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FDA approves epcoritamab for r/r DLBCL
Epcoritamab is the first subcutaneous bispecific antibody approved for the indication. The biologic simultaneously binds CD3 on cytotoxic T cells to CD20 on lymphomic B cells, inducing T-cell mediated destruction.
“Together with our partner, AbbVie, we recognize the unmet need for safe, effective, and accessible treatments for patients with B-cell malignancies and we believe that epcoritamab has the potential to become a core therapy in this patient population,” Jan van de Winkel, PhD, CEO of Genmab, said in a press release announcing the FDA’s acceptance of its biologic licensing application in November 2022.
A potential competitor, Roche’s bispecific antibody mosunetuzumab (Lunsumio), was approved in December 2022. Mosunetuzumab has the same mechanism of action as epcoritamab but is indicated for relapsed or refractory follicular lymphoma after at least two lines of systemic therapy. A phase 3 trial is currently underway exploring epcoritamab for relapsed or refractory follicular lymphoma as part of combination therapy.
The current approval was based on the open-label phase 2 EPCORE NHL-1 trial conducted by AbbVie and Genmab. The trial’s efficacy population included 148 adults with relapsed or refractory CD20+ large B-cell lymphoma who had received at least two prior lines of therapy, including anti-CD20 therapies. Almost 40% had undergone CAR-T cell therapy.
Epcoritamab was administered initially once weekly, then every 2 weeks, and then every 4 weeks until disease progression or unacceptable toxicity. The trial had no comparator arm.
At a median follow-up of 10.7 months, the overall response rate was 61% and the complete response rate was 38%. At a median follow-up of 9.8 months among responders, the median duration of response was 15.6 months.
The prescribing information comes with a boxed warning for serious or life-threatening cytokine release syndrome and life-threatening or fatal immune effector cell–associated neurotoxicity syndrome. Warnings and precautions include infections and cytopenias.
Among the 157 patients who received epcoritamab in the trial at the recommended dose, grade 1-3 cytokine release syndrome occurred in 51%, immune effector cell–associated neurotoxicity syndrome occurred in 6% (with one fatal case), and 15% experienced serious infections.
The most common grade 3 or 4 events included neutropenia (14.6%), anemia (10.2%), and thrombocytopenia (5.7%).
The FDA recommends epcoritamab be administered subcutaneously in 28-day cycles until disease progression or unacceptable toxicity.
The FDA also noted that “this indication is approved under accelerated approval based on response rate and durability of response. Continued approval for this indication may be contingent upon verification and description of clinical benefit in a confirmatory trial.”
A version of this article first appeared on Medscape.com.
Epcoritamab is the first subcutaneous bispecific antibody approved for the indication. The biologic simultaneously binds CD3 on cytotoxic T cells to CD20 on lymphomic B cells, inducing T-cell mediated destruction.
“Together with our partner, AbbVie, we recognize the unmet need for safe, effective, and accessible treatments for patients with B-cell malignancies and we believe that epcoritamab has the potential to become a core therapy in this patient population,” Jan van de Winkel, PhD, CEO of Genmab, said in a press release announcing the FDA’s acceptance of its biologic licensing application in November 2022.
A potential competitor, Roche’s bispecific antibody mosunetuzumab (Lunsumio), was approved in December 2022. Mosunetuzumab has the same mechanism of action as epcoritamab but is indicated for relapsed or refractory follicular lymphoma after at least two lines of systemic therapy. A phase 3 trial is currently underway exploring epcoritamab for relapsed or refractory follicular lymphoma as part of combination therapy.
The current approval was based on the open-label phase 2 EPCORE NHL-1 trial conducted by AbbVie and Genmab. The trial’s efficacy population included 148 adults with relapsed or refractory CD20+ large B-cell lymphoma who had received at least two prior lines of therapy, including anti-CD20 therapies. Almost 40% had undergone CAR-T cell therapy.
Epcoritamab was administered initially once weekly, then every 2 weeks, and then every 4 weeks until disease progression or unacceptable toxicity. The trial had no comparator arm.
At a median follow-up of 10.7 months, the overall response rate was 61% and the complete response rate was 38%. At a median follow-up of 9.8 months among responders, the median duration of response was 15.6 months.
The prescribing information comes with a boxed warning for serious or life-threatening cytokine release syndrome and life-threatening or fatal immune effector cell–associated neurotoxicity syndrome. Warnings and precautions include infections and cytopenias.
Among the 157 patients who received epcoritamab in the trial at the recommended dose, grade 1-3 cytokine release syndrome occurred in 51%, immune effector cell–associated neurotoxicity syndrome occurred in 6% (with one fatal case), and 15% experienced serious infections.
The most common grade 3 or 4 events included neutropenia (14.6%), anemia (10.2%), and thrombocytopenia (5.7%).
The FDA recommends epcoritamab be administered subcutaneously in 28-day cycles until disease progression or unacceptable toxicity.
The FDA also noted that “this indication is approved under accelerated approval based on response rate and durability of response. Continued approval for this indication may be contingent upon verification and description of clinical benefit in a confirmatory trial.”
A version of this article first appeared on Medscape.com.
Epcoritamab is the first subcutaneous bispecific antibody approved for the indication. The biologic simultaneously binds CD3 on cytotoxic T cells to CD20 on lymphomic B cells, inducing T-cell mediated destruction.
“Together with our partner, AbbVie, we recognize the unmet need for safe, effective, and accessible treatments for patients with B-cell malignancies and we believe that epcoritamab has the potential to become a core therapy in this patient population,” Jan van de Winkel, PhD, CEO of Genmab, said in a press release announcing the FDA’s acceptance of its biologic licensing application in November 2022.
A potential competitor, Roche’s bispecific antibody mosunetuzumab (Lunsumio), was approved in December 2022. Mosunetuzumab has the same mechanism of action as epcoritamab but is indicated for relapsed or refractory follicular lymphoma after at least two lines of systemic therapy. A phase 3 trial is currently underway exploring epcoritamab for relapsed or refractory follicular lymphoma as part of combination therapy.
The current approval was based on the open-label phase 2 EPCORE NHL-1 trial conducted by AbbVie and Genmab. The trial’s efficacy population included 148 adults with relapsed or refractory CD20+ large B-cell lymphoma who had received at least two prior lines of therapy, including anti-CD20 therapies. Almost 40% had undergone CAR-T cell therapy.
Epcoritamab was administered initially once weekly, then every 2 weeks, and then every 4 weeks until disease progression or unacceptable toxicity. The trial had no comparator arm.
At a median follow-up of 10.7 months, the overall response rate was 61% and the complete response rate was 38%. At a median follow-up of 9.8 months among responders, the median duration of response was 15.6 months.
The prescribing information comes with a boxed warning for serious or life-threatening cytokine release syndrome and life-threatening or fatal immune effector cell–associated neurotoxicity syndrome. Warnings and precautions include infections and cytopenias.
Among the 157 patients who received epcoritamab in the trial at the recommended dose, grade 1-3 cytokine release syndrome occurred in 51%, immune effector cell–associated neurotoxicity syndrome occurred in 6% (with one fatal case), and 15% experienced serious infections.
The most common grade 3 or 4 events included neutropenia (14.6%), anemia (10.2%), and thrombocytopenia (5.7%).
The FDA recommends epcoritamab be administered subcutaneously in 28-day cycles until disease progression or unacceptable toxicity.
The FDA also noted that “this indication is approved under accelerated approval based on response rate and durability of response. Continued approval for this indication may be contingent upon verification and description of clinical benefit in a confirmatory trial.”
A version of this article first appeared on Medscape.com.
FDA OKs stem cell therapy for blood cancer patients to reduce infection risks
Omidubicel is made from umbilical cord donor stem cells that are processed with nicotinamide, a form of vitamin B3, to enhance and expand the number of progenitor cells, the product’s maker, Jerusalem-based Gamida Cell, explained in a press announcement.
The FDA approval was based on phase 3 testing that pitted the use of omidubicel in 62 patients against standard unmanipulated cord blood transplants in 63 patients following myeloablative conditioning.
The median time to neutrophil recovery was 12 days in the omidubicel group, compared with 22 days with standard care. Overall, 87% of patients who received omidubicel achieved neutrophil recovery versus 83% of patients with standard transplants.
The incidence of grade 2/3 bacterial or grade 3 fungal infections 100 days following transplant was 39% with omidubicel versus 60% with standard transplants.
The FDA’s “approval is an important advance in cell therapy treatment in patients with blood cancers. Hastening the return of the body’s white blood cells can reduce the possibility of serious or overwhelming infection associated with stem cell transplantation,” Peter Marks, MD, PhD, director of the FDA’s Center for Biologics Evaluation and Research, said in an agency press release.
Abbey Jenkins, president and CEO of Gamida, called the approval “a major advancement in the treatment of patients with hematologic malignancies that we believe may increase access to stem cell transplant and help improve patient outcomes.”
The most common grade 3–5 adverse reactions in the approval study were pain (33%), mucosal inflammation (31%), hypertension (25%), and gastrointestinal toxicity (19%).
Adverse events are consistent with allogeneic hematopoietic stem cell transplantation. Among 117 patients who received omidubicel for any indication, infusion reactions occurred in 47% of patients, acute graft-versus-host disease occurred in 58%, chronic GVHD occurred in 35%, and graft failure occurred in 3%. Labeling includes a boxed warning of the possibilities. There is also a small risk of infections and malignancies from donor blood.
Omidubicel is manufactured in Gamida’s facility in Kiryat Gat, Israel. It is available for order now and is expected to be delivered to transplant centers within 30 days after the start of manufacturing, the company said.
A version of this article originally appeared on Medscape.com.
Omidubicel is made from umbilical cord donor stem cells that are processed with nicotinamide, a form of vitamin B3, to enhance and expand the number of progenitor cells, the product’s maker, Jerusalem-based Gamida Cell, explained in a press announcement.
The FDA approval was based on phase 3 testing that pitted the use of omidubicel in 62 patients against standard unmanipulated cord blood transplants in 63 patients following myeloablative conditioning.
The median time to neutrophil recovery was 12 days in the omidubicel group, compared with 22 days with standard care. Overall, 87% of patients who received omidubicel achieved neutrophil recovery versus 83% of patients with standard transplants.
The incidence of grade 2/3 bacterial or grade 3 fungal infections 100 days following transplant was 39% with omidubicel versus 60% with standard transplants.
The FDA’s “approval is an important advance in cell therapy treatment in patients with blood cancers. Hastening the return of the body’s white blood cells can reduce the possibility of serious or overwhelming infection associated with stem cell transplantation,” Peter Marks, MD, PhD, director of the FDA’s Center for Biologics Evaluation and Research, said in an agency press release.
Abbey Jenkins, president and CEO of Gamida, called the approval “a major advancement in the treatment of patients with hematologic malignancies that we believe may increase access to stem cell transplant and help improve patient outcomes.”
The most common grade 3–5 adverse reactions in the approval study were pain (33%), mucosal inflammation (31%), hypertension (25%), and gastrointestinal toxicity (19%).
Adverse events are consistent with allogeneic hematopoietic stem cell transplantation. Among 117 patients who received omidubicel for any indication, infusion reactions occurred in 47% of patients, acute graft-versus-host disease occurred in 58%, chronic GVHD occurred in 35%, and graft failure occurred in 3%. Labeling includes a boxed warning of the possibilities. There is also a small risk of infections and malignancies from donor blood.
Omidubicel is manufactured in Gamida’s facility in Kiryat Gat, Israel. It is available for order now and is expected to be delivered to transplant centers within 30 days after the start of manufacturing, the company said.
