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Combo demonstrates potential in MM
ROME—Early results of a pilot study indicate that a 3-agent combination regimen can produce responses in patients with relapsed or refractory multiple myeloma (MM).
The treatment consists of carfilzomib, dexamethasone, and pelareorep (Reolysin), a proprietary isolate of human reovirus (Type 3 Dearing strain).
All 8 evaluable patients treated with this regimen experienced an objective response, although 1 patient later progressed.
The investigators said the regimen has been relatively well tolerated, but most patients experience flu-like symptoms over the first week of treatment. And cytopenias, especially thrombocytopenia, are common.
Douglas Sborov, MD, of The Ohio State University in Columbus, and his colleagues presented this research at the 15th International Myeloma Workshop (poster #379).
The investigators noted that this is the first time a pelareorep-based combination has been tested in relapsed MM patients. A previous single-agent study indicated that pelareorep was well tolerated, and preclinical research has shown that reovirus and carfilzomib synergize to kill MM cells.
To expand upon these results, Dr Sborov and colleagues began testing pelareorep with carfilzomib and dexamethasone in patients with relapsed/refractory MM. The ongoing study, known as NCI-9603, is sponsored by the National Cancer Institute.
Of the 8 patients enrolled thus far, 5 had intermediate- or high-risk disease at baseline, and 1 patient was dialysis-dependent. The median age was 63 (range, 43-70).
Patients had received a median of 2 prior lines of therapy (range, 1-6) and a median of 4 prior treatments (range, 2-8). All of the patients had received lenalidomide, 1 had received carfilzomib, and 4 were refractory to bortezomib.
For the current study, patients were assigned to receive dexamethasone, carfilzomib over 10 minutes, and pelareorep over 60 minutes on days 1, 2, 8, 9, 15, and 16. Treatment is set to repeat every 28 days in the absence of disease progression or unacceptable toxicity.
Patients who achieve a minimal response or better may reduce treatment to days 1, 8, and 15 after 4 courses and to days 1 and 15 after 12 courses.
Treatment results
The investigators said the treatment produced a significant (P=0.005) increase in caspase-3, a marker associated with apoptotic cell death.
The combination was also associated with an increased infiltration of CD8+ T cells and the significant (P=0.005) upregulation of PD-L1, suggesting the addition of a PD-1 or PD-L1 inhibitor might further optimize the regimen.
All 8 patients experienced an objective response to treatment, as measured by changes in blood monoclonal protein. Two patients had a very good partial response, 3 had a partial response, and 3 had a minor response.
Five of the patients remain on study. The dialysis-dependent patient discontinued treatment due to progression after 3 treatment cycles. And 2 patients discontinued treatment due to dose-limiting toxicities after 2 doses.
One of the patients with dose-limiting toxicities had grade 4 myocarditis, grade 3 left ventricular dysfunction, and grade 4 respiratory failure possibly attributable to pelareorep and carfilzomib. The other patient had lower gastrointestinal bleeding that was not attributed to treatment.
Adverse events in cycle 1 that were possibly, likely, or definitely attributed to treatment included hypertension (n=5), thrombocytopenia (n=4), anemia (n=4), dyspnea on exertion (n=4), fatigue (n=4), myalgia (n=3), fever (n=2), leukopenia (n=2), lymphopenia (n=2), nausea (n=2), and diarrhea (n=2).
For more details, visit the Oncolytics Biotech Inc. website to view the poster. Oncolytics is the company developing pelareorep. 
ROME—Early results of a pilot study indicate that a 3-agent combination regimen can produce responses in patients with relapsed or refractory multiple myeloma (MM).
The treatment consists of carfilzomib, dexamethasone, and pelareorep (Reolysin), a proprietary isolate of human reovirus (Type 3 Dearing strain).
All 8 evaluable patients treated with this regimen experienced an objective response, although 1 patient later progressed.
The investigators said the regimen has been relatively well tolerated, but most patients experience flu-like symptoms over the first week of treatment. And cytopenias, especially thrombocytopenia, are common.
Douglas Sborov, MD, of The Ohio State University in Columbus, and his colleagues presented this research at the 15th International Myeloma Workshop (poster #379).
The investigators noted that this is the first time a pelareorep-based combination has been tested in relapsed MM patients. A previous single-agent study indicated that pelareorep was well tolerated, and preclinical research has shown that reovirus and carfilzomib synergize to kill MM cells.
To expand upon these results, Dr Sborov and colleagues began testing pelareorep with carfilzomib and dexamethasone in patients with relapsed/refractory MM. The ongoing study, known as NCI-9603, is sponsored by the National Cancer Institute.
Of the 8 patients enrolled thus far, 5 had intermediate- or high-risk disease at baseline, and 1 patient was dialysis-dependent. The median age was 63 (range, 43-70).
Patients had received a median of 2 prior lines of therapy (range, 1-6) and a median of 4 prior treatments (range, 2-8). All of the patients had received lenalidomide, 1 had received carfilzomib, and 4 were refractory to bortezomib.
For the current study, patients were assigned to receive dexamethasone, carfilzomib over 10 minutes, and pelareorep over 60 minutes on days 1, 2, 8, 9, 15, and 16. Treatment is set to repeat every 28 days in the absence of disease progression or unacceptable toxicity.
Patients who achieve a minimal response or better may reduce treatment to days 1, 8, and 15 after 4 courses and to days 1 and 15 after 12 courses.
Treatment results
The investigators said the treatment produced a significant (P=0.005) increase in caspase-3, a marker associated with apoptotic cell death.
The combination was also associated with an increased infiltration of CD8+ T cells and the significant (P=0.005) upregulation of PD-L1, suggesting the addition of a PD-1 or PD-L1 inhibitor might further optimize the regimen.
All 8 patients experienced an objective response to treatment, as measured by changes in blood monoclonal protein. Two patients had a very good partial response, 3 had a partial response, and 3 had a minor response.
Five of the patients remain on study. The dialysis-dependent patient discontinued treatment due to progression after 3 treatment cycles. And 2 patients discontinued treatment due to dose-limiting toxicities after 2 doses.
One of the patients with dose-limiting toxicities had grade 4 myocarditis, grade 3 left ventricular dysfunction, and grade 4 respiratory failure possibly attributable to pelareorep and carfilzomib. The other patient had lower gastrointestinal bleeding that was not attributed to treatment.
Adverse events in cycle 1 that were possibly, likely, or definitely attributed to treatment included hypertension (n=5), thrombocytopenia (n=4), anemia (n=4), dyspnea on exertion (n=4), fatigue (n=4), myalgia (n=3), fever (n=2), leukopenia (n=2), lymphopenia (n=2), nausea (n=2), and diarrhea (n=2).
For more details, visit the Oncolytics Biotech Inc. website to view the poster. Oncolytics is the company developing pelareorep.
ROME—Early results of a pilot study indicate that a 3-agent combination regimen can produce responses in patients with relapsed or refractory multiple myeloma (MM).
The treatment consists of carfilzomib, dexamethasone, and pelareorep (Reolysin), a proprietary isolate of human reovirus (Type 3 Dearing strain).
All 8 evaluable patients treated with this regimen experienced an objective response, although 1 patient later progressed.
The investigators said the regimen has been relatively well tolerated, but most patients experience flu-like symptoms over the first week of treatment. And cytopenias, especially thrombocytopenia, are common.
Douglas Sborov, MD, of The Ohio State University in Columbus, and his colleagues presented this research at the 15th International Myeloma Workshop (poster #379).
The investigators noted that this is the first time a pelareorep-based combination has been tested in relapsed MM patients. A previous single-agent study indicated that pelareorep was well tolerated, and preclinical research has shown that reovirus and carfilzomib synergize to kill MM cells.
To expand upon these results, Dr Sborov and colleagues began testing pelareorep with carfilzomib and dexamethasone in patients with relapsed/refractory MM. The ongoing study, known as NCI-9603, is sponsored by the National Cancer Institute.
Of the 8 patients enrolled thus far, 5 had intermediate- or high-risk disease at baseline, and 1 patient was dialysis-dependent. The median age was 63 (range, 43-70).
Patients had received a median of 2 prior lines of therapy (range, 1-6) and a median of 4 prior treatments (range, 2-8). All of the patients had received lenalidomide, 1 had received carfilzomib, and 4 were refractory to bortezomib.
For the current study, patients were assigned to receive dexamethasone, carfilzomib over 10 minutes, and pelareorep over 60 minutes on days 1, 2, 8, 9, 15, and 16. Treatment is set to repeat every 28 days in the absence of disease progression or unacceptable toxicity.
Patients who achieve a minimal response or better may reduce treatment to days 1, 8, and 15 after 4 courses and to days 1 and 15 after 12 courses.
Treatment results
The investigators said the treatment produced a significant (P=0.005) increase in caspase-3, a marker associated with apoptotic cell death.
The combination was also associated with an increased infiltration of CD8+ T cells and the significant (P=0.005) upregulation of PD-L1, suggesting the addition of a PD-1 or PD-L1 inhibitor might further optimize the regimen.
All 8 patients experienced an objective response to treatment, as measured by changes in blood monoclonal protein. Two patients had a very good partial response, 3 had a partial response, and 3 had a minor response.
Five of the patients remain on study. The dialysis-dependent patient discontinued treatment due to progression after 3 treatment cycles. And 2 patients discontinued treatment due to dose-limiting toxicities after 2 doses.
One of the patients with dose-limiting toxicities had grade 4 myocarditis, grade 3 left ventricular dysfunction, and grade 4 respiratory failure possibly attributable to pelareorep and carfilzomib. The other patient had lower gastrointestinal bleeding that was not attributed to treatment.
Adverse events in cycle 1 that were possibly, likely, or definitely attributed to treatment included hypertension (n=5), thrombocytopenia (n=4), anemia (n=4), dyspnea on exertion (n=4), fatigue (n=4), myalgia (n=3), fever (n=2), leukopenia (n=2), lymphopenia (n=2), nausea (n=2), and diarrhea (n=2).
For more details, visit the Oncolytics Biotech Inc. website to view the poster. Oncolytics is the company developing pelareorep.
CHMP recommends blinatumomab for ALL
The European Medicines Agency’s Committee for Medicinal Products for Human Use (CHMP) has recommended conditional marketing authorization for blinatumomab (Blincyto) to treat adults with relapsed or refractory Philadelphia chromosome-negative (Ph-) B-precursor acute lymphoblastic leukemia (ALL).
Blinatumomab is a bispecific T-cell engager (BiTE®) antibody construct that binds to CD19 on the surface of B cells and CD3 on the surface of T cells.
The product already has conditional approval in the US to treat patients with relapsed or refractory Ph- B-precursor ALL.
The CHMP’s positive opinion of blinatumomab will be reviewed by the European Commission (EC).
The EC usually follows the CHMP’s recommendations and is expected to deliver its final decision within 3 months. The EC’s decision will apply to the 28 member countries of the European Union, as well as Iceland, Lichtenstein, and Norway.
Conditional marketing authorizations are valid for 1 year, on a renewable basis. The holder is required to complete ongoing studies or conduct new studies with the goal of confirming that a drug’s benefit-risk balance is positive.
Conditional marketing authorization is converted to a full authorization once these commitments have been fulfilled.
The conditional marketing authorization application for blinatumomab is based on a pair of phase 2 trials—Study ‘211 and Study ‘206.
