User login
CARs race for supremacy against aggressive non-Hodgkin lymphoma
MADRID – Two chimeric antigen receptor T cell (CAR-T) constructs are showing promising activity against treatment-refractory, aggressive forms of non-Hodgkin lymphoma in multicenter clinical trials.
In the ZUMA-1 trial, axicabtagene ciloleucel (axi-cel), an autologous anti-CD19 CAR-T product, was associated with an 82% objective response rate (ORR), including 54% complete responses, in patients with refractory diffuse large B cell lymphoma (DLBCL), primary mediastinal B-cell lymphoma (PMBCL), or transformed follicular lymphoma (TFL), reported Yi Lin, MD, PhD, from the Mayo Clinic in Rochester Minnesota.
In an interim analysis from the JULIET study, a different anti-CD19 CAR-T construct labeled CTL019 was associated with a 59% ORR, consisting of 43% complete responses and 16% partial responses (PR) in patients with relapsed or refractory DLBCL, reported Gilles Salles, MD, PhD, from the University of Lyon, France.
The analysis “confirms the high response rates and durable responses observed in the previous single-center trial,” Dr. Salles said.
Although the CAR-T cell constructs in the study have different costimulatory molecules, each is created in a centralized facility, which allows for consistent manufacturing of cells sufficient for harvesting, transfecting, expanding, and reinfusing into heavily pretreated patients.
The construct used in ZUMA-1, also called KTE-C19 (Kite Pharma), has CD28 and CD3-zeta signaling domains. CTL019 (Novarits, U. Pennsylvania, and Oxford Biomedica) has CD3-zeta and 4-1BB costimulatory domains.
ZUMA-1
Dr. Lin reported phase II results from ZUMA-1, investigating axi-cel at a target dose of 2 x 106 cells per kilogram in 72 patients with refractory DLBCL (cohort 1), and 20 patients with refractory PMBCL or TFL (cohort 2).
The median patient age was 58 years. Patients had stage III or IV disease, 47% had International Prognostic Index (IPI) scores of 3-4, 77% had disease that was refractory to second-line therapies or beyond, and 21% had disease that relapsed within 12 months of an autologous bone marrow transplant
The axi-cel construct was successfully manufactured in 99% of patients, with an average turnaround time from apheresis to the clinical site of 17 days.
As noted before, the trial met its primary endpoint with an 82% ORR, consisting of 54% complete responses and 28% partial responses.
The median duration of response was 8.2 months, and for patients with complete responses the median duration has not been reached.
Median overall survival has also not been reached.
The treatment was generally safe, with only 13% of patients experiencing grade 3 or greater cytokine release syndrome (CRS), and 28% having grade 3 or greater neurologic events. The events were generally reversible, and the rates of each declined over time. The use of tociluzumab or steroids to control adverse events did not have a negative effect on responses, Dr. Lin said.
JULIET
In the ongoing JULIET study, patients with relapsed/refractory DLBCL after at least two prior lines of therapy and who are not candidates for stem cell transplants are enrolled.
In a safety analysis including 85 patients, the CRS was seen in 57% of all patients, including grade 3 in 17% and grade 4 in 9%.
Other common adverse events occurring within 8 weeks of CTL019 infusion were infections in 26% of patients, cytopenias lasting longer than 28 days in 26%, neurologic events in 21%, febrile neutropenia in 14%, and tumor lysis syndrome in 1%.
There were no cases of cerebral edema, and no deaths attributable to the CAR-T cell construct, Dr. Salles said.
Peter Borchmann, MD, from the University of Cologne, Germany, who attended the briefing but was not involved with either study, commented that investigators in ZUMA-1 need to monitor patients carefully, because previous clinical trials using other CAR-T cells with CD28 costimuatory domains have been associated with several cases of fatal cerebral edema.
“I think you can use CD28 in lymphoma, and it’s highly active as we have seen, but my personal impression is that you have to be aware that this might happen,” he said in an interview.
The ZUMA-1 study is funded by Kite Pharma. Dr. Lin disclosed research funding from Janssen. The JULIET study is supported by Novartis. Dr. Salles disclosed serving on an advisory board for the company. Dr. Borchmann had no disclosures.
MADRID – Two chimeric antigen receptor T cell (CAR-T) constructs are showing promising activity against treatment-refractory, aggressive forms of non-Hodgkin lymphoma in multicenter clinical trials.
In the ZUMA-1 trial, axicabtagene ciloleucel (axi-cel), an autologous anti-CD19 CAR-T product, was associated with an 82% objective response rate (ORR), including 54% complete responses, in patients with refractory diffuse large B cell lymphoma (DLBCL), primary mediastinal B-cell lymphoma (PMBCL), or transformed follicular lymphoma (TFL), reported Yi Lin, MD, PhD, from the Mayo Clinic in Rochester Minnesota.
In an interim analysis from the JULIET study, a different anti-CD19 CAR-T construct labeled CTL019 was associated with a 59% ORR, consisting of 43% complete responses and 16% partial responses (PR) in patients with relapsed or refractory DLBCL, reported Gilles Salles, MD, PhD, from the University of Lyon, France.
The analysis “confirms the high response rates and durable responses observed in the previous single-center trial,” Dr. Salles said.
Although the CAR-T cell constructs in the study have different costimulatory molecules, each is created in a centralized facility, which allows for consistent manufacturing of cells sufficient for harvesting, transfecting, expanding, and reinfusing into heavily pretreated patients.
The construct used in ZUMA-1, also called KTE-C19 (Kite Pharma), has CD28 and CD3-zeta signaling domains. CTL019 (Novarits, U. Pennsylvania, and Oxford Biomedica) has CD3-zeta and 4-1BB costimulatory domains.
ZUMA-1
Dr. Lin reported phase II results from ZUMA-1, investigating axi-cel at a target dose of 2 x 106 cells per kilogram in 72 patients with refractory DLBCL (cohort 1), and 20 patients with refractory PMBCL or TFL (cohort 2).
The median patient age was 58 years. Patients had stage III or IV disease, 47% had International Prognostic Index (IPI) scores of 3-4, 77% had disease that was refractory to second-line therapies or beyond, and 21% had disease that relapsed within 12 months of an autologous bone marrow transplant
The axi-cel construct was successfully manufactured in 99% of patients, with an average turnaround time from apheresis to the clinical site of 17 days.
As noted before, the trial met its primary endpoint with an 82% ORR, consisting of 54% complete responses and 28% partial responses.
The median duration of response was 8.2 months, and for patients with complete responses the median duration has not been reached.
Median overall survival has also not been reached.
The treatment was generally safe, with only 13% of patients experiencing grade 3 or greater cytokine release syndrome (CRS), and 28% having grade 3 or greater neurologic events. The events were generally reversible, and the rates of each declined over time. The use of tociluzumab or steroids to control adverse events did not have a negative effect on responses, Dr. Lin said.
JULIET
In the ongoing JULIET study, patients with relapsed/refractory DLBCL after at least two prior lines of therapy and who are not candidates for stem cell transplants are enrolled.
In a safety analysis including 85 patients, the CRS was seen in 57% of all patients, including grade 3 in 17% and grade 4 in 9%.
Other common adverse events occurring within 8 weeks of CTL019 infusion were infections in 26% of patients, cytopenias lasting longer than 28 days in 26%, neurologic events in 21%, febrile neutropenia in 14%, and tumor lysis syndrome in 1%.
There were no cases of cerebral edema, and no deaths attributable to the CAR-T cell construct, Dr. Salles said.
Peter Borchmann, MD, from the University of Cologne, Germany, who attended the briefing but was not involved with either study, commented that investigators in ZUMA-1 need to monitor patients carefully, because previous clinical trials using other CAR-T cells with CD28 costimuatory domains have been associated with several cases of fatal cerebral edema.
“I think you can use CD28 in lymphoma, and it’s highly active as we have seen, but my personal impression is that you have to be aware that this might happen,” he said in an interview.
The ZUMA-1 study is funded by Kite Pharma. Dr. Lin disclosed research funding from Janssen. The JULIET study is supported by Novartis. Dr. Salles disclosed serving on an advisory board for the company. Dr. Borchmann had no disclosures.
MADRID – Two chimeric antigen receptor T cell (CAR-T) constructs are showing promising activity against treatment-refractory, aggressive forms of non-Hodgkin lymphoma in multicenter clinical trials.
In the ZUMA-1 trial, axicabtagene ciloleucel (axi-cel), an autologous anti-CD19 CAR-T product, was associated with an 82% objective response rate (ORR), including 54% complete responses, in patients with refractory diffuse large B cell lymphoma (DLBCL), primary mediastinal B-cell lymphoma (PMBCL), or transformed follicular lymphoma (TFL), reported Yi Lin, MD, PhD, from the Mayo Clinic in Rochester Minnesota.