A version of this article originally appeared on Medscape.com.
Omidubicel is made from umbilical cord donor stem cells that are processed with nicotinamide, a form of vitamin B3, to enhance and expand the number of progenitor cells, the product’s maker, Jerusalem-based Gamida Cell, explained in a press announcement.
The FDA approval was based on phase 3 testing that pitted the use of omidubicel in 62 patients against standard unmanipulated cord blood transplants in 63 patients following myeloablative conditioning.
The median time to neutrophil recovery was 12 days in the omidubicel group, compared with 22 days with standard care. Overall, 87% of patients who received omidubicel achieved neutrophil recovery versus 83% of patients with standard transplants.
The incidence of grade 2/3 bacterial or grade 3 fungal infections 100 days following transplant was 39% with omidubicel versus 60% with standard transplants.
The FDA’s “approval is an important advance in cell therapy treatment in patients with blood cancers. Hastening the return of the body’s white blood cells can reduce the possibility of serious or overwhelming infection associated with stem cell transplantation,” Peter Marks, MD, PhD, director of the FDA’s Center for Biologics Evaluation and Research, said in an agency press release.
Abbey Jenkins, president and CEO of Gamida, called the approval “a major advancement in the treatment of patients with hematologic malignancies that we believe may increase access to stem cell transplant and help improve patient outcomes.”
The most common grade 3–5 adverse reactions in the approval study were pain (33%), mucosal inflammation (31%), hypertension (25%), and gastrointestinal toxicity (19%).
Adverse events are consistent with allogeneic hematopoietic stem cell transplantation. Among 117 patients who received omidubicel for any indication, infusion reactions occurred in 47% of patients, acute graft-versus-host disease occurred in 58%, chronic GVHD occurred in 35%, and graft failure occurred in 3%. Labeling includes a boxed warning of the possibilities. There is also a small risk of infections and malignancies from donor blood.
Omidubicel is manufactured in Gamida’s facility in Kiryat Gat, Israel. It is available for order now and is expected to be delivered to transplant centers within 30 days after the start of manufacturing, the company said.
A version of this article originally appeared on Medscape.com.
AFib risk with cancer drugs underestimated
Atrial fibrillation (AFib) is a known and serious side effect of some cancer treatments, but it is underreported in cancer drug trials, French investigators said in a new report.
As a result, oncologists likely underestimate the risk of atrial fibrillation when new cancer drugs come to market, they said.
The team came to these conclusions after conducting a meta-analysis of 191 phase 2 or 3 clinical trials that included 26,604 patients. The trials investigated 15 anticancer drugs used as monotherapy.
The meta-analysis showed that the annualized incidence rate of AFib ranged from 0.26 cases per 100 person-years – about the same as placebo – to 4.92 cases, a nearly 20 times’ higher risk.
Rates were the highest for ibrutinib, clofarabine, and ponatinib.
The study was published in JACC: CardioOncology, a journal of the American College of Cardiology.
Actual rates of AFib are probably higher than what they found in this meta-analysis, the authors suspect, because most oncology trials only identify and report severe cases of AFib that require immediate medical attention. Less severe cases can also lead to serious complications, including strokes, but they go unreported, said the investigators, led by Joachim Alexandre, MD, PhD, a member of the cardio-oncology program at the University of Caen Normandie Hospital Center, France.
“These findings suggest a global and systemic underreporting and/or underidentification of cardiotoxicity among cancer clinical trial participants,” and AFib reporting is “particularly affected,” they said.
Call for routine monitoring
The root of the problem is the lack of routine rhythm monitoring in cancer trials. This in turn “leads to a significant underestimation of AFib incidence” and rates “markedly lower than those observed among real-life” patients, the authors pointed out.
To address the issue, Dr. Alexandre and his team called for routine cardiac monitoring in trials to capture the true incidence of AFib and to “clearly define which anticancer drugs are significantly associated” with the condition.
Approached for comment, Michael G. Fradley, MD, medical director of cardio-oncology at the University of Pennsylvania, Philadelphia, agreed.
“It’s incredibly important” to “identify the drugs most likely to cause arrhythmias and determine the best prevention and treatment strategies. Unfortunately, systematic evaluation of arrhythmias in cancer clinical trials has often been lacking,” Dr. Fradley told this news organization.
The investigators said the issue is particularly pressing for drugs known to be associated with AFib. For Bruton’s tyrosine kinase inhibitors such as ibrutinib, for instance, they call for standardize AFib detection in trials “not only on 12-lead ECGs” for symptomatic AFib but also with “longer-term ambulatory monitoring or insertable cardiac monitors to detect subclinical AFib.”
Dr. Fradley said there might also be a role for newer wearable technologies that can detect arrhythmias through a skin patch or by other means.
Details of the meta-analysis
The investigators pulled the 191 studies they used in their meta-analysis from the ClinicalTrials.gov database.
The trials covered anticancer drugs used as monotherapy up to Sept. 18, 2020. Almost half were randomized trials, but only seven had placebo arms. Trials involving hematologic cancers outnumbered those involving solid tumors.
The 15 drugs examined were dacarbazine, abiraterone, clofarabine, azacitidine, ibrutinib, nilotinib, ponatinib, midostaurin, ipilimumab, aldesleukin, lenalidomide, pomalidomide, rituximab, bortezomib, and docetaxel.
The annualized incidence AFib rates per 100 person-years were 4.92 cases for ibrutinib, 2.38 cases for clofarabine, and 2.35 cases for ponatinib.
The lowest AFib rates were for ipilimumab (0.26 cases), rituximab (0.27), and nilotinib (0.29).
For placebo, the annualized rate was 0.25 cases per 100 person-years.
The team said caution is warranted regarding their estimations for clofarabine and midostaurin (0.65 cases) because no trials were registered after September 2009, when adverse event reporting became mandatory. As a result, estimates may be artificially low.
One of the limits of the study is that it focused on monotherapy in an age when combination treatment is generally the rule for cancer, the authors noted.
No external funding was reported for the study. Dr. Alexandre has received honoraria for presentations and consulting fees from Bayer, BMS, Pfizer, Amgen, and Bioserenity.
A version of this article first appeared on Medscape.com.
Atrial fibrillation (AFib) is a known and serious side effect of some cancer treatments, but it is underreported in cancer drug trials, French investigators said in a new report.
As a result, oncologists likely underestimate the risk of atrial fibrillation when new cancer drugs come to market, they said.
The team came to these conclusions after conducting a meta-analysis of 191 phase 2 or 3 clinical trials that included 26,604 patients. The trials investigated 15 anticancer drugs used as monotherapy.
The meta-analysis showed that the annualized incidence rate of AFib ranged from 0.26 cases per 100 person-years – about the same as placebo – to 4.92 cases, a nearly 20 times’ higher risk.
Rates were the highest for ibrutinib, clofarabine, and ponatinib.
The study was published in JACC: CardioOncology, a journal of the American College of Cardiology.
Actual rates of AFib are probably higher than what they found in this meta-analysis, the authors suspect, because most oncology trials only identify and report severe cases of AFib that require immediate medical attention. Less severe cases can also lead to serious complications, including strokes, but they go unreported, said the investigators, led by Joachim Alexandre, MD, PhD, a member of the cardio-oncology program at the University of Caen Normandie Hospital Center, France.
“These findings suggest a global and systemic underreporting and/or underidentification of cardiotoxicity among cancer clinical trial participants,” and AFib reporting is “particularly affected,” they said.
Call for routine monitoring
The root of the problem is the lack of routine rhythm monitoring in cancer trials. This in turn “leads to a significant underestimation of AFib incidence” and rates “markedly lower than those observed among real-life” patients, the authors pointed out.
To address the issue, Dr. Alexandre and his team called for routine cardiac monitoring in trials to capture the true incidence of AFib and to “clearly define which anticancer drugs are significantly associated” with the condition.
Approached for comment, Michael G. Fradley, MD, medical director of cardio-oncology at the University of Pennsylvania, Philadelphia, agreed.
“It’s incredibly important” to “identify the drugs most likely to cause arrhythmias and determine the best prevention and treatment strategies. Unfortunately, systematic evaluation of arrhythmias in cancer clinical trials has often been lacking,” Dr. Fradley told this news organization.
The investigators said the issue is particularly pressing for drugs known to be associated with AFib. For Bruton’s tyrosine kinase inhibitors such as ibrutinib, for instance, they call for standardize AFib detection in trials “not only on 12-lead ECGs” for symptomatic AFib but also with “longer-term ambulatory monitoring or insertable cardiac monitors to detect subclinical AFib.”
Dr. Fradley said there might also be a role for newer wearable technologies that can detect arrhythmias through a skin patch or by other means.
Details of the meta-analysis
The investigators pulled the 191 studies they used in their meta-analysis from the ClinicalTrials.gov database.
The trials covered anticancer drugs used as monotherapy up to Sept. 18, 2020. Almost half were randomized trials, but only seven had placebo arms. Trials involving hematologic cancers outnumbered those involving solid tumors.
The 15 drugs examined were dacarbazine, abiraterone, clofarabine, azacitidine, ibrutinib, nilotinib, ponatinib, midostaurin, ipilimumab, aldesleukin, lenalidomide, pomalidomide, rituximab, bortezomib, and docetaxel.
The annualized incidence AFib rates per 100 person-years were 4.92 cases for ibrutinib, 2.38 cases for clofarabine, and 2.35 cases for ponatinib.
The lowest AFib rates were for ipilimumab (0.26 cases), rituximab (0.27), and nilotinib (0.29).
For placebo, the annualized rate was 0.25 cases per 100 person-years.
The team said caution is warranted regarding their estimations for clofarabine and midostaurin (0.65 cases) because no trials were registered after September 2009, when adverse event reporting became mandatory. As a result, estimates may be artificially low.
One of the limits of the study is that it focused on monotherapy in an age when combination treatment is generally the rule for cancer, the authors noted.
No external funding was reported for the study. Dr. Alexandre has received honoraria for presentations and consulting fees from Bayer, BMS, Pfizer, Amgen, and Bioserenity.
A version of this article first appeared on Medscape.com.
Atrial fibrillation (AFib) is a known and serious side effect of some cancer treatments, but it is underreported in cancer drug trials, French investigators said in a new report.
As a result, oncologists likely underestimate the risk of atrial fibrillation when new cancer drugs come to market, they said.
The team came to these conclusions after conducting a meta-analysis of 191 phase 2 or 3 clinical trials that included 26,604 patients. The trials investigated 15 anticancer drugs used as monotherapy.
The meta-analysis showed that the annualized incidence rate of AFib ranged from 0.26 cases per 100 person-years – about the same as placebo – to 4.92 cases, a nearly 20 times’ higher risk.
Rates were the highest for ibrutinib, clofarabine, and ponatinib.
The study was published in JACC: CardioOncology, a journal of the American College of Cardiology.
Actual rates of AFib are probably higher than what they found in this meta-analysis, the authors suspect, because most oncology trials only identify and report severe cases of AFib that require immediate medical attention. Less severe cases can also lead to serious complications, including strokes, but they go unreported, said the investigators, led by Joachim Alexandre, MD, PhD, a member of the cardio-oncology program at the University of Caen Normandie Hospital Center, France.
“These findings suggest a global and systemic underreporting and/or underidentification of cardiotoxicity among cancer clinical trial participants,” and AFib reporting is “particularly affected,” they said.
