFR in DAPA-CKD was about 43 mL/min/1.73 m2. In addition, all patients had at least microalbuminuria, with a minimum urinary albumin-to-creatinine ratio of 200. In CREDENCE, the minimum eGFR for enrollment was 30 mL/min/1.73 m2, and the average eGFR was about 56 mL/min/1.73 m2. All patients in CREDENCE had to have macroalbuminuria, with a urinary albumin-to-creatinine ratio of more than 300.
According to the researchers who designed EMPA-KIDNEY, the trial enrollment criteria aimed to include adults with CKD “who are frequently seen in practice but were under-represented in previous SGLT2 inhibitor trials.”
Indications for empagliflozin are expanding
The success of empagliflozin in EMPA-KIDNEY follows its positive results in both the EMPEROR-Reduced and EMPEROR-Preserved trials, which collectively proved the efficacy of the agent for patients with heart failure regardless of their left ventricular ejection fraction and regardless of whether they also had diabetes.
These results led the U.S. Food and Drug Administration to recently expand the labeled indication for empagliflozin to all patients with heart failure. Empagliflozin also has labeled indications for glycemic control in patients with type 2 diabetes and to reduce the risk of cardiovascular death in adults with type 2 diabetes and established cardiovascular disease.
As of today, empagliflozin has no labeled indication for treating patients with CKD. Dapagliflozin received that indication in April 2021, and canagliflozin received an indication for treating patients with type 2 diabetes, diabetic nephropathy, and albuminuria in September 2019.
EMPA-KIDNEY is sponsored by Boehringer Ingelheim and Lilly, the two companies that jointly market empagliflozin (Jardiance).
A version of this article first appeared on Medscape.com.
Ways to lessen toxic effects of chemo in older adults
Age-related changes that potentiate adverse drug reactions include alterations in absorption, distribution, metabolism, and excretion. As such, older patients often require adjustments in medications to optimize safety and use. Medication adjustment is especially important for older patients on complex medication regimens for multiple conditions, such as those undergoing cancer treatment. Three recent high-quality randomized trials evaluated the use of geriatric assessment (GA) in older adults with cancer.1-3
Interdisciplinary GA can identify aging-related conditions associated with poor outcomes in older patients with cancer (e.g., toxic effects of chemotherapy) and provide recommendations aimed at improving health outcomes. The results of these trials suggest that interdisciplinary GA can improve care outcomes and oncologists’ communication for older adults with cancer, and should be considered an emerging standard of care.
Geriatric assessment and chemotherapy-related toxic effects
A cluster randomized trial1 at City of Hope National Medical Center conducted between August 2015 and February 2019 enrolled 613 participants and randomly assigned them to receive a GA-guided intervention or usual standard of care in a 2-to-1 ratio. Participants were eligible for the study if they were aged ≥65 years; had a diagnosis of solid malignant neoplasm of any stage; were starting a new chemotherapy regimen; and were fluent in English, Spanish, or Chinese.
The intervention included a GA at baseline followed by assessments focused on six common areas: sleep problems, problems with eating and feeding, incontinence, confusion, evidence of falls, and skin breakdown. An interdisciplinary team (oncologist, nurse practitioner, pharmacist, physical therapist, occupational therapist, social worker, and nutritionist) performed the assessment and developed a plan of care. Interventions were multifactorial and could include referral to specialists; recommendations for medication changes; symptom management; nutritional intervention with diet recommendations and supplementation; and interventions targeting social, spiritual, and functional well-being. Follow-up by a nurse practitioner continued until completion of chemotherapy or 6 months after starting chemotherapy, whichever was earlier.
The primary outcome was grade 3 or higher chemotherapy-related toxic effects using National Cancer Institute criteria, and secondary outcomes were advance directive completion, emergency room visits and unplanned hospitalizations, and survival up to 12 months. Results showed a 10% absolute reduction in the incidence of grade 3 or higher toxic effects (P = .02), with a number needed to treat of 10. Advance directive completion also increased by 15%, but no differences were observed for other outcomes. This study offers high-quality evidence that a GA-based intervention can reduce toxic effects of chemotherapy regimens for older adults with cancer.