Study ‘211
Results of Study ‘211 were presented at EHA 2014. The trial included 189 patients with Ph- relapsed or refractory B-precursor ALL.
The primary endpoint was complete remission or complete remission with partial hematologic recovery (CR/CRh). About 43% of patients achieved this endpoint within 2 cycles of therapy.
According to researchers, the most serious adverse events in this study were infection (31.7%), neurologic events (16.4%), neutropenia/febrile neutropenia (15.3%), cytokine release syndrome (CRS, 0.5%), and tumor lysis syndrome (0.5%).
Study ‘206
Results of Study ‘206 were presented at ASCO 2012. The trial included 36 patients with relapsed or refractory B-precursor ALL.
In this trial, the CR/CRh rate was 69.4% (25/36), with 15 patients achieving a CR (41.7%), and 10 patients achieving CRh (27.8%).
The “medically important” adverse events in this study, according to researchers, were CRS (n=3), central nervous system (CNS) events (3 seizures and 3 cases of encephalopathy), and fungal infection resulting in death (n=1).
However, the researchers found they could prevent CRS with dexamethasone. In addition, the CNS events were reversible, and blinatumomab could be reintroduced in 4 of the 6 patients with CNS events.
Blinatumomab is under development by Amgen. For more details on the drug, visit www.blincyto.com.
The European Medicines Agency’s Committee for Medicinal Products for Human Use (CHMP) has recommended conditional marketing authorization for blinatumomab (Blincyto) to treat adults with relapsed or refractory Philadelphia chromosome-negative (Ph-) B-precursor acute lymphoblastic leukemia (ALL).
Blinatumomab is a bispecific T-cell engager (BiTE®) antibody construct that binds to CD19 on the surface of B cells and CD3 on the surface of T cells.
The product already has conditional approval in the US to treat patients with relapsed or refractory Ph- B-precursor ALL.
The CHMP’s positive opinion of blinatumomab will be reviewed by the European Commission (EC).
The EC usually follows the CHMP’s recommendations and is expected to deliver its final decision within 3 months. The EC’s decision will apply to the 28 member countries of the European Union, as well as Iceland, Lichtenstein, and Norway.
Conditional marketing authorizations are valid for 1 year, on a renewable basis. The holder is required to complete ongoing studies or conduct new studies with the goal of confirming that a drug’s benefit-risk balance is positive.
Conditional marketing authorization is converted to a full authorization once these commitments have been fulfilled.
The conditional marketing authorization application for blinatumomab is based on a pair of phase 2 trials—Study ‘211 and Study ‘206.
Study ‘211
Results of Study ‘211 were presented at EHA 2014. The trial included 189 patients with Ph- relapsed or refractory B-precursor ALL.
The primary endpoint was complete remission or complete remission with partial hematologic recovery (CR/CRh). About 43% of patients achieved this endpoint within 2 cycles of therapy.
According to researchers, the most serious adverse events in this study were infection (31.7%), neurologic events (16.4%), neutropenia/febrile neutropenia (15.3%), cytokine release syndrome (CRS, 0.5%), and tumor lysis syndrome (0.5%).
Study ‘206
Results of Study ‘206 were presented at ASCO 2012. The trial included 36 patients with relapsed or refractory B-precursor ALL.
In this trial, the CR/CRh rate was 69.4% (25/36), with 15 patients achieving a CR (41.7%), and 10 patients achieving CRh (27.8%).
The “medically important” adverse events in this study, according to researchers, were CRS (n=3), central nervous system (CNS) events (3 seizures and 3 cases of encephalopathy), and fungal infection resulting in death (n=1).
However, the researchers found they could prevent CRS with dexamethasone. In addition, the CNS events were reversible, and blinatumomab could be reintroduced in 4 of the 6 patients with CNS events.
Blinatumomab is under development by Amgen. For more details on the drug, visit www.blincyto.com.
The European Medicines Agency’s Committee for Medicinal Products for Human Use (CHMP) has recommended conditional marketing authorization for blinatumomab (Blincyto) to treat adults with relapsed or refractory Philadelphia chromosome-negative (Ph-) B-precursor acute lymphoblastic leukemia (ALL).
Blinatumomab is a bispecific T-cell engager (BiTE®) antibody construct that binds to CD19 on the surface of B cells and CD3 on the surface of T cells.
The product already has conditional approval in the US to treat patients with relapsed or refractory Ph- B-precursor ALL.
The CHMP’s positive opinion of blinatumomab will be reviewed by the European Commission (EC).
The EC usually follows the CHMP’s recommendations and is expected to deliver its final decision within 3 months. The EC’s decision will apply to the 28 member countries of the European Union, as well as Iceland, Lichtenstein, and Norway.
Conditional marketing authorizations are valid for 1 year, on a renewable basis. The holder is required to complete ongoing studies or conduct new studies with the goal of confirming that a drug’s benefit-risk balance is positive.
Conditional marketing authorization is converted to a full authorization once these commitments have been fulfilled.
The conditional marketing authorization application for blinatumomab is based on a pair of phase 2 trials—Study ‘211 and Study ‘206.
Study ‘211
Results of Study ‘211 were presented at EHA 2014. The trial included 189 patients with Ph- relapsed or refractory B-precursor ALL.
The primary endpoint was complete remission or complete remission with partial hematologic recovery (CR/CRh). About 43% of patients achieved this endpoint within 2 cycles of therapy.
According to researchers, the most serious adverse events in this study were infection (31.7%), neurologic events (16.4%), neutropenia/febrile neutropenia (15.3%), cytokine release syndrome (CRS, 0.5%), and tumor lysis syndrome (0.5%).
Study ‘206
Results of Study ‘206 were presented at ASCO 2012. The trial included 36 patients with relapsed or refractory B-precursor ALL.
In this trial, the CR/CRh rate was 69.4% (25/36), with 15 patients achieving a CR (41.7%), and 10 patients achieving CRh (27.8%).
The “medically important” adverse events in this study, according to researchers, were CRS (n=3), central nervous system (CNS) events (3 seizures and 3 cases of encephalopathy), and fungal infection resulting in death (n=1).
However, the researchers found they could prevent CRS with dexamethasone. In addition, the CNS events were reversible, and blinatumomab could be reintroduced in 4 of the 6 patients with CNS events.
Blinatumomab is under development by Amgen. For more details on the drug, visit www.blincyto.com.
CHMP recommends authorization for idarucizumab
Image by Andre E.X. Brown
The European Medicines Agency’s Committee for Medicinal Products for Human Use (CHMP) is recommending that idarucizumab receive marketing authorization in the European Union.
Idarucizumab (to be marketed as Praxbind) is a humanized antibody fragment designed to reverse the anticoagulant effects of dabigatran etexilate (Pradaxa).
Idarucizumab is intended for patients who must undergo emergency surgery/urgent procedures and those who experience uncontrolled or life-threatening bleeding while on dabigatran.
The CHMP’s positive opinion of idarucizumab will be reviewed by the European Commission (EC).
The EC usually follows the CHMP’s recommendations and is expected to deliver its final decision within 3 months. The EC’s decision will apply to the 28 member countries of the European Union, as well as Iceland, Lichtenstein, and Norway.
The CHMP’s positive opinion was based on results with idarucizumab in healthy volunteers and an interim analysis of the phase 3 RE-VERSE AD trial.
In the study of healthy volunteers, the pharmacokinetic profile of idarucizumab met the requirement for rapid peak exposure and rapid elimination, with no effect on pharmacodynamic parameters. And researchers said the drug was well tolerated.
In RE-VERSE AD, researchers evaluated idarucizumab in emergency settings. The drug normalized diluted thrombin time and ecarin clotting time in a majority of dabigatran-treated patients with uncontrolled or life-threatening bleeding complications and most patients who required emergency surgery or an invasive procedure.
The researchers said there were no safety concerns related to idarucizumab. However, 23% of patients in this trial experienced serious adverse events, 20% of patients died, and several patients had thrombotic or bleeding events.
Idarucizumab is being developed by Boehringer Ingelheim, the company that makes dabigatran.
Idarucizumab is currently under review by regulatory authorities worldwide, including the US Food and Drug Administration. Boehringer Ingelheim plans to submit idarucizumab in all countries where dabigatran is licensed.
Image by Andre E.X. Brown
The European Medicines Agency’s Committee for Medicinal Products for Human Use (CHMP) is recommending that idarucizumab receive marketing authorization in the European Union.
Idarucizumab (to be marketed as Praxbind) is a humanized antibody fragment designed to reverse the anticoagulant effects of dabigatran etexilate (Pradaxa).
Idarucizumab is intended for patients who must undergo emergency surgery/urgent procedures and those who experience uncontrolled or life-threatening bleeding while on dabigatran.
The CHMP’s positive opinion of idarucizumab will be reviewed by the European Commission (EC).
The EC usually follows the CHMP’s recommendations and is expected to deliver its final decision within 3 months. The EC’s decision will apply to the 28 member countries of the European Union, as well as Iceland, Lichtenstein, and Norway.
The CHMP’s positive opinion was based on results with idarucizumab in healthy volunteers and an interim analysis of the phase 3 RE-VERSE AD trial.
In the study of healthy volunteers, the pharmacokinetic profile of idarucizumab met the requirement for rapid peak exposure and rapid elimination, with no effect on pharmacodynamic parameters. And researchers said the drug was well tolerated.
In RE-VERSE AD, researchers evaluated idarucizumab in emergency settings. The drug normalized diluted thrombin time and ecarin clotting time in a majority of dabigatran-treated patients with uncontrolled or life-threatening bleeding complications and most patients who required emergency surgery or an invasive procedure.
The researchers said there were no safety concerns related to idarucizumab. However, 23% of patients in this trial experienced serious adverse events, 20% of patients died, and several patients had thrombotic or bleeding events.
Idarucizumab is being developed by Boehringer Ingelheim, the company that makes dabigatran.
Idarucizumab is currently under review by regulatory authorities worldwide, including the US Food and Drug Administration. Boehringer Ingelheim plans to submit idarucizumab in all countries where dabigatran is licensed.
Image by Andre E.X. Brown
The European Medicines Agency’s Committee for Medicinal Products for Human Use (CHMP) is recommending that idarucizumab receive marketing authorization in the European Union.
Idarucizumab (to be marketed as Praxbind) is a humanized antibody fragment designed to reverse the anticoagulant effects of dabigatran etexilate (Pradaxa).
Idarucizumab is intended for patients who must undergo emergency surgery/urgent procedures and those who experience uncontrolled or life-threatening bleeding while on dabigatran.
The CHMP’s positive opinion of idarucizumab will be reviewed by the European Commission (EC).
The EC usually follows the CHMP’s recommendations and is expected to deliver its final decision within 3 months. The EC’s decision will apply to the 28 member countries of the European Union, as well as Iceland, Lichtenstein, and Norway.
The CHMP’s positive opinion was based on results with idarucizumab in healthy volunteers and an interim analysis of the phase 3 RE-VERSE AD trial.
In the study of healthy volunteers, the pharmacokinetic profile of idarucizumab met the requirement for rapid peak exposure and rapid elimination, with no effect on pharmacodynamic parameters. And researchers said the drug was well tolerated.