Call for routine monitoring
The root of the problem is the lack of routine rhythm monitoring in cancer trials. This in turn “leads to a significant underestimation of AFib incidence” and rates “markedly lower than those observed among real-life” patients, the authors pointed out.
To address the issue, Dr. Alexandre and his team called for routine cardiac monitoring in trials to capture the true incidence of AFib and to “clearly define which anticancer drugs are significantly associated” with the condition.
Approached for comment, Michael G. Fradley, MD, medical director of cardio-oncology at the University of Pennsylvania, Philadelphia, agreed.
“It’s incredibly important” to “identify the drugs most likely to cause arrhythmias and determine the best prevention and treatment strategies. Unfortunately, systematic evaluation of arrhythmias in cancer clinical trials has often been lacking,” Dr. Fradley told this news organization.
The investigators said the issue is particularly pressing for drugs known to be associated with AFib. For Bruton’s tyrosine kinase inhibitors such as ibrutinib, for instance, they call for standardize AFib detection in trials “not only on 12-lead ECGs” for symptomatic AFib but also with “longer-term ambulatory monitoring or insertable cardiac monitors to detect subclinical AFib.”
Dr. Fradley said there might also be a role for newer wearable technologies that can detect arrhythmias through a skin patch or by other means.
Details of the meta-analysis
The investigators pulled the 191 studies they used in their meta-analysis from the ClinicalTrials.gov database.
The trials covered anticancer drugs used as monotherapy up to Sept. 18, 2020. Almost half were randomized trials, but only seven had placebo arms. Trials involving hematologic cancers outnumbered those involving solid tumors.
The 15 drugs examined were dacarbazine, abiraterone, clofarabine, azacitidine, ibrutinib, nilotinib, ponatinib, midostaurin, ipilimumab, aldesleukin, lenalidomide, pomalidomide, rituximab, bortezomib, and docetaxel.
The annualized incidence AFib rates per 100 person-years were 4.92 cases for ibrutinib, 2.38 cases for clofarabine, and 2.35 cases for ponatinib.
The lowest AFib rates were for ipilimumab (0.26 cases), rituximab (0.27), and nilotinib (0.29).
For placebo, the annualized rate was 0.25 cases per 100 person-years.
The team said caution is warranted regarding their estimations for clofarabine and midostaurin (0.65 cases) because no trials were registered after September 2009, when adverse event reporting became mandatory. As a result, estimates may be artificially low.
One of the limits of the study is that it focused on monotherapy in an age when combination treatment is generally the rule for cancer, the authors noted.
No external funding was reported for the study. Dr. Alexandre has received honoraria for presentations and consulting fees from Bayer, BMS, Pfizer, Amgen, and Bioserenity.
A version of this article first appeared on Medscape.com.
Erythema extent predicts death in cutaneous GVHD
“There is value in collecting erythema serially over time as a continuous variable on a scale of 0%-100%” to identify high-risk patients for prophylactic and preemptive treatment, say investigators led by dermatologist Emily Baumrin, MD, director of the GVHD clinic at the University of Pennsylvania, Philadelphia.
They report a study of more than 300 patients with ccGVHD, which found that the extent of skin erythema strongly predicted the risk for death from GVHD.
Of the 267 patients with cutaneous GVHD at baseline, 103 patients died, the majority without a relapse of their blood cancer.
With additional research, erythema body surface area (BSA) should be “introduced as an outcome measure in clinical practice and trials,” they conclude.
At the moment, the NIH Skin Score is commonly used for risk assessment in cutaneous GVHD, but the researchers found that erythema BSA out-predicts this score.
The investigators explain that the NIH Skin Score does incorporate erythema surface area, but it does so as a categorical variable, not a continuous variable. Among other additional factors, it also includes assessments of skin sclerosis, which the investigators found was not associated with GVHD mortality.
Overall, the composite score waters down the weight given to erythema BSA because the score is “driven by stable sclerotic features, and erythema changes are missed,” they explain.
The study was published online in JAMA Dermatology.
Study details
The study included 469 patients with chronic GVHD (cGVHD), of whom 267 (57%) had cutaneous cGVHD at enrollment and 89 (19%) developed skin involvement subsequently.
All of the patients were on systemic immunosuppression for GVHD after allogeneic stem cell transplants for various blood cancers.
They were enrolled from 2007 through 2012 at nine U.S. medical centers – all members of the Chronic Graft Versus Host Disease Consortium – and they were followed until 2018.
Erythema BSA and NIH Skin Score were assessed at baseline and then every 3-6 months. Erythema was the first manifestation of skin involvement in the majority of patients, with a median surface area involvement of 11% at baseline.
The study team found that the extent of erythema at first follow-up visit was associated with both nonrelapse mortality (hazard ratio, 1.33 per 10% BSA increase; P < .001) and overall survival (HR, 1.28 per 10% BSA increase; P < .001), whereas extent of sclerotic skin involvement was not associated with either.
Participants in the study were predominantly White. The investigators note that “BSA assessments of erythema may be less reliable in patients with darker skin.”
The work was funded by the Department of Veterans Affairs and the National Institutes of Health. Dr. Baumrin had no disclosures; one coauthor is an employee of CorEvitas, and two others reported grants/adviser fees from several companies, including Janssen, Mallinckrodt, and Pfizer.
A version of this article first appeared on Medscape.com.
“There is value in collecting erythema serially over time as a continuous variable on a scale of 0%-100%” to identify high-risk patients for prophylactic and preemptive treatment, say investigators led by dermatologist Emily Baumrin, MD, director of the GVHD clinic at the University of Pennsylvania, Philadelphia.
They report a study of more than 300 patients with ccGVHD, which found that the extent of skin erythema strongly predicted the risk for death from GVHD.
Of the 267 patients with cutaneous GVHD at baseline, 103 patients died, the majority without a relapse of their blood cancer.
With additional research, erythema body surface area (BSA) should be “introduced as an outcome measure in clinical practice and trials,” they conclude.
At the moment, the NIH Skin Score is commonly used for risk assessment in cutaneous GVHD, but the researchers found that erythema BSA out-predicts this score.
The investigators explain that the NIH Skin Score does incorporate erythema surface area, but it does so as a categorical variable, not a continuous variable. Among other additional factors, it also includes assessments of skin sclerosis, which the investigators found was not associated with GVHD mortality.
Overall, the composite score waters down the weight given to erythema BSA because the score is “driven by stable sclerotic features, and erythema changes are missed,” they explain.
The study was published online in JAMA Dermatology.
Study details
The study included 469 patients with chronic GVHD (cGVHD), of whom 267 (57%) had cutaneous cGVHD at enrollment and 89 (19%) developed skin involvement subsequently.
All of the patients were on systemic immunosuppression for GVHD after allogeneic stem cell transplants for various blood cancers.
They were enrolled from 2007 through 2012 at nine U.S. medical centers – all members of the Chronic Graft Versus Host Disease Consortium – and they were followed until 2018.
Erythema BSA and NIH Skin Score were assessed at baseline and then every 3-6 months. Erythema was the first manifestation of skin involvement in the majority of patients, with a median surface area involvement of 11% at baseline.
The study team found that the extent of erythema at first follow-up visit was associated with both nonrelapse mortality (hazard ratio, 1.33 per 10% BSA increase; P < .001) and overall survival (HR, 1.28 per 10% BSA increase; P < .001), whereas extent of sclerotic skin involvement was not associated with either.
Participants in the study were predominantly White. The investigators note that “BSA assessments of erythema may be less reliable in patients with darker skin.”
The work was funded by the Department of Veterans Affairs and the National Institutes of Health. Dr. Baumrin had no disclosures; one coauthor is an employee of CorEvitas, and two others reported grants/adviser fees from several companies, including Janssen, Mallinckrodt, and Pfizer.
A version of this article first appeared on Medscape.com.
“There is value in collecting erythema serially over time as a continuous variable on a scale of 0%-100%” to identify high-risk patients for prophylactic and preemptive treatment, say investigators led by dermatologist Emily Baumrin, MD, director of the GVHD clinic at the University of Pennsylvania, Philadelphia.
They report a study of more than 300 patients with ccGVHD, which found that the extent of skin erythema strongly predicted the risk for death from GVHD.
Of the 267 patients with cutaneous GVHD at baseline, 103 patients died, the majority without a relapse of their blood cancer.
With additional research, erythema body surface area (BSA) should be “introduced as an outcome measure in clinical practice and trials,” they conclude.
At the moment, the NIH Skin Score is commonly used for risk assessment in cutaneous GVHD, but the researchers found that erythema BSA out-predicts this score.
The investigators explain that the NIH Skin Score does incorporate erythema surface area, but it does so as a categorical variable, not a continuous variable. Among other additional factors, it also includes assessments of skin sclerosis, which the investigators found was not associated with GVHD mortality.
Overall, the composite score waters down the weight given to erythema BSA because the score is “driven by stable sclerotic features, and erythema changes are missed,” they explain.
The study was published online in JAMA Dermatology.
Study details
The study included 469 patients with chronic GVHD (cGVHD), of whom 267 (57%) had cutaneous cGVHD at enrollment and 89 (19%) developed skin involvement subsequently.
All of the patients were on systemic immunosuppression for GVHD after allogeneic stem cell transplants for various blood cancers.
They were enrolled from 2007 through 2012 at nine U.S. medical centers – all members of the Chronic Graft Versus Host Disease Consortium – and they were followed until 2018.
Erythema BSA and NIH Skin Score were assessed at baseline and then every 3-6 months. Erythema was the first manifestation of skin involvement in the majority of patients, with a median surface area involvement of 11% at baseline.
The study team found that the extent of erythema at first follow-up visit was associated with both nonrelapse mortality (hazard ratio, 1.33 per 10% BSA increase; P < .001) and overall survival (HR, 1.28 per 10% BSA increase; P < .001), whereas extent of sclerotic skin involvement was not associated with either.
Participants in the study were predominantly White. The investigators note that “BSA assessments of erythema may be less reliable in patients with darker skin.”
The work was funded by the Department of Veterans Affairs and the National Institutes of Health. Dr. Baumrin had no disclosures; one coauthor is an employee of CorEvitas, and two others reported grants/adviser fees from several companies, including Janssen, Mallinckrodt, and Pfizer.
A version of this article first appeared on Medscape.com.
Nicotinamide does not prevent skin cancer after organ transplant
published in the New England Journal of Medicine.
“No signal of efficacy was observed,” said investigators led by Nicholas Allen, MPH, of the University of Sydney department of dermatology.
These results fill an “important gap in our understanding” and “will probably change the practice of many skin-cancer physicians,” two experts on the topic commented in a related editorial.
The editorialists are David Miller, MD, PhD, a dermatologist and medical oncologist at Massachusetts General Hospital, and Kevin Emerick, MD, a head and neck surgeon as Massachusetts Eye and Ear, both in Boston.
Transplant patients have 50 times the risk of nonmelanoma skin cancers – also known as keratinocyte cancers – than the general public, owing to immunosuppression, and their lesions are more aggressive and are more likely to metastasize, they explain.
Nicotinamide (vitamin B3) has been shown to prevent nonmelanoma skin cancers in healthy, immunocompetent people, so physicians routinely prescribe it to transplant patients on the assumption that it will do the same for them, they comment.
The Australian investigators decided to put the assumption to the test.
The team randomly assigned 79 patients who had undergone solid-organ transplant to receive nicotinamide 500 mg twice a day and 79 other patients to receive twice-daily placebo for a year. Participants underwent dermatology exams every 3 months to check for new lesions.
The participants were at high risk for new lesions; some had had more than 40 in the previous 5 years. The two groups were well balanced; kidney transplants were the most common.