Geriatric assessment in community oncology practices
A recent study by Supriya G. Mohile, MD, and colleagues2 is the first nationwide multicenter clinical trial to demonstrate the effects of GA and GA-guided management. This study was conducted in 40 oncology practices from the University of Rochester National Cancer Institute Community Oncology Research Program network. Centers were randomly assigned to intervention or usual care (362 patients treated by 68 oncologists in the intervention group and 371 patients treated by 91 oncologists in the usual-care group). Eligibility criteria were age ≥70 years; impairment in at least one GA domain other than polypharmacy; incurable advanced solid tumor or lymphoma with a plan to start new cancer treatment with a high risk for toxic effects within 4 weeks; and English language fluency. Both study groups underwent a baseline GA that assessed patients’ physical performance, functional status, comorbidity, cognition, nutrition, social support, polypharmacy, and psychological status. For the intervention group, a summary and management recommendations were provided to the treating oncologists.
The primary outcome was grade 3 or higher toxic effects within 3 months of starting a new regimen; secondary outcomes included treatment intensity and survival and GA outcomes within 3 months. A smaller proportion of patients in the intervention group experienced toxicity (51% vs. 71%), with an absolute risk reduction of 20%. Patients in the intervention group also had fewer falls and a greater reduction in medications used; there were no other differences in secondary outcomes. This study offers very strong and generalizable evidence that incorporating GA in the care of older adults with cancer at risk for toxicity can reduce toxicity as well as improve other outcomes, such as falls and polypharmacy.
Geriatric assessment and oncologist-patient communication
A secondary analysis3 of data from Dr. Mohile and colleagues2 evaluated the effect of GA-guided recommendations on oncologist-patient communication regarding comorbidities. Patients (n = 541) included in this analysis were 76.6 years of age on average and had 3.2 (standard deviation, 1.9) comorbid conditions. All patients underwent GA, but only oncologists in the intervention arm received GA-based recommendations. Clinical encounters between oncologist and patient immediately following the GA were audio recorded and analyzed to examine communication between oncologists and participants as it relates to chronic comorbid conditions.
In the intervention arm, more discussions regarding comorbidities took place, and more participants’ concerns about comorbidities were acknowledged. More importantly, participants in the intervention group were 2.4 times more likely to have their concerns about comorbidities addressed through referral or education, compared with the usual-care group (P = .004). Moreover, 41% of oncologists in the intervention arm modified dosage or cancer treatment schedule because of concern about tolerability or comorbidities. This study demonstrates beneficial effects of GA in increasing communication and perhaps consideration of comorbidities of older adults when planning cancer treatment.
Dr. Hung is professor of geriatrics and palliative care at Mount Sinai Hospital, New York. He disclosed no relevant conflicts of interest.
References
1. Li D et al. JAMA Oncol. 2021;7:e214158.
2. Mohile SG et al. Lancet. 2021;398:1894-1904.
3. Kleckner AS et al. JCO Oncol Pract. 2022;18:e9-19.
A version of this article first appeared on Medscape.com.
Age-related changes that potentiate adverse drug reactions include alterations in absorption, distribution, metabolism, and excretion. As such, older patients often require adjustments in medications to optimize safety and use. Medication adjustment is especially important for older patients on complex medication regimens for multiple conditions, such as those undergoing cancer treatment. Three recent high-quality randomized trials evaluated the use of geriatric assessment (GA) in older adults with cancer.1-3
Interdisciplinary GA can identify aging-related conditions associated with poor outcomes in older patients with cancer (e.g., toxic effects of chemotherapy) and provide recommendations aimed at improving health outcomes. The results of these trials suggest that interdisciplinary GA can improve care outcomes and oncologists’ communication for older adults with cancer, and should be considered an emerging standard of care.
Geriatric assessment and chemotherapy-related toxic effects
A cluster randomized trial1 at City of Hope National Medical Center conducted between August 2015 and February 2019 enrolled 613 participants and randomly assigned them to receive a GA-guided intervention or usual standard of care in a 2-to-1 ratio. Participants were eligible for the study if they were aged ≥65 years; had a diagnosis of solid malignant neoplasm of any stage; were starting a new chemotherapy regimen; and were fluent in English, Spanish, or Chinese.
The intervention included a GA at baseline followed by assessments focused on six common areas: sleep problems, problems with eating and feeding, incontinence, confusion, evidence of falls, and skin breakdown. An interdisciplinary team (oncologist, nurse practitioner, pharmacist, physical therapist, occupational therapist, social worker, and nutritionist) performed the assessment and developed a plan of care. Interventions were multifactorial and could include referral to specialists; recommendations for medication changes; symptom management; nutritional intervention with diet recommendations and supplementation; and interventions targeting social, spiritual, and functional well-being. Follow-up by a nurse practitioner continued until completion of chemotherapy or 6 months after starting chemotherapy, whichever was earlier.