In an interim analysis from the JULIET study, a different anti-CD19 CAR-T construct labeled CTL019 was associated with a 59% ORR, consisting of 43% complete responses and 16% partial responses (PR) in patients with relapsed or refractory DLBCL, reported Gilles Salles, MD, PhD, from the University of Lyon, France.
The analysis “confirms the high response rates and durable responses observed in the previous single-center trial,” Dr. Salles said.
Although the CAR-T cell constructs in the study have different costimulatory molecules, each is created in a centralized facility, which allows for consistent manufacturing of cells sufficient for harvesting, transfecting, expanding, and reinfusing into heavily pretreated patients.
The construct used in ZUMA-1, also called KTE-C19 (Kite Pharma), has CD28 and CD3-zeta signaling domains. CTL019 (Novarits, U. Pennsylvania, and Oxford Biomedica) has CD3-zeta and 4-1BB costimulatory domains.
ZUMA-1
Dr. Lin reported phase II results from ZUMA-1, investigating axi-cel at a target dose of 2 x 106 cells per kilogram in 72 patients with refractory DLBCL (cohort 1), and 20 patients with refractory PMBCL or TFL (cohort 2).
The median patient age was 58 years. Patients had stage III or IV disease, 47% had International Prognostic Index (IPI) scores of 3-4, 77% had disease that was refractory to second-line therapies or beyond, and 21% had disease that relapsed within 12 months of an autologous bone marrow transplant
The axi-cel construct was successfully manufactured in 99% of patients, with an average turnaround time from apheresis to the clinical site of 17 days.
As noted before, the trial met its primary endpoint with an 82% ORR, consisting of 54% complete responses and 28% partial responses.
The median duration of response was 8.2 months, and for patients with complete responses the median duration has not been reached.
Median overall survival has also not been reached.
The treatment was generally safe, with only 13% of patients experiencing grade 3 or greater cytokine release syndrome (CRS), and 28% having grade 3 or greater neurologic events. The events were generally reversible, and the rates of each declined over time. The use of tociluzumab or steroids to control adverse events did not have a negative effect on responses, Dr. Lin said.
JULIET
In the ongoing JULIET study, patients with relapsed/refractory DLBCL after at least two prior lines of therapy and who are not candidates for stem cell transplants are enrolled.
In a safety analysis including 85 patients, the CRS was seen in 57% of all patients, including grade 3 in 17% and grade 4 in 9%.
Other common adverse events occurring within 8 weeks of CTL019 infusion were infections in 26% of patients, cytopenias lasting longer than 28 days in 26%, neurologic events in 21%, febrile neutropenia in 14%, and tumor lysis syndrome in 1%.
There were no cases of cerebral edema, and no deaths attributable to the CAR-T cell construct, Dr. Salles said.
Peter Borchmann, MD, from the University of Cologne, Germany, who attended the briefing but was not involved with either study, commented that investigators in ZUMA-1 need to monitor patients carefully, because previous clinical trials using other CAR-T cells with CD28 costimuatory domains have been associated with several cases of fatal cerebral edema.
“I think you can use CD28 in lymphoma, and it’s highly active as we have seen, but my personal impression is that you have to be aware that this might happen,” he said in an interview.
The ZUMA-1 study is funded by Kite Pharma. Dr. Lin disclosed research funding from Janssen. The JULIET study is supported by Novartis. Dr. Salles disclosed serving on an advisory board for the company. Dr. Borchmann had no disclosures.
AT EHA 2017
Key clinical point: CAR-T cell therapies are showing good activity against relapsed/refractory non-Hodgkin lymphomas.
Major finding: In ZUMA-1, the objective response rate was 82%. In JULIET, it was 59%
Data source: Two multicenter trials of CAR-T cells in patients with relapsed/refractory DLBCL, PMBCL, and TFL.
Disclosures: The ZUMA-1 study is funded by Kite Pharma. Dr. Lin disclosed research funding from Janssen. The JULIET study is supported by Novartis. Dr. Salles disclosed serving on an advisory board for the company. Dr. Borchmann had no disclosures.
New SC rituximab formulation approved, reduces administration time
The US Food and Drug Administration (FDA) approved a new, subcutaneous (SC) formulation of rituximab with hyaluronidase human (Rituxan Hycela™).
The new formulation includes the same monoclonal antibody as intravenous rituximab, but is combined with an enzyme that helps to deliver rituximab under the skin.
The new treatment reduces administration time from 1.5 hours or more for intravenous rituximab to 5 to 7 minutes for the subcutaneous injection.
It is approved for use in adults with previously untreated and relapsed or refractory follicular lymphoma (FL), previously untreated diffuse large B-cell lymphoma (DLBCL), and previously untreated and previously treated chronic lymphocytic leukemia (CLL).
“[P]eople with 3 of the most common blood cancers now have a new treatment option which provides efficacy comparable with intravenous Rituxan and can be delivered under the skin in minutes instead of hours through IV infusion,” said Sandra Horning, MD, chief medical officer of Genentech.
Rituxan Hycela is manufactured by Genentech, Inc, a member of the Roche Group, and jointly marketed by Biogen and Genentech USA, Inc.
“People who benefit from Rituxan may receive years of repeated treatments for their blood cancer, so an option that reduces the administration time can be important,” she noted.
The FDA based its decision on results from 4 clinical studies:
- SABRINA (NCT01200758): Phase 3 combination study with chemotherapy and maintenance study in previously untreated FL
- SAWYER (NCT01292603): Phase 1b study in previously untreated CLL
- MabEase (NCT01649856): Phase 3 study in previously untreated DLBCL
- PrefMab (NCT01724021): Phase 3 patient preference study in previously untreated FL and DLBCL
This last study showed that 77% of patients preferred subcutaneous over intravenous administration, primarily because it reduced administration time.
Together, these trials represented nearly 2,000 people and demonstrated that subcutaneous administration of rituximab/hyaluronidase resulted in non-inferior levels of rituximab in the blood compared to intravenous rituximab.
And the subcutaneous formulation also demonstrated comparable clinical efficacy outcomes to the intravenous formulation.
Patients must have had at least 1 full dose of intravenous rituximab without severe adverse reactions before receiving the subcutaneous injection. There is a higher risk of certain severe adverse reactions during the first infusion.
The safety profile of rituximab/hyaluronidase is also comparable to intravenous rituximab, except for cutaneous reactions.
The most common (≥20%) adverse reactions observed with rituximab/hyaluronidase were:
- In FL, infections, neutropenia, nausea, constipation, cough, and fatigue.
- In DLBCL, infections, neutropenia, alopecia, nausea, and anemia.
- In CLL, infections, neutropenia, nausea, thrombocytopenia, pyrexia, vomiting, and erythema at the injection site.
Rituxan Hycela will be available in the US within 1 to 2 weeks, according to the manufacturer. Intravenous rituximab will continue to be available.
A subcutaneous formulation of rituximab (MabThera) had previously been approved for use in European markets by the European Commission.
For further information on the new US formulation, see the full prescribing information. 
The US Food and Drug Administration (FDA) approved a new, subcutaneous (SC) formulation of rituximab with hyaluronidase human (Rituxan Hycela™).
The new formulation includes the same monoclonal antibody as intravenous rituximab, but is combined with an enzyme that helps to deliver rituximab under the skin.
The new treatment reduces administration time from 1.5 hours or more for intravenous rituximab to 5 to 7 minutes for the subcutaneous injection.
It is approved for use in adults with previously untreated and relapsed or refractory follicular lymphoma (FL), previously untreated diffuse large B-cell lymphoma (DLBCL), and previously untreated and previously treated chronic lymphocytic leukemia (CLL).
“[P]eople with 3 of the most common blood cancers now have a new treatment option which provides efficacy comparable with intravenous Rituxan and can be delivered under the skin in minutes instead of hours through IV infusion,” said Sandra Horning, MD, chief medical officer of Genentech.
Rituxan Hycela is manufactured by Genentech, Inc, a member of the Roche Group, and jointly marketed by Biogen and Genentech USA, Inc.
“People who benefit from Rituxan may receive years of repeated treatments for their blood cancer, so an option that reduces the administration time can be important,” she noted.
The FDA based its decision on results from 4 clinical studies:
- SABRINA (NCT01200758): Phase 3 combination study with chemotherapy and maintenance study in previously untreated FL
- SAWYER (NCT01292603): Phase 1b study in previously untreated CLL
- MabEase (NCT01649856): Phase 3 study in previously untreated DLBCL
- PrefMab (NCT01724021): Phase 3 patient preference study in previously untreated FL and DLBCL
This last study showed that 77% of patients preferred subcutaneous over intravenous administration, primarily because it reduced administration time.
Together, these trials represented nearly 2,000 people and demonstrated that subcutaneous administration of rituximab/hyaluronidase resulted in non-inferior levels of rituximab in the blood compared to intravenous rituximab.
And the subcutaneous formulation also demonstrated comparable clinical efficacy outcomes to the intravenous formulation.