In RE-VERSE AD, researchers evaluated idarucizumab in emergency settings. The drug normalized diluted thrombin time and ecarin clotting time in a majority of dabigatran-treated patients with uncontrolled or life-threatening bleeding complications and most patients who required emergency surgery or an invasive procedure.
The researchers said there were no safety concerns related to idarucizumab. However, 23% of patients in this trial experienced serious adverse events, 20% of patients died, and several patients had thrombotic or bleeding events.
Idarucizumab is being developed by Boehringer Ingelheim, the company that makes dabigatran.
Idarucizumab is currently under review by regulatory authorities worldwide, including the US Food and Drug Administration. Boehringer Ingelheim plans to submit idarucizumab in all countries where dabigatran is licensed.
Variations in blood cancer survival across Europe
chemotherapy
Photo by Rhoda Baer
VIENNA—Results of the EUROCARE-5 study have revealed regional differences in survival for European patients with hematologic malignancies.
The data showed regional variations in 5-year relative survival rates for a number of cancers.
But the differences were particularly pronounced for leukemias, non-Hodgkin lymphomas (NHLs), and plasma cell neoplasms (PCNs).
Milena Sant, MD, of the Fondazione IRCCS Istituto Nazionale dei Tumori in Milan, Italy, presented these results at the 2015 European Cancer Congress (LBA 1).
Data from this study have also been published in several articles in the October 2015 issue of the European Journal of Cancer.
EUROCARE-5 includes records from 22 million cancer patients diagnosed between 1978 and 2007. The latest data encompass more than 10 million patients (ages 15 and older) diagnosed from 1995 to 2007 and followed up to 2008.
The data came from 107 cancer registries in 29 countries. The researchers estimated 5-year relative survival and trends from 1999 to 2007 according to region—Ireland/UK, Northern Europe, Central Europe, Southern Europe, and Eastern Europe.
“In general, 5-year relative survival—survival that is adjusted for causes of death other than cancer—increased steadily over time in Europe, particularly in Eastern Europe, for most cancers,” Dr Sant said.
“However, the most dramatic geographical variations were observed for cancers of the blood where there have been recent advances in treatment, such as chronic myeloid and lymphocytic leukemias, non-Hodgkin lymphoma and 2 of its subtypes (follicular and diffuse large B-cell lymphoma), and multiple myeloma. Hodgkin lymphoma was the exception, with smaller regional variations and a fairly good prognosis in most countries.”
Hodgkin lymphoma and NHL
Of all the hematologic malignancies, 5-year relative survival was highest for Hodgkin lymphoma, at 80.8% (40,625 cases). Five-year survival was 79.4% in Ireland and the UK, 85% in Northern countries, and 74.3% in Eastern Europe, which was significantly below the European average (P<0.0001).
For NHL, the 5-year relative survival was 59.4% (329,204 cases). Survival rates for NHL patients ranged from 49.7% in Eastern Europe to 63.3% in Northern Europe.
CLL/SLL
For chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL), the 5-year relative survival was 70.4% (81,914 cases). CLL/SLL survival ranged from 58% in Eastern Europe to about 74% in Central and Northern Europe.
The researchers noted that between-country variations in CLL/SLL survival were high in all regions. Outliers that were significantly below the regional average were Austria (67%), Croatia (52%), and Bulgaria (45.5%).
PCNs
PCNs included multiple myeloma, plasmacytoma, and plasma cell leukemias. The 5-year relative survival for all PCNs was 39.2% (94,024 cases).
PCN survival rates were lowest in Eastern Europe (31.7%), slightly higher in the UK/Ireland (35.9%), and between 39.1% and 42% in the rest of Europe.
Myeloid leukemias
Of all the hematologic malignancies, 5-year relative survival was poorest for patients with acute myeloid leukemia (AML), at 17.1% (57,026 cases).
AML survival rates in Ireland/UK (15.0%) and Eastern Europe (13.0%) were significantly below the European average. But AML survival in Sweden, Belgium, France, and Germany was significantly higher than the average (P<0.005).
Five-year relative survival for chronic myeloid leukemia (CML) was 52.9% (17,713 cases).
Of all the hematologic malignancies, the survival gap between Eastern Europe and the rest of Europe was highest for CML. Five-year survival for CML patients was 33% in Eastern Europe and ranged from 51% to 58% in the rest of Europe.
The researchers also said there were striking survival variations by country in all areas. They found significant deviations from the regional average in Sweden (69.7%), Scotland (64.6%), France (71.7%), Austria (48.2%), Croatia (37.8%), Estonia (48.9%), Czech Republic (45.2%), and Latvia (22.1%).
“Results from EUROCARE can help to identify regions of low survival where action is needed to improve patients’ outcomes,” Dr Sant noted.
“Population-based survival information is essential for physicians, policy-makers, administrators, researchers, and patient organizations who deal with the needs of cancer patients, as well as with the issue of the growing expenditure on healthcare.”
chemotherapy
Photo by Rhoda Baer
VIENNA—Results of the EUROCARE-5 study have revealed regional differences in survival for European patients with hematologic malignancies.
The data showed regional variations in 5-year relative survival rates for a number of cancers.
But the differences were particularly pronounced for leukemias, non-Hodgkin lymphomas (NHLs), and plasma cell neoplasms (PCNs).
Milena Sant, MD, of the Fondazione IRCCS Istituto Nazionale dei Tumori in Milan, Italy, presented these results at the 2015 European Cancer Congress (LBA 1).
Data from this study have also been published in several articles in the October 2015 issue of the European Journal of Cancer.
EUROCARE-5 includes records from 22 million cancer patients diagnosed between 1978 and 2007. The latest data encompass more than 10 million patients (ages 15 and older) diagnosed from 1995 to 2007 and followed up to 2008.
The data came from 107 cancer registries in 29 countries. The researchers estimated 5-year relative survival and trends from 1999 to 2007 according to region—Ireland/UK, Northern Europe, Central Europe, Southern Europe, and Eastern Europe.
“In general, 5-year relative survival—survival that is adjusted for causes of death other than cancer—increased steadily over time in Europe, particularly in Eastern Europe, for most cancers,” Dr Sant said.
“However, the most dramatic geographical variations were observed for cancers of the blood where there have been recent advances in treatment, such as chronic myeloid and lymphocytic leukemias, non-Hodgkin lymphoma and 2 of its subtypes (follicular and diffuse large B-cell lymphoma), and multiple myeloma. Hodgkin lymphoma was the exception, with smaller regional variations and a fairly good prognosis in most countries.”
Hodgkin lymphoma and NHL
Of all the hematologic malignancies, 5-year relative survival was highest for Hodgkin lymphoma, at 80.8% (40,625 cases). Five-year survival was 79.4% in Ireland and the UK, 85% in Northern countries, and 74.3% in Eastern Europe, which was significantly below the European average (P<0.0001).
For NHL, the 5-year relative survival was 59.4% (329,204 cases). Survival rates for NHL patients ranged from 49.7% in Eastern Europe to 63.3% in Northern Europe.
CLL/SLL
For chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL), the 5-year relative survival was 70.4% (81,914 cases). CLL/SLL survival ranged from 58% in Eastern Europe to about 74% in Central and Northern Europe.
The researchers noted that between-country variations in CLL/SLL survival were high in all regions. Outliers that were significantly below the regional average were Austria (67%), Croatia (52%), and Bulgaria (45.5%).
PCNs
PCNs included multiple myeloma, plasmacytoma, and plasma cell leukemias. The 5-year relative survival for all PCNs was 39.2% (94,024 cases).
PCN survival rates were lowest in Eastern Europe (31.7%), slightly higher in the UK/Ireland (35.9%), and between 39.1% and 42% in the rest of Europe.
Myeloid leukemias
Of all the hematologic malignancies, 5-year relative survival was poorest for patients with acute myeloid leukemia (AML), at 17.1% (57,026 cases).
AML survival rates in Ireland/UK (15.0%) and Eastern Europe (13.0%) were significantly below the European average. But AML survival in Sweden, Belgium, France, and Germany was significantly higher than the average (P<0.005).
Five-year relative survival for chronic myeloid leukemia (CML) was 52.9% (17,713 cases).
Of all the hematologic malignancies, the survival gap between Eastern Europe and the rest of Europe was highest for CML. Five-year survival for CML patients was 33% in Eastern Europe and ranged from 51% to 58% in the rest of Europe.
The researchers also said there were striking survival variations by country in all areas. They found significant deviations from the regional average in Sweden (69.7%), Scotland (64.6%), France (71.7%), Austria (48.2%), Croatia (37.8%), Estonia (48.9%), Czech Republic (45.2%), and Latvia (22.1%).
“Results from EUROCARE can help to identify regions of low survival where action is needed to improve patients’ outcomes,” Dr Sant noted.
“Population-based survival information is essential for physicians, policy-makers, administrators, researchers, and patient organizations who deal with the needs of cancer patients, as well as with the issue of the growing expenditure on healthcare.”
chemotherapy
Photo by Rhoda Baer
VIENNA—Results of the EUROCARE-5 study have revealed regional differences in survival for European patients with hematologic malignancies.
The data showed regional variations in 5-year relative survival rates for a number of cancers.
But the differences were particularly pronounced for leukemias, non-Hodgkin lymphomas (NHLs), and plasma cell neoplasms (PCNs).
Milena Sant, MD, of the Fondazione IRCCS Istituto Nazionale dei Tumori in Milan, Italy, presented these results at the 2015 European Cancer Congress (LBA 1).
Data from this study have also been published in several articles in the October 2015 issue of the European Journal of Cancer.
EUROCARE-5 includes records from 22 million cancer patients diagnosed between 1978 and 2007. The latest data encompass more than 10 million patients (ages 15 and older) diagnosed from 1995 to 2007 and followed up to 2008.
The data came from 107 cancer registries in 29 countries. The researchers estimated 5-year relative survival and trends from 1999 to 2007 according to region—Ireland/UK, Northern Europe, Central Europe, Southern Europe, and Eastern Europe.
“In general, 5-year relative survival—survival that is adjusted for causes of death other than cancer—increased steadily over time in Europe, particularly in Eastern Europe, for most cancers,” Dr Sant said.
“However, the most dramatic geographical variations were observed for cancers of the blood where there have been recent advances in treatment, such as chronic myeloid and lymphocytic leukemias, non-Hodgkin lymphoma and 2 of its subtypes (follicular and diffuse large B-cell lymphoma), and multiple myeloma. Hodgkin lymphoma was the exception, with smaller regional variations and a fairly good prognosis in most countries.”
Hodgkin lymphoma and NHL
Of all the hematologic malignancies, 5-year relative survival was highest for Hodgkin lymphoma, at 80.8% (40,625 cases). Five-year survival was 79.4% in Ireland and the UK, 85% in Northern countries, and 74.3% in Eastern Europe, which was significantly below the European average (P<0.0001).
For NHL, the 5-year relative survival was 59.4% (329,204 cases). Survival rates for NHL patients ranged from 49.7% in Eastern Europe to 63.3% in Northern Europe.
CLL/SLL
For chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL), the 5-year relative survival was 70.4% (81,914 cases). CLL/SLL survival ranged from 58% in Eastern Europe to about 74% in Central and Northern Europe.
The researchers noted that between-country variations in CLL/SLL survival were high in all regions. Outliers that were significantly below the regional average were Austria (67%), Croatia (52%), and Bulgaria (45.5%).