The primary outcome was grade 3 or higher chemotherapy-related toxic effects using National Cancer Institute criteria, and secondary outcomes were advance directive completion, emergency room visits and unplanned hospitalizations, and survival up to 12 months. Results showed a 10% absolute reduction in the incidence of grade 3 or higher toxic effects (P = .02), with a number needed to treat of 10. Advance directive completion also increased by 15%, but no differences were observed for other outcomes. This study offers high-quality evidence that a GA-based intervention can reduce toxic effects of chemotherapy regimens for older adults with cancer.
Geriatric assessment in community oncology practices
A recent study by Supriya G. Mohile, MD, and colleagues2 is the first nationwide multicenter clinical trial to demonstrate the effects of GA and GA-guided management. This study was conducted in 40 oncology practices from the University of Rochester National Cancer Institute Community Oncology Research Program network. Centers were randomly assigned to intervention or usual care (362 patients treated by 68 oncologists in the intervention group and 371 patients treated by 91 oncologists in the usual-care group). Eligibility criteria were age ≥70 years; impairment in at least one GA domain other than polypharmacy; incurable advanced solid tumor or lymphoma with a plan to start new cancer treatment with a high risk for toxic effects within 4 weeks; and English language fluency. Both study groups underwent a baseline GA that assessed patients’ physical performance, functional status, comorbidity, cognition, nutrition, social support, polypharmacy, and psychological status. For the intervention group, a summary and management recommendations were provided to the treating oncologists.
The primary outcome was grade 3 or higher toxic effects within 3 months of starting a new regimen; secondary outcomes included treatment intensity and survival and GA outcomes within 3 months. A smaller proportion of patients in the intervention group experienced toxicity (51% vs. 71%), with an absolute risk reduction of 20%. Patients in the intervention group also had fewer falls and a greater reduction in medications used; there were no other differences in secondary outcomes. This study offers very strong and generalizable evidence that incorporating GA in the care of older adults with cancer at risk for toxicity can reduce toxicity as well as improve other outcomes, such as falls and polypharmacy.
Geriatric assessment and oncologist-patient communication
A secondary analysis3 of data from Dr. Mohile and colleagues2 evaluated the effect of GA-guided recommendations on oncologist-patient communication regarding comorbidities. Patients (n = 541) included in this analysis were 76.6 years of age on average and had 3.2 (standard deviation, 1.9) comorbid conditions. All patients underwent GA, but only oncologists in the intervention arm received GA-based recommendations. Clinical encounters between oncologist and patient immediately following the GA were audio recorded and analyzed to examine communication between oncologists and participants as it relates to chronic comorbid conditions.
In the intervention arm, more discussions regarding comorbidities took place, and more participants’ concerns about comorbidities were acknowledged. More importantly, participants in the intervention group were 2.4 times more likely to have their concerns about comorbidities addressed through referral or education, compared with the usual-care group (P = .004). Moreover, 41% of oncologists in the intervention arm modified dosage or cancer treatment schedule because of concern about tolerability or comorbidities. This study demonstrates beneficial effects of GA in increasing communication and perhaps consideration of comorbidities of older adults when planning cancer treatment.
Dr. Hung is professor of geriatrics and palliative care at Mount Sinai Hospital, New York. He disclosed no relevant conflicts of interest.
References
1. Li D et al. JAMA Oncol. 2021;7:e214158.
2. Mohile SG et al. Lancet. 2021;398:1894-1904.
3. Kleckner AS et al. JCO Oncol Pract. 2022;18:e9-19.
A version of this article first appeared on Medscape.com.
Age-related changes that potentiate adverse drug reactions include alterations in absorption, distribution, metabolism, and excretion. As such, older patients often require adjustments in medications to optimize safety and use. Medication adjustment is especially important for older patients on complex medication regimens for multiple conditions, such as those undergoing cancer treatment. Three recent high-quality randomized trials evaluated the use of geriatric assessment (GA) in older adults with cancer.1-3
Interdisciplinary GA can identify aging-related conditions associated with poor outcomes in older patients with cancer (e.g., toxic effects of chemotherapy) and provide recommendations aimed at improving health outcomes. The results of these trials suggest that interdisciplinary GA can improve care outcomes and oncologists’ communication for older adults with cancer, and should be considered an emerging standard of care.