Patients must have had at least 1 full dose of intravenous rituximab without severe adverse reactions before receiving the subcutaneous injection. There is a higher risk of certain severe adverse reactions during the first infusion.
The safety profile of rituximab/hyaluronidase is also comparable to intravenous rituximab, except for cutaneous reactions.
The most common (≥20%) adverse reactions observed with rituximab/hyaluronidase were:
- In FL, infections, neutropenia, nausea, constipation, cough, and fatigue.
- In DLBCL, infections, neutropenia, alopecia, nausea, and anemia.
- In CLL, infections, neutropenia, nausea, thrombocytopenia, pyrexia, vomiting, and erythema at the injection site.
Rituxan Hycela will be available in the US within 1 to 2 weeks, according to the manufacturer. Intravenous rituximab will continue to be available.
A subcutaneous formulation of rituximab (MabThera) had previously been approved for use in European markets by the European Commission.
For further information on the new US formulation, see the full prescribing information.
The US Food and Drug Administration (FDA) approved a new, subcutaneous (SC) formulation of rituximab with hyaluronidase human (Rituxan Hycela™).
The new formulation includes the same monoclonal antibody as intravenous rituximab, but is combined with an enzyme that helps to deliver rituximab under the skin.
The new treatment reduces administration time from 1.5 hours or more for intravenous rituximab to 5 to 7 minutes for the subcutaneous injection.
It is approved for use in adults with previously untreated and relapsed or refractory follicular lymphoma (FL), previously untreated diffuse large B-cell lymphoma (DLBCL), and previously untreated and previously treated chronic lymphocytic leukemia (CLL).
“[P]eople with 3 of the most common blood cancers now have a new treatment option which provides efficacy comparable with intravenous Rituxan and can be delivered under the skin in minutes instead of hours through IV infusion,” said Sandra Horning, MD, chief medical officer of Genentech.
Rituxan Hycela is manufactured by Genentech, Inc, a member of the Roche Group, and jointly marketed by Biogen and Genentech USA, Inc.
“People who benefit from Rituxan may receive years of repeated treatments for their blood cancer, so an option that reduces the administration time can be important,” she noted.
The FDA based its decision on results from 4 clinical studies:
- SABRINA (NCT01200758): Phase 3 combination study with chemotherapy and maintenance study in previously untreated FL
- SAWYER (NCT01292603): Phase 1b study in previously untreated CLL
- MabEase (NCT01649856): Phase 3 study in previously untreated DLBCL
- PrefMab (NCT01724021): Phase 3 patient preference study in previously untreated FL and DLBCL
This last study showed that 77% of patients preferred subcutaneous over intravenous administration, primarily because it reduced administration time.
Together, these trials represented nearly 2,000 people and demonstrated that subcutaneous administration of rituximab/hyaluronidase resulted in non-inferior levels of rituximab in the blood compared to intravenous rituximab.
And the subcutaneous formulation also demonstrated comparable clinical efficacy outcomes to the intravenous formulation.
Patients must have had at least 1 full dose of intravenous rituximab without severe adverse reactions before receiving the subcutaneous injection. There is a higher risk of certain severe adverse reactions during the first infusion.
The safety profile of rituximab/hyaluronidase is also comparable to intravenous rituximab, except for cutaneous reactions.
The most common (≥20%) adverse reactions observed with rituximab/hyaluronidase were:
- In FL, infections, neutropenia, nausea, constipation, cough, and fatigue.
- In DLBCL, infections, neutropenia, alopecia, nausea, and anemia.
- In CLL, infections, neutropenia, nausea, thrombocytopenia, pyrexia, vomiting, and erythema at the injection site.
Rituxan Hycela will be available in the US within 1 to 2 weeks, according to the manufacturer. Intravenous rituximab will continue to be available.
A subcutaneous formulation of rituximab (MabThera) had previously been approved for use in European markets by the European Commission.
For further information on the new US formulation, see the full prescribing information.
Twofer drug blocks SYK/JAK pathways in advanced NHL
MADRID – Cerdulatinib, a single oral agent targeting two different pathways that lymphomas rely on for survival, produced rapid tumor responses in patients with relapsed or refractory non-Hodgkin lymphomas (NHL) in a phase II study.
The overall response rate among 47 patients enrolled in a phase II study was 50%, including responses among 67% of patients with chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL) and 56% of patients with follicular lymphoma (FL), reported Paul A. Hamlin, MD, of the Memorial Sloan Kettering Cancer Center in New York.
“At a dose of 30 mg b.i.d., cerdulatinib inhibited pathways of interest, so both SYK and JAK are inhibited at maximum amounts at physiologically attained doses,” he said at a briefing at the annual congress of the European Hematology Association.
Certain B cell malignancies are “addicted” to B cell antigen-receptor (BCR) signaling. A combination of selective SYK and JAK inhibitors can syngergistically suppress this response in B cell malignancies, he said.
In a phase I dose escalation study of cerdulatinib in 43 patients with relapsed/refractory CLL and NHL reported by Dr. Hamlin and his colleagues at the 2016 EHA annual congress, inhibition with cerdulatinib of both the BCR/SYK and JAK/STAT pathways in peripheral blood assays was well tolerated.
In the current phase II, multicenter, open-label study, the investigators plan on enrolling up to 40 patients in each of three cohorts: relapsed refractory CLL/SLL, relapsed/refractory indolent NHL, and relapsed diffuse large B cell lymphoma (DLBCL), mantle cell lymphoma (MCL) and transformed FL. The investigators have also begun to enroll patients with peripheral T-cell lymphoma (PTCL) based on efficacy of the dual pathway inhibitor against this malignancy.
The patients received 30-mg cerdulatinib orally twice daily until disease progression or intolerable toxicity.
As noted, the overall response rate was 50% (47 patients), including partial responses (PR) in 12 of 18 (67%) of patients with CLL/SLL, in five of nine patients (56%) with FL, and in one of seven patients with relapsed refractory marginal zone lymphoma and Waldenstrom macroglobulinemia.
In addition, the investigators identified one complete response in the first enrolled patient with PTCL.
“I think this is a proof of principle that the biology suggesting that SYK is expressed in T-cell lymphomas and may have an important role in its pathogenesis holds true,” Dr. Hamlin said.
Responses have been detected in heavily pretreated patients, including one patient with FL who had a relapse on ibrutinib and a patient with SLL who had a relapse during treatment with venetoclax. Both patients remain on cerdulatinib after 10 months. At the time of the data presentation, 15 patients are continuing therapy with the dual inhibitor, including 4 who have been taking it for more than 300 days.
The responses occurred after a median of two cycles, Dr. Hamlin noted, and improved over time, as seen in seven of nine patients with increased reduction of nodal masses at the second or third rescan.
The most frequent adverse events with cerdulatinib at the target dose of 30 mg are fatigue, diarrhea, nausea, and cytopenias.
In the dose-escalation phase, three patients at a dose of 35 mg b.i.d. had higher than expected drug concentrations and experienced severe adverse events, including two fatal infections and one grade 3 pancreatitis. The investigators launched a pharmacokinetics monitoring strategy in hopes of avoiding this complication in the future.
Dr. Hamlin said the efficacy to date suggests the cerdulatinib could be used as a single agent but added that its generally favorable safety profile may make it a good partner in combination therapies.
The study is supported by Molecular Templates. Dr. Hamlin disclosed grant/research support and/or consultant role for Spectrum, GlaxoSmithKline, Pfizer, Seattle Genetics, Genentech, and Gilead.
MADRID – Cerdulatinib, a single oral agent targeting two different pathways that lymphomas rely on for survival, produced rapid tumor responses in patients with relapsed or refractory non-Hodgkin lymphomas (NHL) in a phase II study.
The overall response rate among 47 patients enrolled in a phase II study was 50%, including responses among 67% of patients with chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL) and 56% of patients with follicular lymphoma (FL), reported Paul A. Hamlin, MD, of the Memorial Sloan Kettering Cancer Center in New York.
“At a dose of 30 mg b.i.d., cerdulatinib inhibited pathways of interest, so both SYK and JAK are inhibited at maximum amounts at physiologically attained doses,” he said at a briefing at the annual congress of the European Hematology Association.
Certain B cell malignancies are “addicted” to B cell antigen-receptor (BCR) signaling. A combination of selective SYK and JAK inhibitors can syngergistically suppress this response in B cell malignancies, he said.
In a phase I dose escalation study of cerdulatinib in 43 patients with relapsed/refractory CLL and NHL reported by Dr. Hamlin and his colleagues at the 2016 EHA annual congress, inhibition with cerdulatinib of both the BCR/SYK and JAK/STAT pathways in peripheral blood assays was well tolerated.
In the current phase II, multicenter, open-label study, the investigators plan on enrolling up to 40 patients in each of three cohorts: relapsed refractory CLL/SLL, relapsed/refractory indolent NHL, and relapsed diffuse large B cell lymphoma (DLBCL), mantle cell lymphoma (MCL) and transformed FL. The investigators have also begun to enroll patients with peripheral T-cell lymphoma (PTCL) based on efficacy of the dual pathway inhibitor against this malignancy.