PCNs
PCNs included multiple myeloma, plasmacytoma, and plasma cell leukemias. The 5-year relative survival for all PCNs was 39.2% (94,024 cases).
PCN survival rates were lowest in Eastern Europe (31.7%), slightly higher in the UK/Ireland (35.9%), and between 39.1% and 42% in the rest of Europe.
Myeloid leukemias
Of all the hematologic malignancies, 5-year relative survival was poorest for patients with acute myeloid leukemia (AML), at 17.1% (57,026 cases).
AML survival rates in Ireland/UK (15.0%) and Eastern Europe (13.0%) were significantly below the European average. But AML survival in Sweden, Belgium, France, and Germany was significantly higher than the average (P<0.005).
Five-year relative survival for chronic myeloid leukemia (CML) was 52.9% (17,713 cases).
Of all the hematologic malignancies, the survival gap between Eastern Europe and the rest of Europe was highest for CML. Five-year survival for CML patients was 33% in Eastern Europe and ranged from 51% to 58% in the rest of Europe.
The researchers also said there were striking survival variations by country in all areas. They found significant deviations from the regional average in Sweden (69.7%), Scotland (64.6%), France (71.7%), Austria (48.2%), Croatia (37.8%), Estonia (48.9%), Czech Republic (45.2%), and Latvia (22.1%).
“Results from EUROCARE can help to identify regions of low survival where action is needed to improve patients’ outcomes,” Dr Sant noted.
“Population-based survival information is essential for physicians, policy-makers, administrators, researchers, and patient organizations who deal with the needs of cancer patients, as well as with the issue of the growing expenditure on healthcare.”
mAb produces ‘encouraging’ results in MM
multiple myeloma
ROME—Combination therapy incorporating a novel monoclonal antibody (mAb) can provide “encouraging, long-lasting tumor control” in heavily pretreated patients with relapsed/refractory multiple myeloma (MM), according to investigators.
The mAb, MOR202, was also considered to be well-tolerated in this ongoing phase 1/2a study.
Early results from this study were presented at the 15th International Myeloma Workshop (poster #156). The study was sponsored by MorphoSys AG, makers of MOR202. The poster is available on the company’s website.
MOR202 is a HuCAL-derived mAb directed against CD38. In the phase 1/2a study, 50 MM patients have received the drug thus far.
At baseline, the patients’ median age was 67. They had received a median of 4 prior therapies, including bortezomib (98%), lenalidomide (92%), melphalan (92%), cyclophosphamide (76%), doxorubicin (60%), thalidomide (32%), pomalidomide (14%), carfilzomib (6%), elotuzumab (4%), and panobinostat (4%). Seventy-six percent had received a stem cell transplant.
Study design
The study consists of several parts and dosing cohorts in which the investigators are assessing MOR202 alone or in combination with other agents.
Treatment in Part A consists of a 2-hour intravenous infusion of MOR202 once every 2 weeks at several different doses: 0.01 mg/kg , 0.04 mg/kg, 0.15 mg/kg, 0.5 mg/kg, 1.5 mg/kg, 4.0 mg/kg, 8.0 mg/kg, or 16.0 mg/kg.
Part B is a 2-hour intravenous infusion of MOR202 once a week at 4 mg/kg, 8 mg/kg, or 16 mg/kg.
Part C is dexamethasone plus MOR202 once a week at 4 mg/kg, 8 mg/kg, or 16 mg/kg.
Part D is pomalidomide, dexamethasone, and MOR202 once a week at 8 mg/kg or 16 mg/kg.
Part E is lenalidomide, dexamethasone, and MOR202 once a week at 8 mg/kg or 16 mg/kg.
In the confirmatory cohorts, patients receive MOR202 with or without dexamethasone once a week or once every 2 weeks, MOR202 with pomalidomide and dexamethasone once a week, or MOR202 with lenalidomide and dexamethasone once a week.
Efficacy
Of the 50 patients treated thus far, 27 were evaluable for efficacy. One patient achieved a very good partial response, 2 had a partial response, and 2 had a minor response. Eleven patients had stable disease, and 11 progressed.
The very good partial response occurred in a patient receiving weekly MOR202 at 4 mg/kg plus dexamethasone.
One partial response occurred in a patient receiving weekly MOR202 at 8 mg/kg plus dexamethasone. The other occurred in a patient receiving weekly MOR202 at 8 mg/kg plus dexamethasone and pomalidomide.
One minor response occurred in a patient receiving weekly MOR202 at 8 mg/kg plus dexamethasone and lenalidomide. The other occurred in a patient receiving weekly MOR202 at 16 mg/kg plus dexamethasone.
“[T]he preliminary efficacy seen so far with MOR202 as single agent and in combinations is promising,” said investigator Marc-Steffen Raab, MD, of Heidelberg University Hospital and the German Cancer Research Center DKFZ in Heidelberg, Germany.
Safety
All 50 patients were evaluable for safety. Ninety-eight percent experienced an adverse event (AE), 66% of which were grade 3 or higher.
The most frequent AEs (overall and grade 3 or higher) were anemia (34%, 6%), leukopenia (30%, 10%), neutropenia (20%, 10%), thrombocytopenia (18%, 8%), fatigue (30%, 0%), nausea (22%, 0%), diarrhea (20%, 0%), and headache (16%, 0%).
Thirty-six percent of patients discontinued MOR202 due to treatment-emergent AEs. However, only 6% (n=3) of these AEs were considered possibly related to MOR202.
Infusion-related reactions occurred in 15 patients (30%). One of these patients received dexamethasone as well and experienced an infusion-related reaction (grade 1).
In the absence of dexamethasone, nearly all infusion reactions were grade 1-2. The exception was 1 patient with a grade 3 reaction that was mainly limited to the first infusion.
The maximum tolerated dose of MOR202 has not been reached.
“Considering the low rate of infusion reactions, even in cohorts without dexamethasone, the short infusion time, and other aspects, MOR202 may turn out to be an excellent choice in terms of safety and tolerability,” Dr Raab concluded.
multiple myeloma
ROME—Combination therapy incorporating a novel monoclonal antibody (mAb) can provide “encouraging, long-lasting tumor control” in heavily pretreated patients with relapsed/refractory multiple myeloma (MM), according to investigators.
The mAb, MOR202, was also considered to be well-tolerated in this ongoing phase 1/2a study.
Early results from this study were presented at the 15th International Myeloma Workshop (poster #156). The study was sponsored by MorphoSys AG, makers of MOR202. The poster is available on the company’s website.
MOR202 is a HuCAL-derived mAb directed against CD38. In the phase 1/2a study, 50 MM patients have received the drug thus far.
At baseline, the patients’ median age was 67. They had received a median of 4 prior therapies, including bortezomib (98%), lenalidomide (92%), melphalan (92%), cyclophosphamide (76%), doxorubicin (60%), thalidomide (32%), pomalidomide (14%), carfilzomib (6%), elotuzumab (4%), and panobinostat (4%). Seventy-six percent had received a stem cell transplant.
Study design
The study consists of several parts and dosing cohorts in which the investigators are assessing MOR202 alone or in combination with other agents.
Treatment in Part A consists of a 2-hour intravenous infusion of MOR202 once every 2 weeks at several different doses: 0.01 mg/kg , 0.04 mg/kg, 0.15 mg/kg, 0.5 mg/kg, 1.5 mg/kg, 4.0 mg/kg, 8.0 mg/kg, or 16.0 mg/kg.
Part B is a 2-hour intravenous infusion of MOR202 once a week at 4 mg/kg, 8 mg/kg, or 16 mg/kg.
Part C is dexamethasone plus MOR202 once a week at 4 mg/kg, 8 mg/kg, or 16 mg/kg.
Part D is pomalidomide, dexamethasone, and MOR202 once a week at 8 mg/kg or 16 mg/kg.
Part E is lenalidomide, dexamethasone, and MOR202 once a week at 8 mg/kg or 16 mg/kg.
In the confirmatory cohorts, patients receive MOR202 with or without dexamethasone once a week or once every 2 weeks, MOR202 with pomalidomide and dexamethasone once a week, or MOR202 with lenalidomide and dexamethasone once a week.
Efficacy
Of the 50 patients treated thus far, 27 were evaluable for efficacy. One patient achieved a very good partial response, 2 had a partial response, and 2 had a minor response. Eleven patients had stable disease, and 11 progressed.
The very good partial response occurred in a patient receiving weekly MOR202 at 4 mg/kg plus dexamethasone.
One partial response occurred in a patient receiving weekly MOR202 at 8 mg/kg plus dexamethasone. The other occurred in a patient receiving weekly MOR202 at 8 mg/kg plus dexamethasone and pomalidomide.
One minor response occurred in a patient receiving weekly MOR202 at 8 mg/kg plus dexamethasone and lenalidomide. The other occurred in a patient receiving weekly MOR202 at 16 mg/kg plus dexamethasone.
“[T]he preliminary efficacy seen so far with MOR202 as single agent and in combinations is promising,” said investigator Marc-Steffen Raab, MD, of Heidelberg University Hospital and the German Cancer Research Center DKFZ in Heidelberg, Germany.
Safety
All 50 patients were evaluable for safety. Ninety-eight percent experienced an adverse event (AE), 66% of which were grade 3 or higher.
The most frequent AEs (overall and grade 3 or higher) were anemia (34%, 6%), leukopenia (30%, 10%), neutropenia (20%, 10%), thrombocytopenia (18%, 8%), fatigue (30%, 0%), nausea (22%, 0%), diarrhea (20%, 0%), and headache (16%, 0%).
Thirty-six percent of patients discontinued MOR202 due to treatment-emergent AEs. However, only 6% (n=3) of these AEs were considered possibly related to MOR202.
Infusion-related reactions occurred in 15 patients (30%). One of these patients received dexamethasone as well and experienced an infusion-related reaction (grade 1).
In the absence of dexamethasone, nearly all infusion reactions were grade 1-2. The exception was 1 patient with a grade 3 reaction that was mainly limited to the first infusion.
The maximum tolerated dose of MOR202 has not been reached.
“Considering the low rate of infusion reactions, even in cohorts without dexamethasone, the short infusion time, and other aspects, MOR202 may turn out to be an excellent choice in terms of safety and tolerability,” Dr Raab concluded.
multiple myeloma
ROME—Combination therapy incorporating a novel monoclonal antibody (mAb) can provide “encouraging, long-lasting tumor control” in heavily pretreated patients with relapsed/refractory multiple myeloma (MM), according to investigators.
The mAb, MOR202, was also considered to be well-tolerated in this ongoing phase 1/2a study.
Early results from this study were presented at the 15th International Myeloma Workshop (poster #156). The study was sponsored by MorphoSys AG, makers of MOR202. The poster is available on the company’s website.
MOR202 is a HuCAL-derived mAb directed against CD38. In the phase 1/2a study, 50 MM patients have received the drug thus far.
At baseline, the patients’ median age was 67. They had received a median of 4 prior therapies, including bortezomib (98%), lenalidomide (92%), melphalan (92%), cyclophosphamide (76%), doxorubicin (60%), thalidomide (32%), pomalidomide (14%), carfilzomib (6%), elotuzumab (4%), and panobinostat (4%). Seventy-six percent had received a stem cell transplant.
Study design
The study consists of several parts and dosing cohorts in which the investigators are assessing MOR202 alone or in combination with other agents.