Geriatric assessment and chemotherapy-related toxic effects
A cluster randomized trial1 at City of Hope National Medical Center conducted between August 2015 and February 2019 enrolled 613 participants and randomly assigned them to receive a GA-guided intervention or usual standard of care in a 2-to-1 ratio. Participants were eligible for the study if they were aged ≥65 years; had a diagnosis of solid malignant neoplasm of any stage; were starting a new chemotherapy regimen; and were fluent in English, Spanish, or Chinese.
The intervention included a GA at baseline followed by assessments focused on six common areas: sleep problems, problems with eating and feeding, incontinence, confusion, evidence of falls, and skin breakdown. An interdisciplinary team (oncologist, nurse practitioner, pharmacist, physical therapist, occupational therapist, social worker, and nutritionist) performed the assessment and developed a plan of care. Interventions were multifactorial and could include referral to specialists; recommendations for medication changes; symptom management; nutritional intervention with diet recommendations and supplementation; and interventions targeting social, spiritual, and functional well-being. Follow-up by a nurse practitioner continued until completion of chemotherapy or 6 months after starting chemotherapy, whichever was earlier.
The primary outcome was grade 3 or higher chemotherapy-related toxic effects using National Cancer Institute criteria, and secondary outcomes were advance directive completion, emergency room visits and unplanned hospitalizations, and survival up to 12 months. Results showed a 10% absolute reduction in the incidence of grade 3 or higher toxic effects (P = .02), with a number needed to treat of 10. Advance directive completion also increased by 15%, but no differences were observed for other outcomes. This study offers high-quality evidence that a GA-based intervention can reduce toxic effects of chemotherapy regimens for older adults with cancer.
Geriatric assessment in community oncology practices
A recent study by Supriya G. Mohile, MD, and colleagues2 is the first nationwide multicenter clinical trial to demonstrate the effects of GA and GA-guided management. This study was conducted in 40 oncology practices from the University of Rochester National Cancer Institute Community Oncology Research Program network. Centers were randomly assigned to intervention or usual care (362 patients treated by 68 oncologists in the intervention group and 371 patients treated by 91 oncologists in the usual-care group). Eligibility criteria were age ≥70 years; impairment in at least one GA domain other than polypharmacy; incurable advanced solid tumor or lymphoma with a plan to start new cancer treatment with a high risk for toxic effects within 4 weeks; and English language fluency. Both study groups underwent a baseline GA that assessed patients’ physical performance, functional status, comorbidity, cognition, nutrition, social support, polypharmacy, and psychological status. For the intervention group, a summary and management recommendations were provided to the treating oncologists.
The primary outcome was grade 3 or higher toxic effects within 3 months of starting a new regimen; secondary outcomes included treatment intensity and survival and GA outcomes within 3 months. A smaller proportion of patients in the intervention group experienced toxicity (51% vs. 71%), with an absolute risk reduction of 20%. Patients in the intervention group also had fewer falls and a greater reduction in medications used; there were no other differences in secondary outcomes. This study offers very strong and generalizable evidence that incorporating GA in the care of older adults with cancer at risk for toxicity can reduce toxicity as well as improve other outcomes, such as falls and polypharmacy.
Geriatric assessment and oncologist-patient communication
A secondary analysis3 of data from Dr. Mohile and colleagues2 evaluated the effect of GA-guided recommendations on oncologist-patient communication regarding comorbidities. Patients (n = 541) included in this analysis were 76.6 years of age on average and had 3.2 (standard deviation, 1.9) comorbid conditions. All patients underwent GA, but only oncologists in the intervention arm received GA-based recommendations. Clinical encounters between oncologist and patient immediately following the GA were audio recorded and analyzed to examine communication between oncologists and participants as it relates to chronic comorbid conditions.
In the intervention arm, more discussions regarding comorbidities took place, and more participants’ concerns about comorbidities were acknowledged. More importantly, participants in the intervention group were 2.4 times more likely to have their concerns about comorbidities addressed through referral or education, compared with the usual-care group (P = .004). Moreover, 41% of oncologists in the intervention arm modified dosage or cancer treatment schedule because of concern about tolerability or comorbidities. This study demonstrates beneficial effects of GA in increasing communication and perhaps consideration of comorbidities of older adults when planning cancer treatment.
Dr. Hung is professor of geriatrics and palliative care at Mount Sinai Hospital, New York. He disclosed no relevant conflicts of interest.
References
1. Li D et al. JAMA Oncol. 2021;7:e214158.
2. Mohile SG et al. Lancet. 2021;398:1894-1904.
3. Kleckner AS et al. JCO Oncol Pract. 2022;18:e9-19.
A version of this article first appeared on Medscape.com.