At 12 months, there was virtually no difference in the incidence of new nonmelanoma skin cancers: 207 in the nicotinamide group and 210 in the placebo group (P = .96).
There was also no significant difference in squamous cell and basal cell carcinoma counts or actinic keratosis counts.
“The interpretation of the results is straightforward: nicotinamide lacks clinical usefulness in preventing the development of keratinocyte carcinomas in solid-organ transplant recipients,” the team concludes.
As for why nicotinamide didn’t work in the trial, the investigators say it could be because it is not potent enough to overcome the stifling of antitumor immunity and DNA-repair enzymes with immunosuppression.
Fewer than half of participants in the trial reported using sunscreen at any point during the study, which is in line with past reports that transplant patients don’t routinely use sunscreen.
Two other strategies for preventing squamous cell carcinoma after transplant – use of oral retinoids and mTOR inhibitors – are problematic for various reasons, and use was low in both study arms.
Editorialists Dr. Miller and Dr. Emerick suggest a possible new approach: immune checkpoint inhibitors before transplant to reduce the risk of nonmelanoma skin cancer afterward. They say the strategy should be explored and that ongoing efforts to minimize or eliminate the need for immunosuppression after transplant are promising.
The investigators originally planned to enroll 254 persons, but the trial was stopped early because of poor recruitment. Potential participants may already have been taking nicotinamide, which is commonly used, and that may have affected recruitment, the investigators say.
The work was funded by Australia’s National Health and Medical Research Council. Dr. Allen has disclosed no relevant financial relationships. One investigator has received speaker’s fees from BMS. Another is a consultant for many companies, including Amgen, BMS, GlaxoSmithKline, and Merck. Dr. Emerick is an advisor for Regeneron, Sanofi, and Castle Biosciences. Dr. Miller is a researcher or consultant for those companies as well as Pfizer and others and has stock options in Avstera.
A version of this article first appeared on Medscape.com.
published in the New England Journal of Medicine.
“No signal of efficacy was observed,” said investigators led by Nicholas Allen, MPH, of the University of Sydney department of dermatology.
These results fill an “important gap in our understanding” and “will probably change the practice of many skin-cancer physicians,” two experts on the topic commented in a related editorial.
The editorialists are David Miller, MD, PhD, a dermatologist and medical oncologist at Massachusetts General Hospital, and Kevin Emerick, MD, a head and neck surgeon as Massachusetts Eye and Ear, both in Boston.
Transplant patients have 50 times the risk of nonmelanoma skin cancers – also known as keratinocyte cancers – than the general public, owing to immunosuppression, and their lesions are more aggressive and are more likely to metastasize, they explain.
Nicotinamide (vitamin B3) has been shown to prevent nonmelanoma skin cancers in healthy, immunocompetent people, so physicians routinely prescribe it to transplant patients on the assumption that it will do the same for them, they comment.
The Australian investigators decided to put the assumption to the test.
The team randomly assigned 79 patients who had undergone solid-organ transplant to receive nicotinamide 500 mg twice a day and 79 other patients to receive twice-daily placebo for a year. Participants underwent dermatology exams every 3 months to check for new lesions.
The participants were at high risk for new lesions; some had had more than 40 in the previous 5 years. The two groups were well balanced; kidney transplants were the most common.
At 12 months, there was virtually no difference in the incidence of new nonmelanoma skin cancers: 207 in the nicotinamide group and 210 in the placebo group (P = .96).
There was also no significant difference in squamous cell and basal cell carcinoma counts or actinic keratosis counts.
“The interpretation of the results is straightforward: nicotinamide lacks clinical usefulness in preventing the development of keratinocyte carcinomas in solid-organ transplant recipients,” the team concludes.
As for why nicotinamide didn’t work in the trial, the investigators say it could be because it is not potent enough to overcome the stifling of antitumor immunity and DNA-repair enzymes with immunosuppression.
Fewer than half of participants in the trial reported using sunscreen at any point during the study, which is in line with past reports that transplant patients don’t routinely use sunscreen.
Two other strategies for preventing squamous cell carcinoma after transplant – use of oral retinoids and mTOR inhibitors – are problematic for various reasons, and use was low in both study arms.
Editorialists Dr. Miller and Dr. Emerick suggest a possible new approach: immune checkpoint inhibitors before transplant to reduce the risk of nonmelanoma skin cancer afterward. They say the strategy should be explored and that ongoing efforts to minimize or eliminate the need for immunosuppression after transplant are promising.
The investigators originally planned to enroll 254 persons, but the trial was stopped early because of poor recruitment. Potential participants may already have been taking nicotinamide, which is commonly used, and that may have affected recruitment, the investigators say.
The work was funded by Australia’s National Health and Medical Research Council. Dr. Allen has disclosed no relevant financial relationships. One investigator has received speaker’s fees from BMS. Another is a consultant for many companies, including Amgen, BMS, GlaxoSmithKline, and Merck. Dr. Emerick is an advisor for Regeneron, Sanofi, and Castle Biosciences. Dr. Miller is a researcher or consultant for those companies as well as Pfizer and others and has stock options in Avstera.
A version of this article first appeared on Medscape.com.
published in the New England Journal of Medicine.
“No signal of efficacy was observed,” said investigators led by Nicholas Allen, MPH, of the University of Sydney department of dermatology.
These results fill an “important gap in our understanding” and “will probably change the practice of many skin-cancer physicians,” two experts on the topic commented in a related editorial.
The editorialists are David Miller, MD, PhD, a dermatologist and medical oncologist at Massachusetts General Hospital, and Kevin Emerick, MD, a head and neck surgeon as Massachusetts Eye and Ear, both in Boston.
Transplant patients have 50 times the risk of nonmelanoma skin cancers – also known as keratinocyte cancers – than the general public, owing to immunosuppression, and their lesions are more aggressive and are more likely to metastasize, they explain.
Nicotinamide (vitamin B3) has been shown to prevent nonmelanoma skin cancers in healthy, immunocompetent people, so physicians routinely prescribe it to transplant patients on the assumption that it will do the same for them, they comment.
The Australian investigators decided to put the assumption to the test.
The team randomly assigned 79 patients who had undergone solid-organ transplant to receive nicotinamide 500 mg twice a day and 79 other patients to receive twice-daily placebo for a year. Participants underwent dermatology exams every 3 months to check for new lesions.
The participants were at high risk for new lesions; some had had more than 40 in the previous 5 years. The two groups were well balanced; kidney transplants were the most common.
At 12 months, there was virtually no difference in the incidence of new nonmelanoma skin cancers: 207 in the nicotinamide group and 210 in the placebo group (P = .96).
There was also no significant difference in squamous cell and basal cell carcinoma counts or actinic keratosis counts.
“The interpretation of the results is straightforward: nicotinamide lacks clinical usefulness in preventing the development of keratinocyte carcinomas in solid-organ transplant recipients,” the team concludes.
As for why nicotinamide didn’t work in the trial, the investigators say it could be because it is not potent enough to overcome the stifling of antitumor immunity and DNA-repair enzymes with immunosuppression.
Fewer than half of participants in the trial reported using sunscreen at any point during the study, which is in line with past reports that transplant patients don’t routinely use sunscreen.
Two other strategies for preventing squamous cell carcinoma after transplant – use of oral retinoids and mTOR inhibitors – are problematic for various reasons, and use was low in both study arms.
Editorialists Dr. Miller and Dr. Emerick suggest a possible new approach: immune checkpoint inhibitors before transplant to reduce the risk of nonmelanoma skin cancer afterward. They say the strategy should be explored and that ongoing efforts to minimize or eliminate the need for immunosuppression after transplant are promising.
The investigators originally planned to enroll 254 persons, but the trial was stopped early because of poor recruitment. Potential participants may already have been taking nicotinamide, which is commonly used, and that may have affected recruitment, the investigators say.
The work was funded by Australia’s National Health and Medical Research Council. Dr. Allen has disclosed no relevant financial relationships. One investigator has received speaker’s fees from BMS. Another is a consultant for many companies, including Amgen, BMS, GlaxoSmithKline, and Merck. Dr. Emerick is an advisor for Regeneron, Sanofi, and Castle Biosciences. Dr. Miller is a researcher or consultant for those companies as well as Pfizer and others and has stock options in Avstera.
A version of this article first appeared on Medscape.com.
FROM THE NEW ENGLAND JOURNAL OF MEDICINE
Hemophilia A gene therapy under FDA review
Hemophilia A (a deficiency of clotting Factor X) is the most common form of the disease, accounting for about 85% of patients.
The other type is hemophilia B (deficiency of clotting Factor VIII), and a gene therapy for this form of the disease has recently been launched – etranacogene dezaparvovec (Hemgenix), at the enormous price tag of $3.5 million.
Both products are comprised of a one-off intravenous IV infusion that delivers a functional gene via an adeno-associated virus that instructs the body to make the missing clotting factor. The hope is that this one-off infusion will act as a ‘cure’ and that the individual will be freed from life-long prophylaxis and/or treatment.
The new clinical data on valoctocogene roxaparvovec, published online in the New England Journal of Medicine, show that the beneficial effects from the gene are largely durable at 2 years, but they are anticipated to fade with time.
Two years after the one-time infusion, there remained “a significant reduction in the annualized bleeding rates” among 132 men who, at baseline, had severe hemophilia A requiring ongoing factor VIII prophylaxis, said the investigators, led by hematologist Johnny Mahlangu, MBBCh, MMed, of the University of the Witwatersrand, Johannesburg, South Africa.
However, the team predicted that median factor VIII activity would decrease below 10% of normal by year 3 or 5 depending on measurement technique, which would still translate to mild disease with an annualized bleeding rate of less than 1 episode per year.
“Although valoctocogene roxaparvovec may not eliminate bleeding, it potentially provides more consistent protection than factor VIII prophylaxis with less treatment burden,” the team said.
New questions
Data from the study “will directly inform therapeutic decision-making” in Europe, where valoctocogene roxaparvovec is already conditionally approved, and the United States, where it is awaiting approval by the FDA, says Lindsey George, MD, a hematologist and gene therapy specialist at Children’s Hospital of Philadelphia, in an accompanying editorial.
The study speaks to an ongoing concern about the durability of gene therapy for hemophilia but also raises new questions, she said.
For instance, while some patients had normal Factor VIII production and activity at 2 years, activity had dropped substantially in others, including in six men who resumed prophylaxis. “The cause of the decrease in factor VIII expression is an unanswered question,” and despite an anticipated U.S. price tag of around $2.5 million per treatment, “it is not possible [at the moment] to predict where an individual patient may fall within this range,” she writes.
Also, some subjects had elevations in liver aminotransferase levels that lasted for several months, including 2 years after infusion in 29% of subjects. Elevations in liver aminotransferase levels were treated with immune suppression for a median of 33 weeks.
“This is a unique finding with an undefined cause and long-term safety implications,” Dr. George said.
Getting to the bottom of such issues will be necessary for hemophilia gene therapy to fulfill its promise as “a one-time, lifelong, disease-ameliorating” fix for the condition, she asserted.
Study details
The new report followed up on the initial trial in 134 men who were treated with a single infusion of 6 × 1013 vector genomes per kilogram of body weight.
Among the 132 subjects available for 2-year evaluation, median factor VIII activity was in the range of mild hemophilia (6%-49% of normal) with an 84.5% reduction in bleeding events from baseline.
More than 80% of participants had no bleeding events requiring treatment, and there was a 98% reduction from baseline in mean use of exogenous factor VIII.