The patients received 30-mg cerdulatinib orally twice daily until disease progression or intolerable toxicity.
As noted, the overall response rate was 50% (47 patients), including partial responses (PR) in 12 of 18 (67%) of patients with CLL/SLL, in five of nine patients (56%) with FL, and in one of seven patients with relapsed refractory marginal zone lymphoma and Waldenstrom macroglobulinemia.
In addition, the investigators identified one complete response in the first enrolled patient with PTCL.
“I think this is a proof of principle that the biology suggesting that SYK is expressed in T-cell lymphomas and may have an important role in its pathogenesis holds true,” Dr. Hamlin said.
Responses have been detected in heavily pretreated patients, including one patient with FL who had a relapse on ibrutinib and a patient with SLL who had a relapse during treatment with venetoclax. Both patients remain on cerdulatinib after 10 months. At the time of the data presentation, 15 patients are continuing therapy with the dual inhibitor, including 4 who have been taking it for more than 300 days.
The responses occurred after a median of two cycles, Dr. Hamlin noted, and improved over time, as seen in seven of nine patients with increased reduction of nodal masses at the second or third rescan.
The most frequent adverse events with cerdulatinib at the target dose of 30 mg are fatigue, diarrhea, nausea, and cytopenias.
In the dose-escalation phase, three patients at a dose of 35 mg b.i.d. had higher than expected drug concentrations and experienced severe adverse events, including two fatal infections and one grade 3 pancreatitis. The investigators launched a pharmacokinetics monitoring strategy in hopes of avoiding this complication in the future.
Dr. Hamlin said the efficacy to date suggests the cerdulatinib could be used as a single agent but added that its generally favorable safety profile may make it a good partner in combination therapies.
The study is supported by Molecular Templates. Dr. Hamlin disclosed grant/research support and/or consultant role for Spectrum, GlaxoSmithKline, Pfizer, Seattle Genetics, Genentech, and Gilead.
MADRID – Cerdulatinib, a single oral agent targeting two different pathways that lymphomas rely on for survival, produced rapid tumor responses in patients with relapsed or refractory non-Hodgkin lymphomas (NHL) in a phase II study.
The overall response rate among 47 patients enrolled in a phase II study was 50%, including responses among 67% of patients with chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL) and 56% of patients with follicular lymphoma (FL), reported Paul A. Hamlin, MD, of the Memorial Sloan Kettering Cancer Center in New York.
“At a dose of 30 mg b.i.d., cerdulatinib inhibited pathways of interest, so both SYK and JAK are inhibited at maximum amounts at physiologically attained doses,” he said at a briefing at the annual congress of the European Hematology Association.
Certain B cell malignancies are “addicted” to B cell antigen-receptor (BCR) signaling. A combination of selective SYK and JAK inhibitors can syngergistically suppress this response in B cell malignancies, he said.
In a phase I dose escalation study of cerdulatinib in 43 patients with relapsed/refractory CLL and NHL reported by Dr. Hamlin and his colleagues at the 2016 EHA annual congress, inhibition with cerdulatinib of both the BCR/SYK and JAK/STAT pathways in peripheral blood assays was well tolerated.
In the current phase II, multicenter, open-label study, the investigators plan on enrolling up to 40 patients in each of three cohorts: relapsed refractory CLL/SLL, relapsed/refractory indolent NHL, and relapsed diffuse large B cell lymphoma (DLBCL), mantle cell lymphoma (MCL) and transformed FL. The investigators have also begun to enroll patients with peripheral T-cell lymphoma (PTCL) based on efficacy of the dual pathway inhibitor against this malignancy.
The patients received 30-mg cerdulatinib orally twice daily until disease progression or intolerable toxicity.
As noted, the overall response rate was 50% (47 patients), including partial responses (PR) in 12 of 18 (67%) of patients with CLL/SLL, in five of nine patients (56%) with FL, and in one of seven patients with relapsed refractory marginal zone lymphoma and Waldenstrom macroglobulinemia.
In addition, the investigators identified one complete response in the first enrolled patient with PTCL.
“I think this is a proof of principle that the biology suggesting that SYK is expressed in T-cell lymphomas and may have an important role in its pathogenesis holds true,” Dr. Hamlin said.
Responses have been detected in heavily pretreated patients, including one patient with FL who had a relapse on ibrutinib and a patient with SLL who had a relapse during treatment with venetoclax. Both patients remain on cerdulatinib after 10 months. At the time of the data presentation, 15 patients are continuing therapy with the dual inhibitor, including 4 who have been taking it for more than 300 days.
The responses occurred after a median of two cycles, Dr. Hamlin noted, and improved over time, as seen in seven of nine patients with increased reduction of nodal masses at the second or third rescan.
The most frequent adverse events with cerdulatinib at the target dose of 30 mg are fatigue, diarrhea, nausea, and cytopenias.
In the dose-escalation phase, three patients at a dose of 35 mg b.i.d. had higher than expected drug concentrations and experienced severe adverse events, including two fatal infections and one grade 3 pancreatitis. The investigators launched a pharmacokinetics monitoring strategy in hopes of avoiding this complication in the future.
Dr. Hamlin said the efficacy to date suggests the cerdulatinib could be used as a single agent but added that its generally favorable safety profile may make it a good partner in combination therapies.
The study is supported by Molecular Templates. Dr. Hamlin disclosed grant/research support and/or consultant role for Spectrum, GlaxoSmithKline, Pfizer, Seattle Genetics, Genentech, and Gilead.
AT EHA 2017
Key clinical point: Cerdulatinib, an inhibitor of the SYK and JAK pathways, has shown efficacy against relapsed/refractory non-Hodgkin lymphomas.
Major finding: The overall response rate was 50%, including one complete response in a patient with peripheral T-cell lymphoma.
Data source: An open label, phase II study in 47 patients with non-Hodgkin lymphoma or peripheral T-cell lymphoma.
Disclosures: The study is supported by Molecular Templates. Dr. Hamlin disclosed grant/research support and/or consultant roles for Spectrum, GlaxoSmithKline, Pfizer, Seattle Genetics, Genentech, and Gilead.
Chemo-free triplet produces ‘favorable’ results in advanced disease
LUGANO, SWITZERLAND—A chemotherapy-free combination regimen has demonstrated “favorable” safety and efficacy in patients with advanced chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL) and non-Hodgkin lymphoma (NHL), according to researchers.
They found that treatment with ublituximab, umbralisib, and ibrutinib produced responses in patients with CLL/SLL, marginal zone lymphoma (MZL), mantle cell lymphoma (MCL), follicular lymphoma (FL), and diffuse large B-cell lymphoma (DLBCL).
Many of these patients are still receiving the combination, some of them beyond 1 year, said Lorretta Nastoupil, MD, of MD Anderson Cancer Center in Houston, Texas.
She presented results with the treatment at the 14th International Conference on Malignant Lymphoma (ICML).
The research was sponsored by TG Therapeutics, the company developing ublituximab (TG-1101) and umbralisib (TGR-1202).
Patients and treatment
Dr Nastoupil presented data on 38 patients—20 with CLL/SLL, and 18 with NHL. Three of the CLL/SLL patients were treatment-naïve. The rest had relapsed/refractory disease.
All NHL patients had relapsed/refractory disease—6 with DLBCL, 6 with FL, 4 with MCL, and 2 with MZL.
For the entire cohort, the median age was 65 (range, 32-85), and most patients (n=29) were male. They had received a median of 3 prior treatment regimens (range, 0-6).
In this trial, the patients received:
- Ublituximab at 900 mg
- Ibrutinib at 420 mg (CLL/SLL) or 560 mg (NHL)
- Umbralisib at 400 mg, 600 mg, or 800 mg.
Eighty-one percent of patients have been on study for more than 6 months. The median time on study is 11.1 months (range, 0.4 to 30+ months).
Safety
There was 1 dose-limiting toxicity in the CLL cohort (umbralisib at 400 mg)—reactivated varicella zoster. And 2 patients discontinued treatment due to an adverse event (AE)—1 due to sepsis and 1 due to pneumonia.
Neutropenia (18%) and pneumonia (11%) were the only grade 3/4 AEs that occurred in more than 10% of patients. Other grade 3/4 AEs included thrombocytopenia (8%), diarrhea (3%), dizziness (3%), pyrexia (3%), rash (3%), anemia (3%), dyspnea (3%), and stomatitis (3%).
The most common AEs of any grade were diarrhea (47%), fatigue (47%), dizziness (37%), insomnia (34%), nausea (34%), neutropenia (32%), cough (32%), and infusion-related reactions (32%).
Efficacy
Thirty-six patients were evaluable for efficacy—19 with CLL/SLL and 17 with NHL patients. Two patients discontinued treatment before the first efficacy assessment—1 due to pneumonia and 1 at investigator discretion.