Treatment in Part A consists of a 2-hour intravenous infusion of MOR202 once every 2 weeks at several different doses: 0.01 mg/kg , 0.04 mg/kg, 0.15 mg/kg, 0.5 mg/kg, 1.5 mg/kg, 4.0 mg/kg, 8.0 mg/kg, or 16.0 mg/kg.
Part B is a 2-hour intravenous infusion of MOR202 once a week at 4 mg/kg, 8 mg/kg, or 16 mg/kg.
Part C is dexamethasone plus MOR202 once a week at 4 mg/kg, 8 mg/kg, or 16 mg/kg.
Part D is pomalidomide, dexamethasone, and MOR202 once a week at 8 mg/kg or 16 mg/kg.
Part E is lenalidomide, dexamethasone, and MOR202 once a week at 8 mg/kg or 16 mg/kg.
In the confirmatory cohorts, patients receive MOR202 with or without dexamethasone once a week or once every 2 weeks, MOR202 with pomalidomide and dexamethasone once a week, or MOR202 with lenalidomide and dexamethasone once a week.
Efficacy
Of the 50 patients treated thus far, 27 were evaluable for efficacy. One patient achieved a very good partial response, 2 had a partial response, and 2 had a minor response. Eleven patients had stable disease, and 11 progressed.
The very good partial response occurred in a patient receiving weekly MOR202 at 4 mg/kg plus dexamethasone.
One partial response occurred in a patient receiving weekly MOR202 at 8 mg/kg plus dexamethasone. The other occurred in a patient receiving weekly MOR202 at 8 mg/kg plus dexamethasone and pomalidomide.
One minor response occurred in a patient receiving weekly MOR202 at 8 mg/kg plus dexamethasone and lenalidomide. The other occurred in a patient receiving weekly MOR202 at 16 mg/kg plus dexamethasone.
“[T]he preliminary efficacy seen so far with MOR202 as single agent and in combinations is promising,” said investigator Marc-Steffen Raab, MD, of Heidelberg University Hospital and the German Cancer Research Center DKFZ in Heidelberg, Germany.
Safety
All 50 patients were evaluable for safety. Ninety-eight percent experienced an adverse event (AE), 66% of which were grade 3 or higher.
The most frequent AEs (overall and grade 3 or higher) were anemia (34%, 6%), leukopenia (30%, 10%), neutropenia (20%, 10%), thrombocytopenia (18%, 8%), fatigue (30%, 0%), nausea (22%, 0%), diarrhea (20%, 0%), and headache (16%, 0%).
Thirty-six percent of patients discontinued MOR202 due to treatment-emergent AEs. However, only 6% (n=3) of these AEs were considered possibly related to MOR202.
Infusion-related reactions occurred in 15 patients (30%). One of these patients received dexamethasone as well and experienced an infusion-related reaction (grade 1).
In the absence of dexamethasone, nearly all infusion reactions were grade 1-2. The exception was 1 patient with a grade 3 reaction that was mainly limited to the first infusion.
The maximum tolerated dose of MOR202 has not been reached.
“Considering the low rate of infusion reactions, even in cohorts without dexamethasone, the short infusion time, and other aspects, MOR202 may turn out to be an excellent choice in terms of safety and tolerability,” Dr Raab concluded.
NICE backs discounted idelalisib for CLL
The UK’s National Institute for Health and Care Excellence (NICE) has issued a final draft guidance recommending that the PI3Kδ inhibitor idelalisib (Zydelig) be made available on the National Health Service (NHS) for some adults with chronic lymphocytic leukemia (CLL).
NICE is recommending idelalisib in combination with rituximab for adults with previously untreated CLL who have a 17p deletion or TP53 mutation and for adults with CLL who have relapsed within 24 months of their previous treatment.
This decision follows a preliminary decision earlier this year, when NICE asked Gilead Sciences, the company developing idelalisib, to provide further information on the cost-effectiveness of the drug.
Gilead responded by submitting new economic analyses and a simple discount agreement to the list price of idelalisib.
NICE’s recommendation for idelalisib is contingent upon the company providing the agreed upon discount.
NICE’s draft guidance is now with consultees, who have the opportunity to appeal against it. Until NICE issues a final guidance, NHS bodies should make decisions locally on the funding of specific treatments.
Patients whose treatment with idelalisib is not recommended in this NICE guidance but was started within the NHS before this guidance was published should be able to continue treatment until they and their NHS clinician consider it appropriate to stop.
Clinical effectiveness
The committee advising NICE concluded that idelalisib could not be recommended for patients whose disease had relapsed more than 24 months after previous treatment, as no evidence was submitted for this patient group.
For the other populations, the clinical effectiveness data from Study 116 showed that idelalisib plus rituximab produced a significant improvement in progression-free survival and overall survival, compared with rituximab alone, for patients with high-risk, relapsed or refractory CLL.
Cost-effectiveness
Idelalisib is priced at £3114.75 for sixty 150-mg tablets (British national formulary 2015). The mean cost of a 1-year treatment course is £37,922.
Gilead’s agreement provides a discount to the list price of idelalisib, but the level of the discount is currently confidential.
Analyses suggested that, at the discount agreement price, idelalisib plus rituximab was associated with higher costs and greater quality-adjusted life-year (QALY) gains when compared with rituximab alone.
The deterministic incremental cost-effectiveness ratio (ICER) for idelalisib plus rituximab compared with rituximab alone was £13,634 per QALY gained (incremental costs £26,128; incremental QALYs 1.92).
Compared with best supportive care, the ICER for idelalisib plus rituximab was £20,461 per QALY gained (incremental costs £39,211; incremental QALYs 1.92). And compared with ofatumumab, the ICER was £1527 per QALY gained (incremental costs £2926; incremental QALYs 1.92).
The UK’s National Institute for Health and Care Excellence (NICE) has issued a final draft guidance recommending that the PI3Kδ inhibitor idelalisib (Zydelig) be made available on the National Health Service (NHS) for some adults with chronic lymphocytic leukemia (CLL).
NICE is recommending idelalisib in combination with rituximab for adults with previously untreated CLL who have a 17p deletion or TP53 mutation and for adults with CLL who have relapsed within 24 months of their previous treatment.
This decision follows a preliminary decision earlier this year, when NICE asked Gilead Sciences, the company developing idelalisib, to provide further information on the cost-effectiveness of the drug.
Gilead responded by submitting new economic analyses and a simple discount agreement to the list price of idelalisib.
NICE’s recommendation for idelalisib is contingent upon the company providing the agreed upon discount.
NICE’s draft guidance is now with consultees, who have the opportunity to appeal against it. Until NICE issues a final guidance, NHS bodies should make decisions locally on the funding of specific treatments.
Patients whose treatment with idelalisib is not recommended in this NICE guidance but was started within the NHS before this guidance was published should be able to continue treatment until they and their NHS clinician consider it appropriate to stop.
Clinical effectiveness
The committee advising NICE concluded that idelalisib could not be recommended for patients whose disease had relapsed more than 24 months after previous treatment, as no evidence was submitted for this patient group.
For the other populations, the clinical effectiveness data from Study 116 showed that idelalisib plus rituximab produced a significant improvement in progression-free survival and overall survival, compared with rituximab alone, for patients with high-risk, relapsed or refractory CLL.
Cost-effectiveness
Idelalisib is priced at £3114.75 for sixty 150-mg tablets (British national formulary 2015). The mean cost of a 1-year treatment course is £37,922.
Gilead’s agreement provides a discount to the list price of idelalisib, but the level of the discount is currently confidential.
Analyses suggested that, at the discount agreement price, idelalisib plus rituximab was associated with higher costs and greater quality-adjusted life-year (QALY) gains when compared with rituximab alone.
The deterministic incremental cost-effectiveness ratio (ICER) for idelalisib plus rituximab compared with rituximab alone was £13,634 per QALY gained (incremental costs £26,128; incremental QALYs 1.92).
Compared with best supportive care, the ICER for idelalisib plus rituximab was £20,461 per QALY gained (incremental costs £39,211; incremental QALYs 1.92). And compared with ofatumumab, the ICER was £1527 per QALY gained (incremental costs £2926; incremental QALYs 1.92).
The UK’s National Institute for Health and Care Excellence (NICE) has issued a final draft guidance recommending that the PI3Kδ inhibitor idelalisib (Zydelig) be made available on the National Health Service (NHS) for some adults with chronic lymphocytic leukemia (CLL).
NICE is recommending idelalisib in combination with rituximab for adults with previously untreated CLL who have a 17p deletion or TP53 mutation and for adults with CLL who have relapsed within 24 months of their previous treatment.
This decision follows a preliminary decision earlier this year, when NICE asked Gilead Sciences, the company developing idelalisib, to provide further information on the cost-effectiveness of the drug.
Gilead responded by submitting new economic analyses and a simple discount agreement to the list price of idelalisib.
NICE’s recommendation for idelalisib is contingent upon the company providing the agreed upon discount.
NICE’s draft guidance is now with consultees, who have the opportunity to appeal against it. Until NICE issues a final guidance, NHS bodies should make decisions locally on the funding of specific treatments.
Patients whose treatment with idelalisib is not recommended in this NICE guidance but was started within the NHS before this guidance was published should be able to continue treatment until they and their NHS clinician consider it appropriate to stop.
Clinical effectiveness
The committee advising NICE concluded that idelalisib could not be recommended for patients whose disease had relapsed more than 24 months after previous treatment, as no evidence was submitted for this patient group.
For the other populations, the clinical effectiveness data from Study 116 showed that idelalisib plus rituximab produced a significant improvement in progression-free survival and overall survival, compared with rituximab alone, for patients with high-risk, relapsed or refractory CLL.
Cost-effectiveness
Idelalisib is priced at £3114.75 for sixty 150-mg tablets (British national formulary 2015). The mean cost of a 1-year treatment course is £37,922.
Gilead’s agreement provides a discount to the list price of idelalisib, but the level of the discount is currently confidential.
Analyses suggested that, at the discount agreement price, idelalisib plus rituximab was associated with higher costs and greater quality-adjusted life-year (QALY) gains when compared with rituximab alone.
The deterministic incremental cost-effectiveness ratio (ICER) for idelalisib plus rituximab compared with rituximab alone was £13,634 per QALY gained (incremental costs £26,128; incremental QALYs 1.92).
Compared with best supportive care, the ICER for idelalisib plus rituximab was £20,461 per QALY gained (incremental costs £39,211; incremental QALYs 1.92). And compared with ofatumumab, the ICER was £1527 per QALY gained (incremental costs £2926; incremental QALYs 1.92).
CHMP recommends carfilzomib for MM
Photo courtesy of Amgen
The European Medicines Agency’s Committee for Medicinal Products for Human Use (CHMP) has issued a positive opinion of the proteasome inhibitor carfilzomib (Kyprolis).
The CHMP is recommending the drug be approved for use in combination with lenalidomide and dexamethasone to treat adults with multiple myeloma (MM) who have received at least 1 prior therapy.
The CHMP’s positive opinion will be reviewed by the European Commission (EC).
The EC usually follows the CHMP’s recommendations and is expected to deliver its final decision within 3 months. The EC’s decision will apply to the 28 member countries of the European Union (EU), as well as Iceland, Lichtenstein, and Norway.