Overall, at year 2, 4.5% of subjects had factor VIII activity consistent with severe hemophilia A; 9.1% had activity consistent with moderate disease; 59.8% had activity consistent with mild disease; and 26.5% had activity in the normal range above 40 IU/dL. The investigators estimated that the typical half-life of the transgene-derived factor VIII production system is 123 weeks.
Among the six men who resumed prophylaxis, most had fewer bleeding events than when they were on prophylaxis before the infusion, investigators noted.
All the subjects developed antibodies to the virus delivery vector, precluding retreatment.
The work was funded by valoctocogene roxaparvovec maker BioMarin Pharmaceuticals. Several investigators are employees. Others reported ties to BioMarin and other companies; Dr. Mahlangu, for instance, reported research grants from BioMarin, Roche, Novo Nordisk, Pfizer, and others. Dr. George reported a research grant from Asklepios Biopharmaceutical and having a patent licensed to the company. The full list of author disclosures can be found with the original article.
A version of this article first appeared on Medscape.com.
Hemophilia A (a deficiency of clotting Factor X) is the most common form of the disease, accounting for about 85% of patients.
The other type is hemophilia B (deficiency of clotting Factor VIII), and a gene therapy for this form of the disease has recently been launched – etranacogene dezaparvovec (Hemgenix), at the enormous price tag of $3.5 million.
Both products are comprised of a one-off intravenous IV infusion that delivers a functional gene via an adeno-associated virus that instructs the body to make the missing clotting factor. The hope is that this one-off infusion will act as a ‘cure’ and that the individual will be freed from life-long prophylaxis and/or treatment.
The new clinical data on valoctocogene roxaparvovec, published online in the New England Journal of Medicine, show that the beneficial effects from the gene are largely durable at 2 years, but they are anticipated to fade with time.
Two years after the one-time infusion, there remained “a significant reduction in the annualized bleeding rates” among 132 men who, at baseline, had severe hemophilia A requiring ongoing factor VIII prophylaxis, said the investigators, led by hematologist Johnny Mahlangu, MBBCh, MMed, of the University of the Witwatersrand, Johannesburg, South Africa.
However, the team predicted that median factor VIII activity would decrease below 10% of normal by year 3 or 5 depending on measurement technique, which would still translate to mild disease with an annualized bleeding rate of less than 1 episode per year.
“Although valoctocogene roxaparvovec may not eliminate bleeding, it potentially provides more consistent protection than factor VIII prophylaxis with less treatment burden,” the team said.
New questions
Data from the study “will directly inform therapeutic decision-making” in Europe, where valoctocogene roxaparvovec is already conditionally approved, and the United States, where it is awaiting approval by the FDA, says Lindsey George, MD, a hematologist and gene therapy specialist at Children’s Hospital of Philadelphia, in an accompanying editorial.
The study speaks to an ongoing concern about the durability of gene therapy for hemophilia but also raises new questions, she said.
For instance, while some patients had normal Factor VIII production and activity at 2 years, activity had dropped substantially in others, including in six men who resumed prophylaxis. “The cause of the decrease in factor VIII expression is an unanswered question,” and despite an anticipated U.S. price tag of around $2.5 million per treatment, “it is not possible [at the moment] to predict where an individual patient may fall within this range,” she writes.
Also, some subjects had elevations in liver aminotransferase levels that lasted for several months, including 2 years after infusion in 29% of subjects. Elevations in liver aminotransferase levels were treated with immune suppression for a median of 33 weeks.
“This is a unique finding with an undefined cause and long-term safety implications,” Dr. George said.
Getting to the bottom of such issues will be necessary for hemophilia gene therapy to fulfill its promise as “a one-time, lifelong, disease-ameliorating” fix for the condition, she asserted.
Study details
The new report followed up on the initial trial in 134 men who were treated with a single infusion of 6 × 1013 vector genomes per kilogram of body weight.
Among the 132 subjects available for 2-year evaluation, median factor VIII activity was in the range of mild hemophilia (6%-49% of normal) with an 84.5% reduction in bleeding events from baseline.
More than 80% of participants had no bleeding events requiring treatment, and there was a 98% reduction from baseline in mean use of exogenous factor VIII.
Overall, at year 2, 4.5% of subjects had factor VIII activity consistent with severe hemophilia A; 9.1% had activity consistent with moderate disease; 59.8% had activity consistent with mild disease; and 26.5% had activity in the normal range above 40 IU/dL. The investigators estimated that the typical half-life of the transgene-derived factor VIII production system is 123 weeks.
Among the six men who resumed prophylaxis, most had fewer bleeding events than when they were on prophylaxis before the infusion, investigators noted.
All the subjects developed antibodies to the virus delivery vector, precluding retreatment.
The work was funded by valoctocogene roxaparvovec maker BioMarin Pharmaceuticals. Several investigators are employees. Others reported ties to BioMarin and other companies; Dr. Mahlangu, for instance, reported research grants from BioMarin, Roche, Novo Nordisk, Pfizer, and others. Dr. George reported a research grant from Asklepios Biopharmaceutical and having a patent licensed to the company. The full list of author disclosures can be found with the original article.
A version of this article first appeared on Medscape.com.
Hemophilia A (a deficiency of clotting Factor X) is the most common form of the disease, accounting for about 85% of patients.
The other type is hemophilia B (deficiency of clotting Factor VIII), and a gene therapy for this form of the disease has recently been launched – etranacogene dezaparvovec (Hemgenix), at the enormous price tag of $3.5 million.
Both products are comprised of a one-off intravenous IV infusion that delivers a functional gene via an adeno-associated virus that instructs the body to make the missing clotting factor. The hope is that this one-off infusion will act as a ‘cure’ and that the individual will be freed from life-long prophylaxis and/or treatment.
The new clinical data on valoctocogene roxaparvovec, published online in the New England Journal of Medicine, show that the beneficial effects from the gene are largely durable at 2 years, but they are anticipated to fade with time.
Two years after the one-time infusion, there remained “a significant reduction in the annualized bleeding rates” among 132 men who, at baseline, had severe hemophilia A requiring ongoing factor VIII prophylaxis, said the investigators, led by hematologist Johnny Mahlangu, MBBCh, MMed, of the University of the Witwatersrand, Johannesburg, South Africa.
However, the team predicted that median factor VIII activity would decrease below 10% of normal by year 3 or 5 depending on measurement technique, which would still translate to mild disease with an annualized bleeding rate of less than 1 episode per year.
“Although valoctocogene roxaparvovec may not eliminate bleeding, it potentially provides more consistent protection than factor VIII prophylaxis with less treatment burden,” the team said.
New questions
Data from the study “will directly inform therapeutic decision-making” in Europe, where valoctocogene roxaparvovec is already conditionally approved, and the United States, where it is awaiting approval by the FDA, says Lindsey George, MD, a hematologist and gene therapy specialist at Children’s Hospital of Philadelphia, in an accompanying editorial.
The study speaks to an ongoing concern about the durability of gene therapy for hemophilia but also raises new questions, she said.
For instance, while some patients had normal Factor VIII production and activity at 2 years, activity had dropped substantially in others, including in six men who resumed prophylaxis. “The cause of the decrease in factor VIII expression is an unanswered question,” and despite an anticipated U.S. price tag of around $2.5 million per treatment, “it is not possible [at the moment] to predict where an individual patient may fall within this range,” she writes.
Also, some subjects had elevations in liver aminotransferase levels that lasted for several months, including 2 years after infusion in 29% of subjects. Elevations in liver aminotransferase levels were treated with immune suppression for a median of 33 weeks.
“This is a unique finding with an undefined cause and long-term safety implications,” Dr. George said.
Getting to the bottom of such issues will be necessary for hemophilia gene therapy to fulfill its promise as “a one-time, lifelong, disease-ameliorating” fix for the condition, she asserted.
Study details
The new report followed up on the initial trial in 134 men who were treated with a single infusion of 6 × 1013 vector genomes per kilogram of body weight.
Among the 132 subjects available for 2-year evaluation, median factor VIII activity was in the range of mild hemophilia (6%-49% of normal) with an 84.5% reduction in bleeding events from baseline.
More than 80% of participants had no bleeding events requiring treatment, and there was a 98% reduction from baseline in mean use of exogenous factor VIII.
Overall, at year 2, 4.5% of subjects had factor VIII activity consistent with severe hemophilia A; 9.1% had activity consistent with moderate disease; 59.8% had activity consistent with mild disease; and 26.5% had activity in the normal range above 40 IU/dL. The investigators estimated that the typical half-life of the transgene-derived factor VIII production system is 123 weeks.
Among the six men who resumed prophylaxis, most had fewer bleeding events than when they were on prophylaxis before the infusion, investigators noted.
All the subjects developed antibodies to the virus delivery vector, precluding retreatment.
The work was funded by valoctocogene roxaparvovec maker BioMarin Pharmaceuticals. Several investigators are employees. Others reported ties to BioMarin and other companies; Dr. Mahlangu, for instance, reported research grants from BioMarin, Roche, Novo Nordisk, Pfizer, and others. Dr. George reported a research grant from Asklepios Biopharmaceutical and having a patent licensed to the company. The full list of author disclosures can be found with the original article.
A version of this article first appeared on Medscape.com.
FROM THE NEW ENGLAND JOURNAL OF MEDICINE
Strategy to reduce peritoneal metastases in gastric cancer
The study covered in this summary was published on researchsquare.com as a preprint and has not yet been peer reviewed.
Key takeaway
Why this matters
- Surgery and postoperative chemotherapy are standard of care for advanced gastric cancer, but up to half of patients develop peritoneal metastases with poor prognosis.
- There is no consensus on how to prevent peritoneal metastases.
- With hyperthermic intraperitoneal chemotherapy, the abdominal cavity is bathed in chemotherapy that has been heated, directly killing free cancer cells and micrometastases.
- The findings suggest that adding hyperthermic intraperitoneal chemotherapy to standard treatment greatly reduces the risk of peritoneal metastases.
Study design
- The investigators randomly assigned 134 patients with advanced gastric cancer evenly to receive either systemic chemotherapy alone or systemic chemotherapy plus hyperthermic intraperitoneal chemotherapy after radical gastrectomy.
- The hyperthermic intraperitoneal chemotherapy group had 3 L of heated saline containing 40 mg/m2 of cisplatin circulated in their peritoneal cavities for an hour. The procedure was performed twice within 72 hours of surgery.
- Systemic chemotherapy consisted of six to eight cycles of S-1 combined with oxaliplatin (SOX regimen) starting 4-6 weeks after surgery.
- Most patients (90%) had stage III disease, and the rest stage II.
- Median follow-up was 44 months.
Key results
- Overall, the 3-year DFS rate was 73.8% with hyperthermic intraperitoneal chemotherapy versus 61.2% without it (P = .031).
- In addition, 21% of patients in the hyperthermic intraperitoneal chemotherapy group developed peritoneal metastases versus 40.3% with standard care (P = .015)
- The 3-year overall survival was 73.9% in the hyperthermic intraperitoneal chemotherapy group versus 77.6% in the standard care arm, but the difference was not significant (P = .737).
- There were no serious adverse events related to hyperthermic intraperitoneal chemotherapy, and postoperative complications were similar between the groups.
- Grade 3 or 4 adverse events occurred in 14.2% of patients; there were no statistically significant between-group differences.
- Metastases to other sites, such as the liver and distant lymph nodes, were also similar between the two arms.
Limitations
- Follow-up might have been too short to detect a difference in overall survival.
- The trial was conducted at a single-center and was relatively small.