For the entire cohort, the overall response rate (ORR) was 83%.
In the CLL/SLL cohort, the ORR was 100% (19/19), and the complete response (CR) rate was 32% (n=6). However, 4 of the 6 CRs are pending bone marrow confirmation.
Dr Nastoupil noted that 8 of the CLL patients had a 17p and/or 11q deletion, and 3 had previously received treatment with a BTK and/or PI3Kδ inhibitor.
One patient who was refractory to both idelalisib and ibrutinib achieved a CR with the triplet regimen, and this response has been ongoing for more than 1.5 years.
Among patients with NHL, the ORR was 100% in patients with MZL (2/2) and MCL (4/4). The ORR was 80% (4/5) in FL patients, and 17% (1/6) in DLBCL patients.
The CR rate was 50% in patients with MZL (1/2) and MCL (2/4) and 20% in patients with FL (1/5).
Dr Nastoupil pointed out that the FL patients were heavily pretreated. Two of them had received an autologous stem cell transplant, 1 was refractory to prior ibrutinib treatment, and 1 had received 5 prior lines of rituximab-based therapy.
She also noted that the DLBCL patients had a median of 4 prior therapies, and 4 of these patients had non-GCB DLBCL, including the only patient who responded to the triplet.
“[T]he combination of ublituximab, umbralisib, and ibrutinib in advanced CLL and NHL demonstrated a favorable toxicity profile as well as favorable efficacy,” Dr Nastoupil said in closing.
“[This] suggests umbralisib may be safely combined with other targeted agents to overcome mechanisms of resistance.”
LUGANO, SWITZERLAND—A chemotherapy-free combination regimen has demonstrated “favorable” safety and efficacy in patients with advanced chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL) and non-Hodgkin lymphoma (NHL), according to researchers.
They found that treatment with ublituximab, umbralisib, and ibrutinib produced responses in patients with CLL/SLL, marginal zone lymphoma (MZL), mantle cell lymphoma (MCL), follicular lymphoma (FL), and diffuse large B-cell lymphoma (DLBCL).
Many of these patients are still receiving the combination, some of them beyond 1 year, said Lorretta Nastoupil, MD, of MD Anderson Cancer Center in Houston, Texas.
She presented results with the treatment at the 14th International Conference on Malignant Lymphoma (ICML).
The research was sponsored by TG Therapeutics, the company developing ublituximab (TG-1101) and umbralisib (TGR-1202).
Patients and treatment
Dr Nastoupil presented data on 38 patients—20 with CLL/SLL, and 18 with NHL. Three of the CLL/SLL patients were treatment-naïve. The rest had relapsed/refractory disease.
All NHL patients had relapsed/refractory disease—6 with DLBCL, 6 with FL, 4 with MCL, and 2 with MZL.
For the entire cohort, the median age was 65 (range, 32-85), and most patients (n=29) were male. They had received a median of 3 prior treatment regimens (range, 0-6).
In this trial, the patients received:
- Ublituximab at 900 mg
- Ibrutinib at 420 mg (CLL/SLL) or 560 mg (NHL)
- Umbralisib at 400 mg, 600 mg, or 800 mg.
Eighty-one percent of patients have been on study for more than 6 months. The median time on study is 11.1 months (range, 0.4 to 30+ months).
Safety
There was 1 dose-limiting toxicity in the CLL cohort (umbralisib at 400 mg)—reactivated varicella zoster. And 2 patients discontinued treatment due to an adverse event (AE)—1 due to sepsis and 1 due to pneumonia.
Neutropenia (18%) and pneumonia (11%) were the only grade 3/4 AEs that occurred in more than 10% of patients. Other grade 3/4 AEs included thrombocytopenia (8%), diarrhea (3%), dizziness (3%), pyrexia (3%), rash (3%), anemia (3%), dyspnea (3%), and stomatitis (3%).
The most common AEs of any grade were diarrhea (47%), fatigue (47%), dizziness (37%), insomnia (34%), nausea (34%), neutropenia (32%), cough (32%), and infusion-related reactions (32%).
Efficacy
Thirty-six patients were evaluable for efficacy—19 with CLL/SLL and 17 with NHL patients. Two patients discontinued treatment before the first efficacy assessment—1 due to pneumonia and 1 at investigator discretion.
For the entire cohort, the overall response rate (ORR) was 83%.
In the CLL/SLL cohort, the ORR was 100% (19/19), and the complete response (CR) rate was 32% (n=6). However, 4 of the 6 CRs are pending bone marrow confirmation.
Dr Nastoupil noted that 8 of the CLL patients had a 17p and/or 11q deletion, and 3 had previously received treatment with a BTK and/or PI3Kδ inhibitor.
One patient who was refractory to both idelalisib and ibrutinib achieved a CR with the triplet regimen, and this response has been ongoing for more than 1.5 years.
Among patients with NHL, the ORR was 100% in patients with MZL (2/2) and MCL (4/4). The ORR was 80% (4/5) in FL patients, and 17% (1/6) in DLBCL patients.
The CR rate was 50% in patients with MZL (1/2) and MCL (2/4) and 20% in patients with FL (1/5).
Dr Nastoupil pointed out that the FL patients were heavily pretreated. Two of them had received an autologous stem cell transplant, 1 was refractory to prior ibrutinib treatment, and 1 had received 5 prior lines of rituximab-based therapy.
She also noted that the DLBCL patients had a median of 4 prior therapies, and 4 of these patients had non-GCB DLBCL, including the only patient who responded to the triplet.
“[T]he combination of ublituximab, umbralisib, and ibrutinib in advanced CLL and NHL demonstrated a favorable toxicity profile as well as favorable efficacy,” Dr Nastoupil said in closing.
“[This] suggests umbralisib may be safely combined with other targeted agents to overcome mechanisms of resistance.”
LUGANO, SWITZERLAND—A chemotherapy-free combination regimen has demonstrated “favorable” safety and efficacy in patients with advanced chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL) and non-Hodgkin lymphoma (NHL), according to researchers.
They found that treatment with ublituximab, umbralisib, and ibrutinib produced responses in patients with CLL/SLL, marginal zone lymphoma (MZL), mantle cell lymphoma (MCL), follicular lymphoma (FL), and diffuse large B-cell lymphoma (DLBCL).
Many of these patients are still receiving the combination, some of them beyond 1 year, said Lorretta Nastoupil, MD, of MD Anderson Cancer Center in Houston, Texas.
She presented results with the treatment at the 14th International Conference on Malignant Lymphoma (ICML).
The research was sponsored by TG Therapeutics, the company developing ublituximab (TG-1101) and umbralisib (TGR-1202).
Patients and treatment
Dr Nastoupil presented data on 38 patients—20 with CLL/SLL, and 18 with NHL. Three of the CLL/SLL patients were treatment-naïve. The rest had relapsed/refractory disease.
All NHL patients had relapsed/refractory disease—6 with DLBCL, 6 with FL, 4 with MCL, and 2 with MZL.
For the entire cohort, the median age was 65 (range, 32-85), and most patients (n=29) were male. They had received a median of 3 prior treatment regimens (range, 0-6).
In this trial, the patients received:
- Ublituximab at 900 mg
- Ibrutinib at 420 mg (CLL/SLL) or 560 mg (NHL)
- Umbralisib at 400 mg, 600 mg, or 800 mg.
Eighty-one percent of patients have been on study for more than 6 months. The median time on study is 11.1 months (range, 0.4 to 30+ months).
Safety
There was 1 dose-limiting toxicity in the CLL cohort (umbralisib at 400 mg)—reactivated varicella zoster. And 2 patients discontinued treatment due to an adverse event (AE)—1 due to sepsis and 1 due to pneumonia.
Neutropenia (18%) and pneumonia (11%) were the only grade 3/4 AEs that occurred in more than 10% of patients. Other grade 3/4 AEs included thrombocytopenia (8%), diarrhea (3%), dizziness (3%), pyrexia (3%), rash (3%), anemia (3%), dyspnea (3%), and stomatitis (3%).
The most common AEs of any grade were diarrhea (47%), fatigue (47%), dizziness (37%), insomnia (34%), nausea (34%), neutropenia (32%), cough (32%), and infusion-related reactions (32%).
Efficacy
Thirty-six patients were evaluable for efficacy—19 with CLL/SLL and 17 with NHL patients. Two patients discontinued treatment before the first efficacy assessment—1 due to pneumonia and 1 at investigator discretion.
For the entire cohort, the overall response rate (ORR) was 83%.
In the CLL/SLL cohort, the ORR was 100% (19/19), and the complete response (CR) rate was 32% (n=6). However, 4 of the 6 CRs are pending bone marrow confirmation.
Dr Nastoupil noted that 8 of the CLL patients had a 17p and/or 11q deletion, and 3 had previously received treatment with a BTK and/or PI3Kδ inhibitor.
One patient who was refractory to both idelalisib and ibrutinib achieved a CR with the triplet regimen, and this response has been ongoing for more than 1.5 years.