ASPIRE trial
The CHMP’s positive opinion of carfilzomib was based on data from the phase 3 ASPIRE trial, which were presented at ASH 2014 and published in NEJM.
The trial enrolled 792 patients with relapsed or refractory MM who had received 1 to 3 prior lines of therapy. The patients were randomized (1:1) to receive carfilzomib plus lenalidomide and dexamethasone (KRd) or just lenalidomide and dexamethasone (Rd) for 18 cycles.
Lenalidomide and dexamethasone were continued thereafter until disease progression. There was no planned cross-over from the control arm to treatment with carfilzomib.
The study’s primary endpoint was progression-free survival. And the median progression-free survival was significantly longer in the KRd arm than the Rd arm—26.3 months and 17.6 months, respectively (hazard ratio=0.69, P=0.0001).
At the time of analysis, the difference in overall survival did not reach the prespecified boundary for statistical significance.
The overall response rate was 87% in the KRd arm and 67% in the Rd arm. The median duration of response was 28.6 months and 21.2 months, respectively.
The rates of death due to adverse events (AEs) within 30 days of the last dose were similar between the treatment arms.
The most common causes of death not due to progressive disease occurring in patients in the KRd arm and the Rd arm, respectively, were cardiac disorders (3% vs 2%), infection (2% vs 3%), renal events (0% vs less than 1%), and other AEs (2% vs 3%).
Serious AEs were reported in 60% of the patients in the KRd arm and 54% in the Rd arm. The most common serious AEs reported in the KRd arm and the Rd arm, respectively, were pneumonia (14% vs 11%), respiratory tract infection (4% vs 2%), pyrexia (4% vs 2%), and pulmonary embolism (3% vs 2%).
Carfilzomib development
Carfilzomib was granted orphan drug designation in the EU in 2008. Last February, the drug’s application for EU approval was granted accelerated assessment.
Carfilzomib was approved as monotherapy in the US in July 2012 and in combination with lenalidomide and dexamethasone in July 2015. Carfilzomib is also approved for use in Argentina, Israel, Kuwait, Mexico, and Thailand.
Carfilzomib is a product of Onyx Pharmaceuticals, Inc., a subsidiary of Amgen that holds development and commercialization rights to the drug globally, excluding Japan. For more information on the drug, visit www.kyprolis.com.
Photo courtesy of Amgen
The European Medicines Agency’s Committee for Medicinal Products for Human Use (CHMP) has issued a positive opinion of the proteasome inhibitor carfilzomib (Kyprolis).
The CHMP is recommending the drug be approved for use in combination with lenalidomide and dexamethasone to treat adults with multiple myeloma (MM) who have received at least 1 prior therapy.
The CHMP’s positive opinion will be reviewed by the European Commission (EC).
The EC usually follows the CHMP’s recommendations and is expected to deliver its final decision within 3 months. The EC’s decision will apply to the 28 member countries of the European Union (EU), as well as Iceland, Lichtenstein, and Norway.
ASPIRE trial
The CHMP’s positive opinion of carfilzomib was based on data from the phase 3 ASPIRE trial, which were presented at ASH 2014 and published in NEJM.
The trial enrolled 792 patients with relapsed or refractory MM who had received 1 to 3 prior lines of therapy. The patients were randomized (1:1) to receive carfilzomib plus lenalidomide and dexamethasone (KRd) or just lenalidomide and dexamethasone (Rd) for 18 cycles.
Lenalidomide and dexamethasone were continued thereafter until disease progression. There was no planned cross-over from the control arm to treatment with carfilzomib.
The study’s primary endpoint was progression-free survival. And the median progression-free survival was significantly longer in the KRd arm than the Rd arm—26.3 months and 17.6 months, respectively (hazard ratio=0.69, P=0.0001).
At the time of analysis, the difference in overall survival did not reach the prespecified boundary for statistical significance.
The overall response rate was 87% in the KRd arm and 67% in the Rd arm. The median duration of response was 28.6 months and 21.2 months, respectively.
The rates of death due to adverse events (AEs) within 30 days of the last dose were similar between the treatment arms.
The most common causes of death not due to progressive disease occurring in patients in the KRd arm and the Rd arm, respectively, were cardiac disorders (3% vs 2%), infection (2% vs 3%), renal events (0% vs less than 1%), and other AEs (2% vs 3%).
Serious AEs were reported in 60% of the patients in the KRd arm and 54% in the Rd arm. The most common serious AEs reported in the KRd arm and the Rd arm, respectively, were pneumonia (14% vs 11%), respiratory tract infection (4% vs 2%), pyrexia (4% vs 2%), and pulmonary embolism (3% vs 2%).
Carfilzomib development
Carfilzomib was granted orphan drug designation in the EU in 2008. Last February, the drug’s application for EU approval was granted accelerated assessment.
Carfilzomib was approved as monotherapy in the US in July 2012 and in combination with lenalidomide and dexamethasone in July 2015. Carfilzomib is also approved for use in Argentina, Israel, Kuwait, Mexico, and Thailand.
Carfilzomib is a product of Onyx Pharmaceuticals, Inc., a subsidiary of Amgen that holds development and commercialization rights to the drug globally, excluding Japan. For more information on the drug, visit www.kyprolis.com.
Photo courtesy of Amgen
The European Medicines Agency’s Committee for Medicinal Products for Human Use (CHMP) has issued a positive opinion of the proteasome inhibitor carfilzomib (Kyprolis).
The CHMP is recommending the drug be approved for use in combination with lenalidomide and dexamethasone to treat adults with multiple myeloma (MM) who have received at least 1 prior therapy.
The CHMP’s positive opinion will be reviewed by the European Commission (EC).
The EC usually follows the CHMP’s recommendations and is expected to deliver its final decision within 3 months. The EC’s decision will apply to the 28 member countries of the European Union (EU), as well as Iceland, Lichtenstein, and Norway.
ASPIRE trial
The CHMP’s positive opinion of carfilzomib was based on data from the phase 3 ASPIRE trial, which were presented at ASH 2014 and published in NEJM.
The trial enrolled 792 patients with relapsed or refractory MM who had received 1 to 3 prior lines of therapy. The patients were randomized (1:1) to receive carfilzomib plus lenalidomide and dexamethasone (KRd) or just lenalidomide and dexamethasone (Rd) for 18 cycles.
Lenalidomide and dexamethasone were continued thereafter until disease progression. There was no planned cross-over from the control arm to treatment with carfilzomib.
The study’s primary endpoint was progression-free survival. And the median progression-free survival was significantly longer in the KRd arm than the Rd arm—26.3 months and 17.6 months, respectively (hazard ratio=0.69, P=0.0001).
At the time of analysis, the difference in overall survival did not reach the prespecified boundary for statistical significance.
The overall response rate was 87% in the KRd arm and 67% in the Rd arm. The median duration of response was 28.6 months and 21.2 months, respectively.
The rates of death due to adverse events (AEs) within 30 days of the last dose were similar between the treatment arms.
The most common causes of death not due to progressive disease occurring in patients in the KRd arm and the Rd arm, respectively, were cardiac disorders (3% vs 2%), infection (2% vs 3%), renal events (0% vs less than 1%), and other AEs (2% vs 3%).
Serious AEs were reported in 60% of the patients in the KRd arm and 54% in the Rd arm. The most common serious AEs reported in the KRd arm and the Rd arm, respectively, were pneumonia (14% vs 11%), respiratory tract infection (4% vs 2%), pyrexia (4% vs 2%), and pulmonary embolism (3% vs 2%).
Carfilzomib development
Carfilzomib was granted orphan drug designation in the EU in 2008. Last February, the drug’s application for EU approval was granted accelerated assessment.
Carfilzomib was approved as monotherapy in the US in July 2012 and in combination with lenalidomide and dexamethasone in July 2015. Carfilzomib is also approved for use in Argentina, Israel, Kuwait, Mexico, and Thailand.
Carfilzomib is a product of Onyx Pharmaceuticals, Inc., a subsidiary of Amgen that holds development and commercialization rights to the drug globally, excluding Japan. For more information on the drug, visit www.kyprolis.com.
Reducing side effects of CAR T-cell therapy
Photo courtesy of UCSF
Researchers have reported progress in developing an “on/off switch” to temper the over-active immune response and severe toxicities that can result from chimeric antigen receptor (CAR) T-cell therapy.
The team created CAR T cells that are “off” by default, homing to CD19-expressing cancer cells but remaining inactive until a small molecule is administered.
This system effectively targeted leukemia and lymphoma cells in preclinical experiments.
But the researchers said it’s not ready for clinical testing, as the small-molecule “trigger” is expensive and lasts only 4 hours.
Still, the team believes this type of CAR T-cell therapy could eventually help doctors gradually increase the immune response to treatment and therefore avoid toxicities such as cytokine release syndrome and tumor lysis syndrome.
Wendell Lim, PhD, of University of California, San Francisco, and his colleagues described this work in Science.
“T cells are really powerful beasts, and they can be lethal when they’re activated,” Dr Lim said. “We’ve needed a remote control system that retains the power of these engineered T cells but allows us to communicate specifically with them and manage them while they’re in the body.”
To that end, he and his colleagues created a CAR that requires both an antigen and a small molecule for activation. They dubbed it the “ON-switch CAR.”
ON-switch CAR
The researchers explained that the ON-switch CAR consists of 2 parts that assemble in a small molecule-dependent manner.
Part 1 consists of a CD8α signal sequence, Myc epitope, anti-CD19 single-chain variable fragment, CD8α hinge and transmembrane domain, 4-1BB costimulatory motif, and FK506 Binding Protein (FKBP) domain for heterodimerization.
Part 2 consists of the ectodomain of DNAX-activating protein 10 (DAP10) for homodimerization, CD8α transmembrane domain for membrane anchoring, 4-1BB costimulatory motif, T2089L mutant of FKBP-rapamycin binding (FRB*) domain, T-cell receptor CD3ζ signaling chain, and mCherry tag.
The FKBP and FRB* domains heterodimerize in the presence of the rapamycin analog AP21967, referred to as the “rapalog.”
The researchers conducted in vitro experiments with this ON-switch CAR in cells expressing CD19 (K562, Raji, and Daudi).
The ON-switch CAR T cells homed to CD19-expressing cells but did nothing else until the rapalog was added. Once the rapalog was added, CD19-expressing cells were killed off in a dose-dependent manner.
The team observed similar results in mice with leukemia. Leukemia cells (K562) were selectively eliminated by the ON-switch CARs only after the rapalog had been administered.
Dr Lim stressed that this work should be considered a proof of principle, as the rapalog has too short a half-life to be clinically useful. Nevertheless, he believes the research provides the foundation for practical remote control of CAR T cells.
Members of his lab are exploring other techniques to accomplish this goal, such as controlling CAR T-cell activation with light.
The team is also working to reduce side effects of CAR T-cell therapy by introducing multiple CARs into T cells so the cells will respond to multiple characteristics that are distinctive to an individual patient’s tumor, rather than to a single protein that may also be found on normal cells.
“That we can engineer CAR T cells to have slightly different, quite powerful effects—even if for a subset of patients or for certain types of cancer—is really remarkable,” Dr Lim said. “And this is just the tip of the iceberg.”
Photo courtesy of UCSF
Researchers have reported progress in developing an “on/off switch” to temper the over-active immune response and severe toxicities that can result from chimeric antigen receptor (CAR) T-cell therapy.