Disclosures
- The study received no external funding, and the investigators did not report any financial relationships.
This is a summary of a preprint research study, “Hyperthermic Intraperitoneal Chemotherapy (HIPEC) Plus Systemic Chemotherapy Versus Systemic Chemotherapy Alone in Locally Advanced Gastric Cancer After D2 Radical Resection: A Randomized Controlled Study,” led by Pengfei Yu of the Zhejiang Cancer Hospital, Hangzhou, China. The study has not been peer reviewed. The full text can be found at researchsquare.com.
A version of this article first appeared on Medscape.com.
The study covered in this summary was published on researchsquare.com as a preprint and has not yet been peer reviewed.
Key takeaway
Why this matters
- Surgery and postoperative chemotherapy are standard of care for advanced gastric cancer, but up to half of patients develop peritoneal metastases with poor prognosis.
- There is no consensus on how to prevent peritoneal metastases.
- With hyperthermic intraperitoneal chemotherapy, the abdominal cavity is bathed in chemotherapy that has been heated, directly killing free cancer cells and micrometastases.
- The findings suggest that adding hyperthermic intraperitoneal chemotherapy to standard treatment greatly reduces the risk of peritoneal metastases.
Study design
- The investigators randomly assigned 134 patients with advanced gastric cancer evenly to receive either systemic chemotherapy alone or systemic chemotherapy plus hyperthermic intraperitoneal chemotherapy after radical gastrectomy.
- The hyperthermic intraperitoneal chemotherapy group had 3 L of heated saline containing 40 mg/m2 of cisplatin circulated in their peritoneal cavities for an hour. The procedure was performed twice within 72 hours of surgery.
- Systemic chemotherapy consisted of six to eight cycles of S-1 combined with oxaliplatin (SOX regimen) starting 4-6 weeks after surgery.
- Most patients (90%) had stage III disease, and the rest stage II.
- Median follow-up was 44 months.
Key results
- Overall, the 3-year DFS rate was 73.8% with hyperthermic intraperitoneal chemotherapy versus 61.2% without it (P = .031).
- In addition, 21% of patients in the hyperthermic intraperitoneal chemotherapy group developed peritoneal metastases versus 40.3% with standard care (P = .015)
- The 3-year overall survival was 73.9% in the hyperthermic intraperitoneal chemotherapy group versus 77.6% in the standard care arm, but the difference was not significant (P = .737).
- There were no serious adverse events related to hyperthermic intraperitoneal chemotherapy, and postoperative complications were similar between the groups.
- Grade 3 or 4 adverse events occurred in 14.2% of patients; there were no statistically significant between-group differences.
- Metastases to other sites, such as the liver and distant lymph nodes, were also similar between the two arms.
Limitations
- Follow-up might have been too short to detect a difference in overall survival.
- The trial was conducted at a single-center and was relatively small.
Disclosures
- The study received no external funding, and the investigators did not report any financial relationships.
This is a summary of a preprint research study, “Hyperthermic Intraperitoneal Chemotherapy (HIPEC) Plus Systemic Chemotherapy Versus Systemic Chemotherapy Alone in Locally Advanced Gastric Cancer After D2 Radical Resection: A Randomized Controlled Study,” led by Pengfei Yu of the Zhejiang Cancer Hospital, Hangzhou, China. The study has not been peer reviewed. The full text can be found at researchsquare.com.
A version of this article first appeared on Medscape.com.
The study covered in this summary was published on researchsquare.com as a preprint and has not yet been peer reviewed.
Key takeaway
Why this matters
- Surgery and postoperative chemotherapy are standard of care for advanced gastric cancer, but up to half of patients develop peritoneal metastases with poor prognosis.
- There is no consensus on how to prevent peritoneal metastases.
- With hyperthermic intraperitoneal chemotherapy, the abdominal cavity is bathed in chemotherapy that has been heated, directly killing free cancer cells and micrometastases.
- The findings suggest that adding hyperthermic intraperitoneal chemotherapy to standard treatment greatly reduces the risk of peritoneal metastases.
Study design
- The investigators randomly assigned 134 patients with advanced gastric cancer evenly to receive either systemic chemotherapy alone or systemic chemotherapy plus hyperthermic intraperitoneal chemotherapy after radical gastrectomy.
- The hyperthermic intraperitoneal chemotherapy group had 3 L of heated saline containing 40 mg/m2 of cisplatin circulated in their peritoneal cavities for an hour. The procedure was performed twice within 72 hours of surgery.
- Systemic chemotherapy consisted of six to eight cycles of S-1 combined with oxaliplatin (SOX regimen) starting 4-6 weeks after surgery.
- Most patients (90%) had stage III disease, and the rest stage II.
- Median follow-up was 44 months.
Key results
- Overall, the 3-year DFS rate was 73.8% with hyperthermic intraperitoneal chemotherapy versus 61.2% without it (P = .031).
- In addition, 21% of patients in the hyperthermic intraperitoneal chemotherapy group developed peritoneal metastases versus 40.3% with standard care (P = .015)
- The 3-year overall survival was 73.9% in the hyperthermic intraperitoneal chemotherapy group versus 77.6% in the standard care arm, but the difference was not significant (P = .737).
- There were no serious adverse events related to hyperthermic intraperitoneal chemotherapy, and postoperative complications were similar between the groups.
- Grade 3 or 4 adverse events occurred in 14.2% of patients; there were no statistically significant between-group differences.
- Metastases to other sites, such as the liver and distant lymph nodes, were also similar between the two arms.
Limitations
- Follow-up might have been too short to detect a difference in overall survival.
- The trial was conducted at a single-center and was relatively small.
Disclosures
- The study received no external funding, and the investigators did not report any financial relationships.
This is a summary of a preprint research study, “Hyperthermic Intraperitoneal Chemotherapy (HIPEC) Plus Systemic Chemotherapy Versus Systemic Chemotherapy Alone in Locally Advanced Gastric Cancer After D2 Radical Resection: A Randomized Controlled Study,” led by Pengfei Yu of the Zhejiang Cancer Hospital, Hangzhou, China. The study has not been peer reviewed. The full text can be found at researchsquare.com.
A version of this article first appeared on Medscape.com.
Omit radiation in older women with low-risk, ER+ breast cancer
say researchers reporting 10-year outcomes from the large phase 3 trial known as PRIME II.
“Our trial provides robust evidence indicating that irradiation can be safely omitted in women 65 years of age or older who have grade 1 or 2 ER-high cancers treated by breast-conserving therapy, provided that they receive 5 years of adjuvant endocrine therapy,” concluded investigators led by Ian Kunkler, MB, a clinical oncology professor at the University of Edinburgh.
The trial randomly assigned 1,326 women who had undergone a lumpectomy to either whole-breast irradiation or no radiation on a background of tamoxifen.
The incidence of local recurrence was lower with radiation (0.9% vs. 9.5%), but there was no significant difference in distant metastases or breast cancer–specific or overall survival.
The findings will “help clinicians guide older patients on whether this particular aspect of early breast cancer treatment can be omitted,” Dr. Kunkler said in a press release. Radiation carries risks of heart and lung damage, and these results show that skipping it does not increase the odds of dying from breast cancer.
The new study was published in the New England Journal of Medicine.
“Any doubt that radiotherapy cannot be omitted in women” who meet the criteria “can be put to rest,” commented breast radiation oncologists Alice Ho, MD, of Duke University in Durham, N.C., and Jennifer Bellon, MD, of Harvard Medical School, Boston, in an accompanying editorial.
Clinical guidelines already support omitting radiation therapy in older women with low-risk tumors treated with lumpectomy and endocrine therapy, but the move has been controversial owing to a lack of long-term data, and use of radiation for such women remains common in the United States, the investigators explain.
The “highly anticipated” results for 10-year outcomes from this trial should help address that issue, as well as “the long-standing problem of overtreatment in older women with low-risk breast cancer,” the editorialists comment.
Study details
PRIME II was conducted from 2003 to 2009 mainly in the United Kingdom. Participants were aged 65 years or older and had T1 or T2 ER-positive tumors no larger than 3 cm and were without nodal involvement.
Following lumpectomies with clear margins, the women underwent endocrine therapy; the investigators recommended tamoxifen at 20 mg/day for 5 years.
Women who were randomly assigned to radiation also received 40-50 Gy of whole-breast irradiation in 20-25 fractions over 3-5 weeks.
At 10 years, 1.6% of women in the no-radiation arm had distant metastases as their first recurrence vs. 3% of women who underwent radiation.
Ten-year breast cancer–specific survival was 97.9% with radiation and 97.4% with no radiation. Ten-year overall survival was 80.7% in the radiotherapy arm vs. 80.8% in the no-radiotherapy group.
In addition, the recurrence rate was lower after radiation. The investigators suggest that lower adherence to endocrine therapy and lower levels of ER positivity increased the risk of local recurrence among women who didn’t receive radiation.
Almost 10% of the women who did not receive radiation had local recurrences by 10 years, but the investigators note that if tumors do recur locally, women still have the option of a second lumpectomy, and if they so choose, they can then receive radiation, so local recurrence “does not necessarily mean loss of the breast.”
PRIME II was funded by the Scottish Government’s chief scientist office and the Breast Cancer Institute at Western General Hospital, Edinburgh. Dr. Kunkler reported no conflicts of interest. A coauthor has acted as a speaker, adviser, and/or researcher for many companies, including Hoffmann-La Roche, Exact Sciences, and Eli Lilly. Dr. Ho reported grants from and/or being a consultant for GlaxoSmithKline, Roche, Merck, and others. Dr. Bellon reported ties to Varian Medical Systems and Veracyte.
A version of this article originally appeared on Medscape.com.
say researchers reporting 10-year outcomes from the large phase 3 trial known as PRIME II.
“Our trial provides robust evidence indicating that irradiation can be safely omitted in women 65 years of age or older who have grade 1 or 2 ER-high cancers treated by breast-conserving therapy, provided that they receive 5 years of adjuvant endocrine therapy,” concluded investigators led by Ian Kunkler, MB, a clinical oncology professor at the University of Edinburgh.
The trial randomly assigned 1,326 women who had undergone a lumpectomy to either whole-breast irradiation or no radiation on a background of tamoxifen.
The incidence of local recurrence was lower with radiation (0.9% vs. 9.5%), but there was no significant difference in distant metastases or breast cancer–specific or overall survival.
The findings will “help clinicians guide older patients on whether this particular aspect of early breast cancer treatment can be omitted,” Dr. Kunkler said in a press release. Radiation carries risks of heart and lung damage, and these results show that skipping it does not increase the odds of dying from breast cancer.
The new study was published in the New England Journal of Medicine.
“Any doubt that radiotherapy cannot be omitted in women” who meet the criteria “can be put to rest,” commented breast radiation oncologists Alice Ho, MD, of Duke University in Durham, N.C., and Jennifer Bellon, MD, of Harvard Medical School, Boston, in an accompanying editorial.
Clinical guidelines already support omitting radiation therapy in older women with low-risk tumors treated with lumpectomy and endocrine therapy, but the move has been controversial owing to a lack of long-term data, and use of radiation for such women remains common in the United States, the investigators explain.
The “highly anticipated” results for 10-year outcomes from this trial should help address that issue, as well as “the long-standing problem of overtreatment in older women with low-risk breast cancer,” the editorialists comment.
Study details
PRIME II was conducted from 2003 to 2009 mainly in the United Kingdom. Participants were aged 65 years or older and had T1 or T2 ER-positive tumors no larger than 3 cm and were without nodal involvement.