Among patients with NHL, the ORR was 100% in patients with MZL (2/2) and MCL (4/4). The ORR was 80% (4/5) in FL patients, and 17% (1/6) in DLBCL patients.
The CR rate was 50% in patients with MZL (1/2) and MCL (2/4) and 20% in patients with FL (1/5).
Dr Nastoupil pointed out that the FL patients were heavily pretreated. Two of them had received an autologous stem cell transplant, 1 was refractory to prior ibrutinib treatment, and 1 had received 5 prior lines of rituximab-based therapy.
She also noted that the DLBCL patients had a median of 4 prior therapies, and 4 of these patients had non-GCB DLBCL, including the only patient who responded to the triplet.
“[T]he combination of ublituximab, umbralisib, and ibrutinib in advanced CLL and NHL demonstrated a favorable toxicity profile as well as favorable efficacy,” Dr Nastoupil said in closing.
“[This] suggests umbralisib may be safely combined with other targeted agents to overcome mechanisms of resistance.”
FDA approves rituximab + hyaluronidase human for FL, DLBCL, and CLL
The Food and Drug Administration has approved rituximab plus hyaluronidase human for adult patients with follicular lymphoma (FL), diffuse large B-cell lymphoma (DLBCL), and chronic lymphocytic leukemia (CLL).
The combination product, to be marketed as Rituxan Hycela, is administered subcutaneously, shortening administration time to 5 to 7 minutes as compared with the several hours needed for intravenous infusion, the FDA said in a statement.
Approval was based on noninferior rituximab trough concentrations for the subcutaneously administered combination, compared with intravenous rituximab, and comparable efficacy and safety results as shown in multiple randomized clinical trials.
The most common adverse events seen with the combination in patients with FL included infections, neutropenia, nausea, constipation, cough, and fatigue. In patients with DLBCL, the most common adverse events were infections, neutropenia, alopecia, nausea, and anemia; in CLL patients, infections, neutropenia, nausea, thrombocytopenia, pyrexia, vomiting, and injection site erythema occurred most commonly.
The combination is indicated for the following previously approved indications for rituximab:
- Relapsed or refractory FL as a single agent.
- Previously untreated FL in combination with first line chemotherapy and, in patients achieving a complete or partial response to rituximab in combination with chemotherapy, as single-agent maintenance therapy.
- Nonprogressing (including stable disease) FL as a single agent after first-line cyclophosphamide, vincristine, and prednisone chemotherapy.
- Previously untreated DLBCL in combination with cyclophosphamide, doxorubicin, vincristine, prednisone or other anthracycline-based chemotherapy regimens.
- Previously untreated and previously treated CLL in combination with fludarabine and cyclophosphamide.
The recommended doses are 1,400 mg rituximab and 23,400 units hyaluronidase human for FL and DLBCL and 1,600 mg rituximab and 26,800 units hyaluronidase human for CLL. The combination treatment should be initiated only after patients have received at least one full dose of a rituximab product by intravenous infusion, according to the prescribing information.
Rituxan Hycela is marketed by Genentech.
The Food and Drug Administration has approved rituximab plus hyaluronidase human for adult patients with follicular lymphoma (FL), diffuse large B-cell lymphoma (DLBCL), and chronic lymphocytic leukemia (CLL).
The combination product, to be marketed as Rituxan Hycela, is administered subcutaneously, shortening administration time to 5 to 7 minutes as compared with the several hours needed for intravenous infusion, the FDA said in a statement.
Approval was based on noninferior rituximab trough concentrations for the subcutaneously administered combination, compared with intravenous rituximab, and comparable efficacy and safety results as shown in multiple randomized clinical trials.
The most common adverse events seen with the combination in patients with FL included infections, neutropenia, nausea, constipation, cough, and fatigue. In patients with DLBCL, the most common adverse events were infections, neutropenia, alopecia, nausea, and anemia; in CLL patients, infections, neutropenia, nausea, thrombocytopenia, pyrexia, vomiting, and injection site erythema occurred most commonly.
The combination is indicated for the following previously approved indications for rituximab:
- Relapsed or refractory FL as a single agent.
- Previously untreated FL in combination with first line chemotherapy and, in patients achieving a complete or partial response to rituximab in combination with chemotherapy, as single-agent maintenance therapy.
- Nonprogressing (including stable disease) FL as a single agent after first-line cyclophosphamide, vincristine, and prednisone chemotherapy.
- Previously untreated DLBCL in combination with cyclophosphamide, doxorubicin, vincristine, prednisone or other anthracycline-based chemotherapy regimens.
- Previously untreated and previously treated CLL in combination with fludarabine and cyclophosphamide.
The recommended doses are 1,400 mg rituximab and 23,400 units hyaluronidase human for FL and DLBCL and 1,600 mg rituximab and 26,800 units hyaluronidase human for CLL. The combination treatment should be initiated only after patients have received at least one full dose of a rituximab product by intravenous infusion, according to the prescribing information.
Rituxan Hycela is marketed by Genentech.
The Food and Drug Administration has approved rituximab plus hyaluronidase human for adult patients with follicular lymphoma (FL), diffuse large B-cell lymphoma (DLBCL), and chronic lymphocytic leukemia (CLL).
The combination product, to be marketed as Rituxan Hycela, is administered subcutaneously, shortening administration time to 5 to 7 minutes as compared with the several hours needed for intravenous infusion, the FDA said in a statement.
Approval was based on noninferior rituximab trough concentrations for the subcutaneously administered combination, compared with intravenous rituximab, and comparable efficacy and safety results as shown in multiple randomized clinical trials.
The most common adverse events seen with the combination in patients with FL included infections, neutropenia, nausea, constipation, cough, and fatigue. In patients with DLBCL, the most common adverse events were infections, neutropenia, alopecia, nausea, and anemia; in CLL patients, infections, neutropenia, nausea, thrombocytopenia, pyrexia, vomiting, and injection site erythema occurred most commonly.
The combination is indicated for the following previously approved indications for rituximab:
- Relapsed or refractory FL as a single agent.
- Previously untreated FL in combination with first line chemotherapy and, in patients achieving a complete or partial response to rituximab in combination with chemotherapy, as single-agent maintenance therapy.
- Nonprogressing (including stable disease) FL as a single agent after first-line cyclophosphamide, vincristine, and prednisone chemotherapy.
- Previously untreated DLBCL in combination with cyclophosphamide, doxorubicin, vincristine, prednisone or other anthracycline-based chemotherapy regimens.
- Previously untreated and previously treated CLL in combination with fludarabine and cyclophosphamide.
The recommended doses are 1,400 mg rituximab and 23,400 units hyaluronidase human for FL and DLBCL and 1,600 mg rituximab and 26,800 units hyaluronidase human for CLL. The combination treatment should be initiated only after patients have received at least one full dose of a rituximab product by intravenous infusion, according to the prescribing information.
Rituxan Hycela is marketed by Genentech.
Inhibitor elicits responses in heavily pretreated FL, DLBCL
LUGANO, SWITZERLAND—Interim results of a phase 2 trial suggest tazemetostat can be effective in patients with heavily pretreated, relapsed or refractory non-Hodgkin lymphoma.
The EZH2 inhibitor produced the highest overall response rate in patients with EZH2-mutated follicular lymphoma (FL), followed by EZH2-mutated diffuse large B-cell lymphoma (DLBCL).
However, the drug also produced complete responses in FL and DLBCL patients with wild-type EZH2.
“If we had focused [only] on patients with EZH2 mutations, we would have missed those other complete responders in the wild-type setting,” said study investigator Franck Morschhauser, MD, PhD, of Centre Hospitalier Régional Universitaire de Lille in France.
He presented results of the trial* during the plenary session of the 14th International Conference on Malignant Lymphoma (ICML). The research was sponsored by Epizyme, the company developing tazemetostat.
The trial enrolled patients with relapsed or refractory DLBCL or FL who had received at least 2 prior therapies. The patients received tazemetostat at 800 mg twice daily until disease progression or study withdrawal.
Efficacy in FL
Dr Morschhauser presented efficacy data on 67 patients with FL. Thirteen had EZH2 mutations, and 54 had wild-type EZH2. The median age was 62 in the mutated group and 61 in the wild-type group.
Both groups had a median of 4 prior lines of therapy. Fifty-four percent of EZH2-mutated patients were refractory to their last treatment, as were 48% of wild-type patients.
The median time from diagnosis was 7.4 years in mutated patients and 4.9 years in wild-type patients. The median time from last therapy was 13 weeks and 41.3 weeks, respectively.
The overall response rate was 92% (12/13) in EZH2-mutated patients and 26% (14/54) in wild-type patients. The complete response rates were 8% (n=1) and 6% (n=3), respectively.
The median time to first response was 11.9 weeks and 15.2 weeks, respectively.
None of the EZH2-mutated patients have progressed, but 13 (24%) wild-type patients have.