The team created CAR T cells that are “off” by default, homing to CD19-expressing cancer cells but remaining inactive until a small molecule is administered.
This system effectively targeted leukemia and lymphoma cells in preclinical experiments.
But the researchers said it’s not ready for clinical testing, as the small-molecule “trigger” is expensive and lasts only 4 hours.
Still, the team believes this type of CAR T-cell therapy could eventually help doctors gradually increase the immune response to treatment and therefore avoid toxicities such as cytokine release syndrome and tumor lysis syndrome.
Wendell Lim, PhD, of University of California, San Francisco, and his colleagues described this work in Science.
“T cells are really powerful beasts, and they can be lethal when they’re activated,” Dr Lim said. “We’ve needed a remote control system that retains the power of these engineered T cells but allows us to communicate specifically with them and manage them while they’re in the body.”
To that end, he and his colleagues created a CAR that requires both an antigen and a small molecule for activation. They dubbed it the “ON-switch CAR.”
ON-switch CAR
The researchers explained that the ON-switch CAR consists of 2 parts that assemble in a small molecule-dependent manner.
Part 1 consists of a CD8α signal sequence, Myc epitope, anti-CD19 single-chain variable fragment, CD8α hinge and transmembrane domain, 4-1BB costimulatory motif, and FK506 Binding Protein (FKBP) domain for heterodimerization.
Part 2 consists of the ectodomain of DNAX-activating protein 10 (DAP10) for homodimerization, CD8α transmembrane domain for membrane anchoring, 4-1BB costimulatory motif, T2089L mutant of FKBP-rapamycin binding (FRB*) domain, T-cell receptor CD3ζ signaling chain, and mCherry tag.
The FKBP and FRB* domains heterodimerize in the presence of the rapamycin analog AP21967, referred to as the “rapalog.”
The researchers conducted in vitro experiments with this ON-switch CAR in cells expressing CD19 (K562, Raji, and Daudi).
The ON-switch CAR T cells homed to CD19-expressing cells but did nothing else until the rapalog was added. Once the rapalog was added, CD19-expressing cells were killed off in a dose-dependent manner.
The team observed similar results in mice with leukemia. Leukemia cells (K562) were selectively eliminated by the ON-switch CARs only after the rapalog had been administered.
Dr Lim stressed that this work should be considered a proof of principle, as the rapalog has too short a half-life to be clinically useful. Nevertheless, he believes the research provides the foundation for practical remote control of CAR T cells.
Members of his lab are exploring other techniques to accomplish this goal, such as controlling CAR T-cell activation with light.
The team is also working to reduce side effects of CAR T-cell therapy by introducing multiple CARs into T cells so the cells will respond to multiple characteristics that are distinctive to an individual patient’s tumor, rather than to a single protein that may also be found on normal cells.
“That we can engineer CAR T cells to have slightly different, quite powerful effects—even if for a subset of patients or for certain types of cancer—is really remarkable,” Dr Lim said. “And this is just the tip of the iceberg.”
Photo courtesy of UCSF
Researchers have reported progress in developing an “on/off switch” to temper the over-active immune response and severe toxicities that can result from chimeric antigen receptor (CAR) T-cell therapy.
The team created CAR T cells that are “off” by default, homing to CD19-expressing cancer cells but remaining inactive until a small molecule is administered.
This system effectively targeted leukemia and lymphoma cells in preclinical experiments.
But the researchers said it’s not ready for clinical testing, as the small-molecule “trigger” is expensive and lasts only 4 hours.
Still, the team believes this type of CAR T-cell therapy could eventually help doctors gradually increase the immune response to treatment and therefore avoid toxicities such as cytokine release syndrome and tumor lysis syndrome.
Wendell Lim, PhD, of University of California, San Francisco, and his colleagues described this work in Science.
“T cells are really powerful beasts, and they can be lethal when they’re activated,” Dr Lim said. “We’ve needed a remote control system that retains the power of these engineered T cells but allows us to communicate specifically with them and manage them while they’re in the body.”
To that end, he and his colleagues created a CAR that requires both an antigen and a small molecule for activation. They dubbed it the “ON-switch CAR.”
ON-switch CAR
The researchers explained that the ON-switch CAR consists of 2 parts that assemble in a small molecule-dependent manner.
Part 1 consists of a CD8α signal sequence, Myc epitope, anti-CD19 single-chain variable fragment, CD8α hinge and transmembrane domain, 4-1BB costimulatory motif, and FK506 Binding Protein (FKBP) domain for heterodimerization.
Part 2 consists of the ectodomain of DNAX-activating protein 10 (DAP10) for homodimerization, CD8α transmembrane domain for membrane anchoring, 4-1BB costimulatory motif, T2089L mutant of FKBP-rapamycin binding (FRB*) domain, T-cell receptor CD3ζ signaling chain, and mCherry tag.
The FKBP and FRB* domains heterodimerize in the presence of the rapamycin analog AP21967, referred to as the “rapalog.”
The researchers conducted in vitro experiments with this ON-switch CAR in cells expressing CD19 (K562, Raji, and Daudi).
The ON-switch CAR T cells homed to CD19-expressing cells but did nothing else until the rapalog was added. Once the rapalog was added, CD19-expressing cells were killed off in a dose-dependent manner.
The team observed similar results in mice with leukemia. Leukemia cells (K562) were selectively eliminated by the ON-switch CARs only after the rapalog had been administered.
Dr Lim stressed that this work should be considered a proof of principle, as the rapalog has too short a half-life to be clinically useful. Nevertheless, he believes the research provides the foundation for practical remote control of CAR T cells.
Members of his lab are exploring other techniques to accomplish this goal, such as controlling CAR T-cell activation with light.
The team is also working to reduce side effects of CAR T-cell therapy by introducing multiple CARs into T cells so the cells will respond to multiple characteristics that are distinctive to an individual patient’s tumor, rather than to a single protein that may also be found on normal cells.
“That we can engineer CAR T cells to have slightly different, quite powerful effects—even if for a subset of patients or for certain types of cancer—is really remarkable,” Dr Lim said. “And this is just the tip of the iceberg.”
Studies raise concerns about drug approval process
Photo courtesy of the FDA
Two newly published studies have raised concerns about the drug approval process in the US.
One study showed that, over the past two decades, the US Food and Drug Administration (FDA) has significantly increased its use of expedited development or review programs when approving new drugs.
Investigators said this increase cannot be attributed to an increase in the number of innovative new drug classes.
The other study revealed “wide variations” in evidence supporting the approval of supplemental drug applications.
Aaron S. Kesselheim, MD, of Brigham and Women’s Hospital in Boston, Massachusetts, and his colleagues conducted these studies and reported the results in The BMJ.
Authors of a related editorial wrote that these studies “give cause for concern about whether most new drugs are any more effective than existing products or whether their safety has been adequately assessed.”
Expedited approval
For the first study, the investigators looked at the FDA’s use of expedited development and review programs for drugs newly approved between 1987 and 2014. This included the orphan designation, fast track designation, priority review, and accelerated approval programs.
The FDA approved 774 drugs during the study period, and 33% of these were first-in-class agents. Priority review (43%) was the most-used program, followed by orphan designation (25%), fast track designation (19%), and accelerated approval (9%).
The investigators observed an increase of 2.6% per year in the number of expedited review and approval programs granted to each newly approved drug (P<0.001) and a 2.4% increase in the proportion of drugs associated with at least one of the programs (P=0.009).
The team noted that “this trend is being driven by drugs that are not first in class and thus potentially less innovative.”
They also said that, by the end of the study period, most newly approved drugs were associated with at least one of the programs. The peak was in 2005, when 75% (15/20) of newly approved drugs were associated with at least one program.
Supplemental approval
For the second study, Dr Kesselheim and his colleagues evaluated the quality of evidence underpinning FDA approval of supplemental drug applications (uses beyond a drug’s original indication) between 2005 and 2014.
The team assessed 295 supplemental drug approvals. They found a lack of trials using clinical outcome endpoints, a lack of trials including active comparators, and differences in the evidence according to types of approval.
Thirty percent of drug approvals for new indications were supported by trials with active comparators, as were 51% of modified-use approvals and 11% of approvals expanding the patient population (P<0.001).
Thirty-two percent of drug approvals for new indications were supported by trials using clinical outcome endpoints, as were 30% of modified-use approvals and 22% of expanded-population approvals (P=0.29).
The investigators said these findings “underscore the need for a robust system of post-approval drug monitoring for efficacy and safety, timely confirmatory studies, and re-examination of existing legislative incentives to promote the optimal delivery of evidence-based medicine.”
Photo courtesy of the FDA
Two newly published studies have raised concerns about the drug approval process in the US.
One study showed that, over the past two decades, the US Food and Drug Administration (FDA) has significantly increased its use of expedited development or review programs when approving new drugs.
Investigators said this increase cannot be attributed to an increase in the number of innovative new drug classes.
The other study revealed “wide variations” in evidence supporting the approval of supplemental drug applications.
Aaron S. Kesselheim, MD, of Brigham and Women’s Hospital in Boston, Massachusetts, and his colleagues conducted these studies and reported the results in The BMJ.
Authors of a related editorial wrote that these studies “give cause for concern about whether most new drugs are any more effective than existing products or whether their safety has been adequately assessed.”
Expedited approval
For the first study, the investigators looked at the FDA’s use of expedited development and review programs for drugs newly approved between 1987 and 2014. This included the orphan designation, fast track designation, priority review, and accelerated approval programs.
The FDA approved 774 drugs during the study period, and 33% of these were first-in-class agents. Priority review (43%) was the most-used program, followed by orphan designation (25%), fast track designation (19%), and accelerated approval (9%).
The investigators observed an increase of 2.6% per year in the number of expedited review and approval programs granted to each newly approved drug (P<0.001) and a 2.4% increase in the proportion of drugs associated with at least one of the programs (P=0.009).
The team noted that “this trend is being driven by drugs that are not first in class and thus potentially less innovative.”
They also said that, by the end of the study period, most newly approved drugs were associated with at least one of the programs. The peak was in 2005, when 75% (15/20) of newly approved drugs were associated with at least one program.
Supplemental approval
For the second study, Dr Kesselheim and his colleagues evaluated the quality of evidence underpinning FDA approval of supplemental drug applications (uses beyond a drug’s original indication) between 2005 and 2014.
The team assessed 295 supplemental drug approvals. They found a lack of trials using clinical outcome endpoints, a lack of trials including active comparators, and differences in the evidence according to types of approval.
Thirty percent of drug approvals for new indications were supported by trials with active comparators, as were 51% of modified-use approvals and 11% of approvals expanding the patient population (P<0.001).
Thirty-two percent of drug approvals for new indications were supported by trials using clinical outcome endpoints, as were 30% of modified-use approvals and 22% of expanded-population approvals (P=0.29).
The investigators said these findings “underscore the need for a robust system of post-approval drug monitoring for efficacy and safety, timely confirmatory studies, and re-examination of existing legislative incentives to promote the optimal delivery of evidence-based medicine.”
Photo courtesy of the FDA
Two newly published studies have raised concerns about the drug approval process in the US.
One study showed that, over the past two decades, the US Food and Drug Administration (FDA) has significantly increased its use of expedited development or review programs when approving new drugs.
Investigators said this increase cannot be attributed to an increase in the number of innovative new drug classes.