Following lumpectomies with clear margins, the women underwent endocrine therapy; the investigators recommended tamoxifen at 20 mg/day for 5 years.
Women who were randomly assigned to radiation also received 40-50 Gy of whole-breast irradiation in 20-25 fractions over 3-5 weeks.
At 10 years, 1.6% of women in the no-radiation arm had distant metastases as their first recurrence vs. 3% of women who underwent radiation.
Ten-year breast cancer–specific survival was 97.9% with radiation and 97.4% with no radiation. Ten-year overall survival was 80.7% in the radiotherapy arm vs. 80.8% in the no-radiotherapy group.
In addition, the recurrence rate was lower after radiation. The investigators suggest that lower adherence to endocrine therapy and lower levels of ER positivity increased the risk of local recurrence among women who didn’t receive radiation.
Almost 10% of the women who did not receive radiation had local recurrences by 10 years, but the investigators note that if tumors do recur locally, women still have the option of a second lumpectomy, and if they so choose, they can then receive radiation, so local recurrence “does not necessarily mean loss of the breast.”
PRIME II was funded by the Scottish Government’s chief scientist office and the Breast Cancer Institute at Western General Hospital, Edinburgh. Dr. Kunkler reported no conflicts of interest. A coauthor has acted as a speaker, adviser, and/or researcher for many companies, including Hoffmann-La Roche, Exact Sciences, and Eli Lilly. Dr. Ho reported grants from and/or being a consultant for GlaxoSmithKline, Roche, Merck, and others. Dr. Bellon reported ties to Varian Medical Systems and Veracyte.
A version of this article originally appeared on Medscape.com.
say researchers reporting 10-year outcomes from the large phase 3 trial known as PRIME II.
“Our trial provides robust evidence indicating that irradiation can be safely omitted in women 65 years of age or older who have grade 1 or 2 ER-high cancers treated by breast-conserving therapy, provided that they receive 5 years of adjuvant endocrine therapy,” concluded investigators led by Ian Kunkler, MB, a clinical oncology professor at the University of Edinburgh.
The trial randomly assigned 1,326 women who had undergone a lumpectomy to either whole-breast irradiation or no radiation on a background of tamoxifen.
The incidence of local recurrence was lower with radiation (0.9% vs. 9.5%), but there was no significant difference in distant metastases or breast cancer–specific or overall survival.
The findings will “help clinicians guide older patients on whether this particular aspect of early breast cancer treatment can be omitted,” Dr. Kunkler said in a press release. Radiation carries risks of heart and lung damage, and these results show that skipping it does not increase the odds of dying from breast cancer.
The new study was published in the New England Journal of Medicine.
“Any doubt that radiotherapy cannot be omitted in women” who meet the criteria “can be put to rest,” commented breast radiation oncologists Alice Ho, MD, of Duke University in Durham, N.C., and Jennifer Bellon, MD, of Harvard Medical School, Boston, in an accompanying editorial.
Clinical guidelines already support omitting radiation therapy in older women with low-risk tumors treated with lumpectomy and endocrine therapy, but the move has been controversial owing to a lack of long-term data, and use of radiation for such women remains common in the United States, the investigators explain.
The “highly anticipated” results for 10-year outcomes from this trial should help address that issue, as well as “the long-standing problem of overtreatment in older women with low-risk breast cancer,” the editorialists comment.
Study details
PRIME II was conducted from 2003 to 2009 mainly in the United Kingdom. Participants were aged 65 years or older and had T1 or T2 ER-positive tumors no larger than 3 cm and were without nodal involvement.
Following lumpectomies with clear margins, the women underwent endocrine therapy; the investigators recommended tamoxifen at 20 mg/day for 5 years.
Women who were randomly assigned to radiation also received 40-50 Gy of whole-breast irradiation in 20-25 fractions over 3-5 weeks.
At 10 years, 1.6% of women in the no-radiation arm had distant metastases as their first recurrence vs. 3% of women who underwent radiation.
Ten-year breast cancer–specific survival was 97.9% with radiation and 97.4% with no radiation. Ten-year overall survival was 80.7% in the radiotherapy arm vs. 80.8% in the no-radiotherapy group.
In addition, the recurrence rate was lower after radiation. The investigators suggest that lower adherence to endocrine therapy and lower levels of ER positivity increased the risk of local recurrence among women who didn’t receive radiation.
Almost 10% of the women who did not receive radiation had local recurrences by 10 years, but the investigators note that if tumors do recur locally, women still have the option of a second lumpectomy, and if they so choose, they can then receive radiation, so local recurrence “does not necessarily mean loss of the breast.”
PRIME II was funded by the Scottish Government’s chief scientist office and the Breast Cancer Institute at Western General Hospital, Edinburgh. Dr. Kunkler reported no conflicts of interest. A coauthor has acted as a speaker, adviser, and/or researcher for many companies, including Hoffmann-La Roche, Exact Sciences, and Eli Lilly. Dr. Ho reported grants from and/or being a consultant for GlaxoSmithKline, Roche, Merck, and others. Dr. Bellon reported ties to Varian Medical Systems and Veracyte.
A version of this article originally appeared on Medscape.com.
FROM THE NEW ENGLAND JOURNAL OF MEDICINE
Docetaxel as alternative to cisplatin for H&N radiotherapy
say researchers reporting a phase 3 trial from India.
“This is the first randomized study demonstrating the benefit of an alternate radiosensitizing agent in cisplatin-ineligible patients,” they wrote.
“We found that the use of docetaxel as a radiosensitizer in cisplatin-ineligible patients,” compared with the use of radiation alone, “led to an improvement in disease-free survival, locoregional control, and overall survival without affecting the quality of life of the patients,” the team reported.
The investigators, led by Vijay Maruti Patil, MD, DM, a medical oncologist at Tata Memorial Hospital, Mumbai, noted that they stopped the trial early after the benefit from adding docetaxel became clear.
Cisplatin is the general standard of care to sensitize locally advanced head and neck tumors to radiation treatment, but up to a third of patients are ineligible because of age, diminished kidney function, hearing loss, and other problems, they wrote.
Many alternatives to cisplatin are used in such settings, but until now, there hasn’t been any level 1, phase 3 evidence to guide the selection.
Cetuximab is the alternative used most often in the United States, but evidence supporting it was generated in trials involving cisplatin-eligible patients, the investigators pointed out. There is also a high incidence of skin and other toxicities and, in some studies, nonideal survival outcomes, they noted.
The new study was published online in the Journal of Clinical Oncology.
It “demonstrates what could be presumed but was not known to be true in the cisplatin-ineligible context: Radiosensitizers improve outcomes over radiotherapy alone,” commented the authors of an accompanying editorial (J Clin Oncol. 2023 Feb 1. doi: 10.1200/JCO.22.02350).
“Docetaxel belongs in the armamentarium of go-to regimens,” wrote radiation oncologist Loren Mell, MD, of the University of California, San Diego, and medical oncologist Stuart Wong, MD, of the Medical College of Wisconsin, Milwaukee.
This study “fills an important gap in the head and neck cancer literature, but “since [docetaxel] was not compared head-to-head against” other radiosensitizing alternatives, it “should not be declared the lone standard. ... It is high time to shift the conversation from whether radiosensitizers are beneficial to which regimen (if any) provides the most benefit and should define the standard of care,” they added.
The trial randomly assigned 356 cisplatin-ineligible adults equally to either radiation alone or radiation with concurrent docetaxel 15 mg/m2 once weekly for a maximum of seven cycles. The investigators planned to enroll 600 patients but stopped the trial early when the survival benefit with docetaxel became clear.
The addition of docetaxel improved 2-year disease-free survival (42% vs. 30.3%; hazard ratio, 0.673; P = .002); 2-year overall survival (50.8% vs. 41.7%; HR, 0.747; P = .035), and the 2-year locoregional failure rate (41.8% vs. 54.7%; HR, 0.661; P = .002).
Median overall survival was 25.5 months with docetaxel versus 15.3 months with radiation alone (P = .035).
Docetaxel’s benefits were most pronounced in patients with hypopharyngeal primary sites and among the 61% of patients treated definitively. There was “possibly” a benefit in the adjuvant setting, but “further study would be required to show definitive applicability,” the investigators said.
There was a higher incidence of grade 3 or greater mucositis (49.7% vs. 22.2%), odynophagia (52.5% vs. 33.5%), and dysphagia (33%), but the “complications were manageable and did not affect the compliance” with either radiation or docetaxel, the team reported. Overall, 86% of patients received five or more cycles docetaxel.
In their editorial, Dr. Mell and Dr. Wong noted that the “majority of patients did not receive intensity-modulated radiotherapy, the standard in higher-income countries,” but added that “we do not expect the use of conventional radiotherapy would reduce the effectiveness of docetaxel.”
The trial was funded by Tata Memorial Hospital, where it was conducted. Several investigators had industry ties, including Dr. Patil, who reported research funding from Johnson & Johnson/Janssen, AstraZeneca, Intas, NATCO Pharma, Eisai Germany, and Novartis. Dr. Mell is an advisor for Cel-Sci and reported research funding from Merck and AstraZeneca. Dr. Wong disclosed research funding from Novartis and Merck.
A version of this article first appeared on Medscape.com.
say researchers reporting a phase 3 trial from India.
“This is the first randomized study demonstrating the benefit of an alternate radiosensitizing agent in cisplatin-ineligible patients,” they wrote.
“We found that the use of docetaxel as a radiosensitizer in cisplatin-ineligible patients,” compared with the use of radiation alone, “led to an improvement in disease-free survival, locoregional control, and overall survival without affecting the quality of life of the patients,” the team reported.
The investigators, led by Vijay Maruti Patil, MD, DM, a medical oncologist at Tata Memorial Hospital, Mumbai, noted that they stopped the trial early after the benefit from adding docetaxel became clear.
Cisplatin is the general standard of care to sensitize locally advanced head and neck tumors to radiation treatment, but up to a third of patients are ineligible because of age, diminished kidney function, hearing loss, and other problems, they wrote.
Many alternatives to cisplatin are used in such settings, but until now, there hasn’t been any level 1, phase 3 evidence to guide the selection.
Cetuximab is the alternative used most often in the United States, but evidence supporting it was generated in trials involving cisplatin-eligible patients, the investigators pointed out. There is also a high incidence of skin and other toxicities and, in some studies, nonideal survival outcomes, they noted.
The new study was published online in the Journal of Clinical Oncology.
It “demonstrates what could be presumed but was not known to be true in the cisplatin-ineligible context: Radiosensitizers improve outcomes over radiotherapy alone,” commented the authors of an accompanying editorial (J Clin Oncol. 2023 Feb 1. doi: 10.1200/JCO.22.02350).
“Docetaxel belongs in the armamentarium of go-to regimens,” wrote radiation oncologist Loren Mell, MD, of the University of California, San Diego, and medical oncologist Stuart Wong, MD, of the Medical College of Wisconsin, Milwaukee.
This study “fills an important gap in the head and neck cancer literature, but “since [docetaxel] was not compared head-to-head against” other radiosensitizing alternatives, it “should not be declared the lone standard. ... It is high time to shift the conversation from whether radiosensitizers are beneficial to which regimen (if any) provides the most benefit and should define the standard of care,” they added.
The trial randomly assigned 356 cisplatin-ineligible adults equally to either radiation alone or radiation with concurrent docetaxel 15 mg/m2 once weekly for a maximum of seven cycles. The investigators planned to enroll 600 patients but stopped the trial early when the survival benefit with docetaxel became clear.