Forty-eight percent of all FL patients remain on study. One EZH2-mutated patient with stable disease is still on study, as are 23 wild-type patients with stable disease.
Efficacy in DLBCL
Dr Morschhauser presented data on 137 patients with DLBCL, 17 with EZH2 mutations and 120 with wild-type EZH2. The median age was 61 in the mutated group and 69 in the wild-type group.
Both groups had a median of 3 prior lines of therapy. Eighty-two percent of EZH2-mutated patients were refractory to their last treatment, as were 63% of wild-type patients.
The median time from diagnosis was 1 year in mutated patients and 2 years in wild-type patients. The median time from last therapy was 8.6 weeks and 11.6 weeks, respectively.
The overall response rate was 29% (5/17) in EZH2-mutated patients and 15% (18/119) in wild-type patients. The complete response rates were 0% (n=0) and 8% (n=10), respectively.
The median time to first response was 8.3 weeks and 8.5 weeks, respectively.
Six (35%) of the EZH2-mutated patients have progressed, as have 60 (50%) wild-type patients.
Twelve percent of all DLBCL patients remain on study. One EZH2-mutated patient with stable disease is still on therapy, as are 4 wild-type patients with stable disease.
Predictors of response
Dr Morschhauser and his colleagues performed next-generation sequencing of samples from 92 patients in an attempt to identify predictors of response to tazemetostat.
The data suggested that EZH2 and MYD88 activating mutations are positive predictors of response, and negative predictors include MYC, TP53, and HIST1H1E.
Safety
Safety data were available for 210 patients. The overall rate of treatment-related adverse events (AEs) was 59%, the rate of grade 3 or higher treatment-related AEs was 18%, and the rate of serious treatment-related AEs was 10%.
There were treatment-related AEs leading to dose interruption (15%), dose reduction (3%), and discontinuation of tazemetostat (2%).
The most common treatment-related AEs were nausea (14%), thrombocytopenia (13%), anemia (10%), neutropenia (9%), diarrhea (8%), asthenia (8%), and fatigue (7%).
Dr Morschhauser said these results “confirm that tazemetostat is quite safe” in this patient population, and enrollment in this trial is ongoing.
*Data in the abstract differ from the presentation.
LUGANO, SWITZERLAND—Interim results of a phase 2 trial suggest tazemetostat can be effective in patients with heavily pretreated, relapsed or refractory non-Hodgkin lymphoma.
The EZH2 inhibitor produced the highest overall response rate in patients with EZH2-mutated follicular lymphoma (FL), followed by EZH2-mutated diffuse large B-cell lymphoma (DLBCL).
However, the drug also produced complete responses in FL and DLBCL patients with wild-type EZH2.
“If we had focused [only] on patients with EZH2 mutations, we would have missed those other complete responders in the wild-type setting,” said study investigator Franck Morschhauser, MD, PhD, of Centre Hospitalier Régional Universitaire de Lille in France.
He presented results of the trial* during the plenary session of the 14th International Conference on Malignant Lymphoma (ICML). The research was sponsored by Epizyme, the company developing tazemetostat.
The trial enrolled patients with relapsed or refractory DLBCL or FL who had received at least 2 prior therapies. The patients received tazemetostat at 800 mg twice daily until disease progression or study withdrawal.
Efficacy in FL
Dr Morschhauser presented efficacy data on 67 patients with FL. Thirteen had EZH2 mutations, and 54 had wild-type EZH2. The median age was 62 in the mutated group and 61 in the wild-type group.
Both groups had a median of 4 prior lines of therapy. Fifty-four percent of EZH2-mutated patients were refractory to their last treatment, as were 48% of wild-type patients.
The median time from diagnosis was 7.4 years in mutated patients and 4.9 years in wild-type patients. The median time from last therapy was 13 weeks and 41.3 weeks, respectively.
The overall response rate was 92% (12/13) in EZH2-mutated patients and 26% (14/54) in wild-type patients. The complete response rates were 8% (n=1) and 6% (n=3), respectively.
The median time to first response was 11.9 weeks and 15.2 weeks, respectively.
None of the EZH2-mutated patients have progressed, but 13 (24%) wild-type patients have.
Forty-eight percent of all FL patients remain on study. One EZH2-mutated patient with stable disease is still on study, as are 23 wild-type patients with stable disease.
Efficacy in DLBCL
Dr Morschhauser presented data on 137 patients with DLBCL, 17 with EZH2 mutations and 120 with wild-type EZH2. The median age was 61 in the mutated group and 69 in the wild-type group.
Both groups had a median of 3 prior lines of therapy. Eighty-two percent of EZH2-mutated patients were refractory to their last treatment, as were 63% of wild-type patients.
The median time from diagnosis was 1 year in mutated patients and 2 years in wild-type patients. The median time from last therapy was 8.6 weeks and 11.6 weeks, respectively.
The overall response rate was 29% (5/17) in EZH2-mutated patients and 15% (18/119) in wild-type patients. The complete response rates were 0% (n=0) and 8% (n=10), respectively.
The median time to first response was 8.3 weeks and 8.5 weeks, respectively.
Six (35%) of the EZH2-mutated patients have progressed, as have 60 (50%) wild-type patients.
Twelve percent of all DLBCL patients remain on study. One EZH2-mutated patient with stable disease is still on therapy, as are 4 wild-type patients with stable disease.
Predictors of response
Dr Morschhauser and his colleagues performed next-generation sequencing of samples from 92 patients in an attempt to identify predictors of response to tazemetostat.
The data suggested that EZH2 and MYD88 activating mutations are positive predictors of response, and negative predictors include MYC, TP53, and HIST1H1E.
Safety
Safety data were available for 210 patients. The overall rate of treatment-related adverse events (AEs) was 59%, the rate of grade 3 or higher treatment-related AEs was 18%, and the rate of serious treatment-related AEs was 10%.
There were treatment-related AEs leading to dose interruption (15%), dose reduction (3%), and discontinuation of tazemetostat (2%).
The most common treatment-related AEs were nausea (14%), thrombocytopenia (13%), anemia (10%), neutropenia (9%), diarrhea (8%), asthenia (8%), and fatigue (7%).
Dr Morschhauser said these results “confirm that tazemetostat is quite safe” in this patient population, and enrollment in this trial is ongoing.
*Data in the abstract differ from the presentation.
LUGANO, SWITZERLAND—Interim results of a phase 2 trial suggest tazemetostat can be effective in patients with heavily pretreated, relapsed or refractory non-Hodgkin lymphoma.
The EZH2 inhibitor produced the highest overall response rate in patients with EZH2-mutated follicular lymphoma (FL), followed by EZH2-mutated diffuse large B-cell lymphoma (DLBCL).
However, the drug also produced complete responses in FL and DLBCL patients with wild-type EZH2.
“If we had focused [only] on patients with EZH2 mutations, we would have missed those other complete responders in the wild-type setting,” said study investigator Franck Morschhauser, MD, PhD, of Centre Hospitalier Régional Universitaire de Lille in France.
He presented results of the trial* during the plenary session of the 14th International Conference on Malignant Lymphoma (ICML). The research was sponsored by Epizyme, the company developing tazemetostat.
The trial enrolled patients with relapsed or refractory DLBCL or FL who had received at least 2 prior therapies. The patients received tazemetostat at 800 mg twice daily until disease progression or study withdrawal.
Efficacy in FL
Dr Morschhauser presented efficacy data on 67 patients with FL. Thirteen had EZH2 mutations, and 54 had wild-type EZH2. The median age was 62 in the mutated group and 61 in the wild-type group.
Both groups had a median of 4 prior lines of therapy. Fifty-four percent of EZH2-mutated patients were refractory to their last treatment, as were 48% of wild-type patients.
The median time from diagnosis was 7.4 years in mutated patients and 4.9 years in wild-type patients. The median time from last therapy was 13 weeks and 41.3 weeks, respectively.
The overall response rate was 92% (12/13) in EZH2-mutated patients and 26% (14/54) in wild-type patients. The complete response rates were 8% (n=1) and 6% (n=3), respectively.
The median time to first response was 11.9 weeks and 15.2 weeks, respectively.
None of the EZH2-mutated patients have progressed, but 13 (24%) wild-type patients have.
Forty-eight percent of all FL patients remain on study. One EZH2-mutated patient with stable disease is still on study, as are 23 wild-type patients with stable disease.
Efficacy in DLBCL
Dr Morschhauser presented data on 137 patients with DLBCL, 17 with EZH2 mutations and 120 with wild-type EZH2. The median age was 61 in the mutated group and 69 in the wild-type group.
Both groups had a median of 3 prior lines of therapy. Eighty-two percent of EZH2-mutated patients were refractory to their last treatment, as were 63% of wild-type patients.
The median time from diagnosis was 1 year in mutated patients and 2 years in wild-type patients. The median time from last therapy was 8.6 weeks and 11.6 weeks, respectively.