The other study revealed “wide variations” in evidence supporting the approval of supplemental drug applications.
Aaron S. Kesselheim, MD, of Brigham and Women’s Hospital in Boston, Massachusetts, and his colleagues conducted these studies and reported the results in The BMJ.
Authors of a related editorial wrote that these studies “give cause for concern about whether most new drugs are any more effective than existing products or whether their safety has been adequately assessed.”
Expedited approval
For the first study, the investigators looked at the FDA’s use of expedited development and review programs for drugs newly approved between 1987 and 2014. This included the orphan designation, fast track designation, priority review, and accelerated approval programs.
The FDA approved 774 drugs during the study period, and 33% of these were first-in-class agents. Priority review (43%) was the most-used program, followed by orphan designation (25%), fast track designation (19%), and accelerated approval (9%).
The investigators observed an increase of 2.6% per year in the number of expedited review and approval programs granted to each newly approved drug (P<0.001) and a 2.4% increase in the proportion of drugs associated with at least one of the programs (P=0.009).
The team noted that “this trend is being driven by drugs that are not first in class and thus potentially less innovative.”
They also said that, by the end of the study period, most newly approved drugs were associated with at least one of the programs. The peak was in 2005, when 75% (15/20) of newly approved drugs were associated with at least one program.
Supplemental approval
For the second study, Dr Kesselheim and his colleagues evaluated the quality of evidence underpinning FDA approval of supplemental drug applications (uses beyond a drug’s original indication) between 2005 and 2014.
The team assessed 295 supplemental drug approvals. They found a lack of trials using clinical outcome endpoints, a lack of trials including active comparators, and differences in the evidence according to types of approval.
Thirty percent of drug approvals for new indications were supported by trials with active comparators, as were 51% of modified-use approvals and 11% of approvals expanding the patient population (P<0.001).
Thirty-two percent of drug approvals for new indications were supported by trials using clinical outcome endpoints, as were 30% of modified-use approvals and 22% of expanded-population approvals (P=0.29).
The investigators said these findings “underscore the need for a robust system of post-approval drug monitoring for efficacy and safety, timely confirmatory studies, and re-examination of existing legislative incentives to promote the optimal delivery of evidence-based medicine.”
Edoxaban to be made available for NVAF
Photo courtesy of the CDC
The UK’s National Institute for Health and Care Excellence (NICE) has issued a final guidance recommending the oral anticoagulant edoxaban tosylate (Lixiana) as an option for preventing stroke and systemic embolism in adults with non-valvular atrial fibrillation (NVAF).
The patients must have one or more risk factors for stroke, including congestive heart failure, hypertension, diabetes, prior stroke or transient ischemic attack, and age of 75 years or older.
In the UK, such patients are generally treated with warfarin or the newer oral anticoagulants dabigatran, rivaroxaban, and apixaban.
NICE decided that edoxaban should be added to that list because data suggest the drug is a clinically and cost-effective treatment option for these patients.
Edoxaban should be available on the National Health Service within 3 months of the date NICE’s final guidance was issued, September 23.
NICE’s guidance says the decision about whether to start treatment with edoxaban should be made after an informed discussion between the clinician and the patient about the risks and benefits of edoxaban compared with warfarin, apixaban, dabigatran, and rivaroxaban.
For patients considering switching from warfarin, edoxaban’s potential benefits should be weighed against its potential risks, taking into account the patient’s level of international normalized ratio control.
Clinical effectiveness
NICE’s conclusion that edoxaban is clinically effective was based primarily on results of the ENGAGE AF-TIMI 48 trial. In this trial, researchers compared edoxaban and warfarin as prophylaxis for stroke or systemic embolism in patients with NVAF.
Results suggested edoxaban was at least non-inferior to warfarin with regard to efficacy, and edoxaban was associated with a significantly lower rate of major and fatal bleeding.
A committee advising NICE also reviewed a meta-analysis prepared by Daiichi Sankyo Co., Ltd., the company developing edoxaban.
The goal of the meta-analysis was to compare edoxaban with rivaroxaban, apixaban, and dabigatran. The analysis included 4 trials: ENGAGE AF-TIMI 48, ARISTOTLE (apixaban), RE-LY (dabigatran), and ROCKET-AF (rivaroxaban). All 4 trials had a warfarin comparator arm.
The results of the meta-analysis indicated that, for the composite endpoint of stroke and systemic embolism, efficacy was similar for high-dose edoxaban and the other new oral anticoagulants.
However, edoxaban significantly reduced major bleeding risk by 24% compared to rivaroxaban, 28% compared to dabigatran at 150 mg, and 17% compared to dabigatran at 110 mg. Major bleeding rates were similar for high-dose edoxaban and apixaban.
The committee advising NICE said these results should be interpreted with caution, but edoxaban is unlikely to be different from rivaroxaban, apixaban, and dabigatran in clinical practice.
Cost-effectiveness
Edoxaban costs £58.80 for a 28-tablet pack (60 mg or 30 mg), and the daily cost of treatment is £2.10 (excluding value-added tax). However, costs may vary in different settings because of negotiated procurement discounts.
The committee advising NICE analyzed cost information and concluded that edoxaban is cost-effective compared with warfarin, but there is insufficient evidence to distinguish between the clinical and cost-effectiveness of edoxaban and the other new oral anticoagulants.
Photo courtesy of the CDC
The UK’s National Institute for Health and Care Excellence (NICE) has issued a final guidance recommending the oral anticoagulant edoxaban tosylate (Lixiana) as an option for preventing stroke and systemic embolism in adults with non-valvular atrial fibrillation (NVAF).
The patients must have one or more risk factors for stroke, including congestive heart failure, hypertension, diabetes, prior stroke or transient ischemic attack, and age of 75 years or older.
In the UK, such patients are generally treated with warfarin or the newer oral anticoagulants dabigatran, rivaroxaban, and apixaban.
NICE decided that edoxaban should be added to that list because data suggest the drug is a clinically and cost-effective treatment option for these patients.
Edoxaban should be available on the National Health Service within 3 months of the date NICE’s final guidance was issued, September 23.
NICE’s guidance says the decision about whether to start treatment with edoxaban should be made after an informed discussion between the clinician and the patient about the risks and benefits of edoxaban compared with warfarin, apixaban, dabigatran, and rivaroxaban.
For patients considering switching from warfarin, edoxaban’s potential benefits should be weighed against its potential risks, taking into account the patient’s level of international normalized ratio control.
Clinical effectiveness
NICE’s conclusion that edoxaban is clinically effective was based primarily on results of the ENGAGE AF-TIMI 48 trial. In this trial, researchers compared edoxaban and warfarin as prophylaxis for stroke or systemic embolism in patients with NVAF.
Results suggested edoxaban was at least non-inferior to warfarin with regard to efficacy, and edoxaban was associated with a significantly lower rate of major and fatal bleeding.
A committee advising NICE also reviewed a meta-analysis prepared by Daiichi Sankyo Co., Ltd., the company developing edoxaban.
The goal of the meta-analysis was to compare edoxaban with rivaroxaban, apixaban, and dabigatran. The analysis included 4 trials: ENGAGE AF-TIMI 48, ARISTOTLE (apixaban), RE-LY (dabigatran), and ROCKET-AF (rivaroxaban). All 4 trials had a warfarin comparator arm.
The results of the meta-analysis indicated that, for the composite endpoint of stroke and systemic embolism, efficacy was similar for high-dose edoxaban and the other new oral anticoagulants.
However, edoxaban significantly reduced major bleeding risk by 24% compared to rivaroxaban, 28% compared to dabigatran at 150 mg, and 17% compared to dabigatran at 110 mg. Major bleeding rates were similar for high-dose edoxaban and apixaban.
The committee advising NICE said these results should be interpreted with caution, but edoxaban is unlikely to be different from rivaroxaban, apixaban, and dabigatran in clinical practice.
Cost-effectiveness
Edoxaban costs £58.80 for a 28-tablet pack (60 mg or 30 mg), and the daily cost of treatment is £2.10 (excluding value-added tax). However, costs may vary in different settings because of negotiated procurement discounts.
The committee advising NICE analyzed cost information and concluded that edoxaban is cost-effective compared with warfarin, but there is insufficient evidence to distinguish between the clinical and cost-effectiveness of edoxaban and the other new oral anticoagulants.
Photo courtesy of the CDC
The UK’s National Institute for Health and Care Excellence (NICE) has issued a final guidance recommending the oral anticoagulant edoxaban tosylate (Lixiana) as an option for preventing stroke and systemic embolism in adults with non-valvular atrial fibrillation (NVAF).
The patients must have one or more risk factors for stroke, including congestive heart failure, hypertension, diabetes, prior stroke or transient ischemic attack, and age of 75 years or older.
In the UK, such patients are generally treated with warfarin or the newer oral anticoagulants dabigatran, rivaroxaban, and apixaban.
NICE decided that edoxaban should be added to that list because data suggest the drug is a clinically and cost-effective treatment option for these patients.
Edoxaban should be available on the National Health Service within 3 months of the date NICE’s final guidance was issued, September 23.
NICE’s guidance says the decision about whether to start treatment with edoxaban should be made after an informed discussion between the clinician and the patient about the risks and benefits of edoxaban compared with warfarin, apixaban, dabigatran, and rivaroxaban.
For patients considering switching from warfarin, edoxaban’s potential benefits should be weighed against its potential risks, taking into account the patient’s level of international normalized ratio control.
Clinical effectiveness
NICE’s conclusion that edoxaban is clinically effective was based primarily on results of the ENGAGE AF-TIMI 48 trial. In this trial, researchers compared edoxaban and warfarin as prophylaxis for stroke or systemic embolism in patients with NVAF.
Results suggested edoxaban was at least non-inferior to warfarin with regard to efficacy, and edoxaban was associated with a significantly lower rate of major and fatal bleeding.
A committee advising NICE also reviewed a meta-analysis prepared by Daiichi Sankyo Co., Ltd., the company developing edoxaban.
The goal of the meta-analysis was to compare edoxaban with rivaroxaban, apixaban, and dabigatran. The analysis included 4 trials: ENGAGE AF-TIMI 48, ARISTOTLE (apixaban), RE-LY (dabigatran), and ROCKET-AF (rivaroxaban). All 4 trials had a warfarin comparator arm.
The results of the meta-analysis indicated that, for the composite endpoint of stroke and systemic embolism, efficacy was similar for high-dose edoxaban and the other new oral anticoagulants.
However, edoxaban significantly reduced major bleeding risk by 24% compared to rivaroxaban, 28% compared to dabigatran at 150 mg, and 17% compared to dabigatran at 110 mg. Major bleeding rates were similar for high-dose edoxaban and apixaban.
The committee advising NICE said these results should be interpreted with caution, but edoxaban is unlikely to be different from rivaroxaban, apixaban, and dabigatran in clinical practice.
Cost-effectiveness
Edoxaban costs £58.80 for a 28-tablet pack (60 mg or 30 mg), and the daily cost of treatment is £2.10 (excluding value-added tax). However, costs may vary in different settings because of negotiated procurement discounts.
The committee advising NICE analyzed cost information and concluded that edoxaban is cost-effective compared with warfarin, but there is insufficient evidence to distinguish between the clinical and cost-effectiveness of edoxaban and the other new oral anticoagulants.