The addition of docetaxel improved 2-year disease-free survival (42% vs. 30.3%; hazard ratio, 0.673; P = .002); 2-year overall survival (50.8% vs. 41.7%; HR, 0.747; P = .035), and the 2-year locoregional failure rate (41.8% vs. 54.7%; HR, 0.661; P = .002).
Median overall survival was 25.5 months with docetaxel versus 15.3 months with radiation alone (P = .035).
Docetaxel’s benefits were most pronounced in patients with hypopharyngeal primary sites and among the 61% of patients treated definitively. There was “possibly” a benefit in the adjuvant setting, but “further study would be required to show definitive applicability,” the investigators said.
There was a higher incidence of grade 3 or greater mucositis (49.7% vs. 22.2%), odynophagia (52.5% vs. 33.5%), and dysphagia (33%), but the “complications were manageable and did not affect the compliance” with either radiation or docetaxel, the team reported. Overall, 86% of patients received five or more cycles docetaxel.
In their editorial, Dr. Mell and Dr. Wong noted that the “majority of patients did not receive intensity-modulated radiotherapy, the standard in higher-income countries,” but added that “we do not expect the use of conventional radiotherapy would reduce the effectiveness of docetaxel.”
The trial was funded by Tata Memorial Hospital, where it was conducted. Several investigators had industry ties, including Dr. Patil, who reported research funding from Johnson & Johnson/Janssen, AstraZeneca, Intas, NATCO Pharma, Eisai Germany, and Novartis. Dr. Mell is an advisor for Cel-Sci and reported research funding from Merck and AstraZeneca. Dr. Wong disclosed research funding from Novartis and Merck.
A version of this article first appeared on Medscape.com.
say researchers reporting a phase 3 trial from India.
“This is the first randomized study demonstrating the benefit of an alternate radiosensitizing agent in cisplatin-ineligible patients,” they wrote.
“We found that the use of docetaxel as a radiosensitizer in cisplatin-ineligible patients,” compared with the use of radiation alone, “led to an improvement in disease-free survival, locoregional control, and overall survival without affecting the quality of life of the patients,” the team reported.
The investigators, led by Vijay Maruti Patil, MD, DM, a medical oncologist at Tata Memorial Hospital, Mumbai, noted that they stopped the trial early after the benefit from adding docetaxel became clear.
Cisplatin is the general standard of care to sensitize locally advanced head and neck tumors to radiation treatment, but up to a third of patients are ineligible because of age, diminished kidney function, hearing loss, and other problems, they wrote.
Many alternatives to cisplatin are used in such settings, but until now, there hasn’t been any level 1, phase 3 evidence to guide the selection.
Cetuximab is the alternative used most often in the United States, but evidence supporting it was generated in trials involving cisplatin-eligible patients, the investigators pointed out. There is also a high incidence of skin and other toxicities and, in some studies, nonideal survival outcomes, they noted.
The new study was published online in the Journal of Clinical Oncology.
It “demonstrates what could be presumed but was not known to be true in the cisplatin-ineligible context: Radiosensitizers improve outcomes over radiotherapy alone,” commented the authors of an accompanying editorial (J Clin Oncol. 2023 Feb 1. doi: 10.1200/JCO.22.02350).
“Docetaxel belongs in the armamentarium of go-to regimens,” wrote radiation oncologist Loren Mell, MD, of the University of California, San Diego, and medical oncologist Stuart Wong, MD, of the Medical College of Wisconsin, Milwaukee.
This study “fills an important gap in the head and neck cancer literature, but “since [docetaxel] was not compared head-to-head against” other radiosensitizing alternatives, it “should not be declared the lone standard. ... It is high time to shift the conversation from whether radiosensitizers are beneficial to which regimen (if any) provides the most benefit and should define the standard of care,” they added.
The trial randomly assigned 356 cisplatin-ineligible adults equally to either radiation alone or radiation with concurrent docetaxel 15 mg/m2 once weekly for a maximum of seven cycles. The investigators planned to enroll 600 patients but stopped the trial early when the survival benefit with docetaxel became clear.
The addition of docetaxel improved 2-year disease-free survival (42% vs. 30.3%; hazard ratio, 0.673; P = .002); 2-year overall survival (50.8% vs. 41.7%; HR, 0.747; P = .035), and the 2-year locoregional failure rate (41.8% vs. 54.7%; HR, 0.661; P = .002).
Median overall survival was 25.5 months with docetaxel versus 15.3 months with radiation alone (P = .035).
Docetaxel’s benefits were most pronounced in patients with hypopharyngeal primary sites and among the 61% of patients treated definitively. There was “possibly” a benefit in the adjuvant setting, but “further study would be required to show definitive applicability,” the investigators said.
There was a higher incidence of grade 3 or greater mucositis (49.7% vs. 22.2%), odynophagia (52.5% vs. 33.5%), and dysphagia (33%), but the “complications were manageable and did not affect the compliance” with either radiation or docetaxel, the team reported. Overall, 86% of patients received five or more cycles docetaxel.
In their editorial, Dr. Mell and Dr. Wong noted that the “majority of patients did not receive intensity-modulated radiotherapy, the standard in higher-income countries,” but added that “we do not expect the use of conventional radiotherapy would reduce the effectiveness of docetaxel.”
The trial was funded by Tata Memorial Hospital, where it was conducted. Several investigators had industry ties, including Dr. Patil, who reported research funding from Johnson & Johnson/Janssen, AstraZeneca, Intas, NATCO Pharma, Eisai Germany, and Novartis. Dr. Mell is an advisor for Cel-Sci and reported research funding from Merck and AstraZeneca. Dr. Wong disclosed research funding from Novartis and Merck.
A version of this article first appeared on Medscape.com.
FROM THE JOURNAL OF CLINICAL ONCOLOGY
Key factors predict gallbladder cancer on routine cholecystectomy
The study covered in this summary was published on researchsquare.com as a preprint and has not yet been peer reviewed.
Key takeaway
Why this matters
- More than 60% of gallbladder cancers are diagnosed incidentally following cholecystectomy for benign reasons.
- Identifying predictors allows surgeons to send high-risk individuals for oncologic evaluation beforehand and to prepare for intraoperative frozen pathology and more appropriate surgery, including extended cholecystectomy and lymph node dissection.
Study design
- The investigators analyzed 403,443 cholecystectomies in the American College of Surgeons’ NSQIP database from 2007 to 2017.
- They used multivariable logistic regression to identify risk factors for gallbladder cancers.
- Patients undergoing cholecystectomy for suspected or confirmed gallbladder cancer were excluded.
Key results
- The incidence of gallbladder cancer was 0.11% (441 of 403,443 patients).
- Preoperative factors significantly associated with gallbladder cancer included age older than 60 years (odds ratio [OR], 6.51), female sex (OR, 1.75), weight loss (OR, 2.58), and elevated alkaline phosphatase level (OR, 1.67).
- Starting with or converting to an open approach – both potential indicators of more complex disease – were associated with seven times’ higher odds of gallbladder cancer (OR, 7.33; P < .001), as were longer operative times (127 minutes vs. 70.7 minutes; P < .001).
Limitations
- There is a risk of selection bias regarding which patients were included in the database.
- Presenting symptoms, preoperative imaging findings, and pathologic staging were not available.
- The database did not record the reasons for choosing open surgery rather than laparoscopic surgery or for converting to an open approach.
Disclosures
- There was no funding for the work, and the investigators did not disclose any relevant financial relationships.
This is a summary of a preprint research study, “Gallbladder Cancer Incidentally Found at Cholecystectomy: Perioperative Risk Factors,” led by Elizabeth Olecki of Penn State University, State College. The study has not been peer reviewed. The full text can be found at researchsquare.com. A version of this article first appeared on Medscape.com.
The study covered in this summary was published on researchsquare.com as a preprint and has not yet been peer reviewed.
Key takeaway
Why this matters
- More than 60% of gallbladder cancers are diagnosed incidentally following cholecystectomy for benign reasons.
- Identifying predictors allows surgeons to send high-risk individuals for oncologic evaluation beforehand and to prepare for intraoperative frozen pathology and more appropriate surgery, including extended cholecystectomy and lymph node dissection.
Study design
- The investigators analyzed 403,443 cholecystectomies in the American College of Surgeons’ NSQIP database from 2007 to 2017.
- They used multivariable logistic regression to identify risk factors for gallbladder cancers.
- Patients undergoing cholecystectomy for suspected or confirmed gallbladder cancer were excluded.
Key results
- The incidence of gallbladder cancer was 0.11% (441 of 403,443 patients).
- Preoperative factors significantly associated with gallbladder cancer included age older than 60 years (odds ratio [OR], 6.51), female sex (OR, 1.75), weight loss (OR, 2.58), and elevated alkaline phosphatase level (OR, 1.67).
- Starting with or converting to an open approach – both potential indicators of more complex disease – were associated with seven times’ higher odds of gallbladder cancer (OR, 7.33; P < .001), as were longer operative times (127 minutes vs. 70.7 minutes; P < .001).
Limitations
- There is a risk of selection bias regarding which patients were included in the database.
- Presenting symptoms, preoperative imaging findings, and pathologic staging were not available.
- The database did not record the reasons for choosing open surgery rather than laparoscopic surgery or for converting to an open approach.
Disclosures
- There was no funding for the work, and the investigators did not disclose any relevant financial relationships.
This is a summary of a preprint research study, “Gallbladder Cancer Incidentally Found at Cholecystectomy: Perioperative Risk Factors,” led by Elizabeth Olecki of Penn State University, State College. The study has not been peer reviewed. The full text can be found at researchsquare.com. A version of this article first appeared on Medscape.com.
The study covered in this summary was published on researchsquare.com as a preprint and has not yet been peer reviewed.
Key takeaway
Why this matters
- More than 60% of gallbladder cancers are diagnosed incidentally following cholecystectomy for benign reasons.
- Identifying predictors allows surgeons to send high-risk individuals for oncologic evaluation beforehand and to prepare for intraoperative frozen pathology and more appropriate surgery, including extended cholecystectomy and lymph node dissection.
Study design
- The investigators analyzed 403,443 cholecystectomies in the American College of Surgeons’ NSQIP database from 2007 to 2017.
- They used multivariable logistic regression to identify risk factors for gallbladder cancers.
- Patients undergoing cholecystectomy for suspected or confirmed gallbladder cancer were excluded.
Key results
- The incidence of gallbladder cancer was 0.11% (441 of 403,443 patients).
- Preoperative factors significantly associated with gallbladder cancer included age older than 60 years (odds ratio [OR], 6.51), female sex (OR, 1.75), weight loss (OR, 2.58), and elevated alkaline phosphatase level (OR, 1.67).
- Starting with or converting to an open approach – both potential indicators of more complex disease – were associated with seven times’ higher odds of gallbladder cancer (OR, 7.33; P < .001), as were longer operative times (127 minutes vs. 70.7 minutes; P < .001).
Limitations
- There is a risk of selection bias regarding which patients were included in the database.
- Presenting symptoms, preoperative imaging findings, and pathologic staging were not available.
- The database did not record the reasons for choosing open surgery rather than laparoscopic surgery or for converting to an open approach.
Disclosures
- There was no funding for the work, and the investigators did not disclose any relevant financial relationships.
This is a summary of a preprint research study, “Gallbladder Cancer Incidentally Found at Cholecystectomy: Perioperative Risk Factors,” led by Elizabeth Olecki of Penn State University, State College. The study has not been peer reviewed. The full text can be found at researchsquare.com. A version of this article first appeared on Medscape.com.