The overall response rate was 29% (5/17) in EZH2-mutated patients and 15% (18/119) in wild-type patients. The complete response rates were 0% (n=0) and 8% (n=10), respectively.
The median time to first response was 8.3 weeks and 8.5 weeks, respectively.
Six (35%) of the EZH2-mutated patients have progressed, as have 60 (50%) wild-type patients.
Twelve percent of all DLBCL patients remain on study. One EZH2-mutated patient with stable disease is still on therapy, as are 4 wild-type patients with stable disease.
Predictors of response
Dr Morschhauser and his colleagues performed next-generation sequencing of samples from 92 patients in an attempt to identify predictors of response to tazemetostat.
The data suggested that EZH2 and MYD88 activating mutations are positive predictors of response, and negative predictors include MYC, TP53, and HIST1H1E.
Safety
Safety data were available for 210 patients. The overall rate of treatment-related adverse events (AEs) was 59%, the rate of grade 3 or higher treatment-related AEs was 18%, and the rate of serious treatment-related AEs was 10%.
There were treatment-related AEs leading to dose interruption (15%), dose reduction (3%), and discontinuation of tazemetostat (2%).
The most common treatment-related AEs were nausea (14%), thrombocytopenia (13%), anemia (10%), neutropenia (9%), diarrhea (8%), asthenia (8%), and fatigue (7%).
Dr Morschhauser said these results “confirm that tazemetostat is quite safe” in this patient population, and enrollment in this trial is ongoing.
*Data in the abstract differ from the presentation.
Lenalidomide-rituximab induces high CR rate in untreated follicular lymphoma
LUGANO, SWITZERLAND – The chemotherapy-free combination of lenalidomide (Revlimid) and rituximab was highly active as frontline therapy for patients with low- and intermediate-risk follicular lymphoma in a multicenter phase II trial.
Among 66 patients with previously untreated follicular lymphoma, the overall response rate to the combination was 95%, including complete responses in 72% of patients. The 5-year progression-free survival (PFS) rate was 70%, reported John P. Leonard, MD, of Weill Cornell Medicine, New York.
“I think this overall is a useful validation – confirmation of the single-center data that showed that this [combination] in a multicenter setting can be a highly effective and reasonably well-tolerated treatment approach for patients with untreated follicular lymphoma,” he said at the International Conference on Malignant Lymphoma, on behalf of colleagues in the National Cancer Institute Alliance for Clinical Trials in Oncology and Cancer and Leukemia Group B (CALGB) 50803 trial.
In the 50803 study, the investigators enrolled 66 treatment-naive patients. The median age was 53 years (range 32-79). Patients were eligible if they had grade 1-3a, stage 3-4 or bulky stage 2 untreated follicular lymphoma, with Follicular Lymphoma International Prognostic Index (FLIPI) scores of 0-2.
They received lenalidomide 20 mg/day on days 1 through 21 of each 28-day cycle for 12 cycles, plus rituximab administered once weekly for each week of cycle 1, and on the first day of cycles 4, 6, 8 and 10.
The investigators also evaluated polymorphisms in the Fc fragment of immunoglobulin G receptor IIa and IIIa (FcGR2A/FcGR3A).
One of the 66 patients never started treatment, leaving 65 for the response analysis.
As noted, the overall response rate was 95%, including 94% of 21 patients with FLIPI 0 or 1 disease, and 96% of 44 patients with FLIPI 2 or 3. There were no associations between FLIPI score and likelihood of achieving a complete response, and no associations between FcR polymorphism or change in angiogenic markers and either complete responses or PFS, Dr. Leonard said.
Complete responses, the primary endpoint, were seen in 15 of the 21 (71%) of patients with FLIPI 0-1, and in 32 of the 44 (73%) with FLIPI 2-3, for an overall complete response rate of 72%.
Partial responses occurred in 5 patients (23%) with FLIPI 0-1 and 10 patients (23%) with FLIPI 2-3, for an overall PR rate of 23%.
Respective rates of stable disease were 0, 2%, and 2%. One patient in each FLIPI group was not evaluated because of adverse events.
After a median follow-up of 5 years, the progression free survival rate was 70%.
The most common grade 3 or 4 adverse events were neutropenia, seen in 21% of patients, and infections, seen in 40% (including one grade 3 febrile neutropenia).
Grade 1-2 fatigue was reported by 51 patients, and grade 3 fatigue was reported by 4.
Other grade 3 or 4 events seen in more than 5% of patients included rash in 9%, and hyperglycemia, hypophosphatemia, or hypertension, each in 6% of patients.
Celgene and Genentech supported the study. Dr. Leonard has served as an adviser/consultant to Celgene and other companies.
LUGANO, SWITZERLAND – The chemotherapy-free combination of lenalidomide (Revlimid) and rituximab was highly active as frontline therapy for patients with low- and intermediate-risk follicular lymphoma in a multicenter phase II trial.
Among 66 patients with previously untreated follicular lymphoma, the overall response rate to the combination was 95%, including complete responses in 72% of patients. The 5-year progression-free survival (PFS) rate was 70%, reported John P. Leonard, MD, of Weill Cornell Medicine, New York.
“I think this overall is a useful validation – confirmation of the single-center data that showed that this [combination] in a multicenter setting can be a highly effective and reasonably well-tolerated treatment approach for patients with untreated follicular lymphoma,” he said at the International Conference on Malignant Lymphoma, on behalf of colleagues in the National Cancer Institute Alliance for Clinical Trials in Oncology and Cancer and Leukemia Group B (CALGB) 50803 trial.
In the 50803 study, the investigators enrolled 66 treatment-naive patients. The median age was 53 years (range 32-79). Patients were eligible if they had grade 1-3a, stage 3-4 or bulky stage 2 untreated follicular lymphoma, with Follicular Lymphoma International Prognostic Index (FLIPI) scores of 0-2.
They received lenalidomide 20 mg/day on days 1 through 21 of each 28-day cycle for 12 cycles, plus rituximab administered once weekly for each week of cycle 1, and on the first day of cycles 4, 6, 8 and 10.
The investigators also evaluated polymorphisms in the Fc fragment of immunoglobulin G receptor IIa and IIIa (FcGR2A/FcGR3A).
One of the 66 patients never started treatment, leaving 65 for the response analysis.
As noted, the overall response rate was 95%, including 94% of 21 patients with FLIPI 0 or 1 disease, and 96% of 44 patients with FLIPI 2 or 3. There were no associations between FLIPI score and likelihood of achieving a complete response, and no associations between FcR polymorphism or change in angiogenic markers and either complete responses or PFS, Dr. Leonard said.
Complete responses, the primary endpoint, were seen in 15 of the 21 (71%) of patients with FLIPI 0-1, and in 32 of the 44 (73%) with FLIPI 2-3, for an overall complete response rate of 72%.
Partial responses occurred in 5 patients (23%) with FLIPI 0-1 and 10 patients (23%) with FLIPI 2-3, for an overall PR rate of 23%.
Respective rates of stable disease were 0, 2%, and 2%. One patient in each FLIPI group was not evaluated because of adverse events.
After a median follow-up of 5 years, the progression free survival rate was 70%.
The most common grade 3 or 4 adverse events were neutropenia, seen in 21% of patients, and infections, seen in 40% (including one grade 3 febrile neutropenia).
Grade 1-2 fatigue was reported by 51 patients, and grade 3 fatigue was reported by 4.
Other grade 3 or 4 events seen in more than 5% of patients included rash in 9%, and hyperglycemia, hypophosphatemia, or hypertension, each in 6% of patients.
Celgene and Genentech supported the study. Dr. Leonard has served as an adviser/consultant to Celgene and other companies.
LUGANO, SWITZERLAND – The chemotherapy-free combination of lenalidomide (Revlimid) and rituximab was highly active as frontline therapy for patients with low- and intermediate-risk follicular lymphoma in a multicenter phase II trial.
Among 66 patients with previously untreated follicular lymphoma, the overall response rate to the combination was 95%, including complete responses in 72% of patients. The 5-year progression-free survival (PFS) rate was 70%, reported John P. Leonard, MD, of Weill Cornell Medicine, New York.
“I think this overall is a useful validation – confirmation of the single-center data that showed that this [combination] in a multicenter setting can be a highly effective and reasonably well-tolerated treatment approach for patients with untreated follicular lymphoma,” he said at the International Conference on Malignant Lymphoma, on behalf of colleagues in the National Cancer Institute Alliance for Clinical Trials in Oncology and Cancer and Leukemia Group B (CALGB) 50803 trial.
In the 50803 study, the investigators enrolled 66 treatment-naive patients. The median age was 53 years (range 32-79). Patients were eligible if they had grade 1-3a, stage 3-4 or bulky stage 2 untreated follicular lymphoma, with Follicular Lymphoma International Prognostic Index (FLIPI) scores of 0-2.
They received lenalidomide 20 mg/day on days 1 through 21 of each 28-day cycle for 12 cycles, plus rituximab administered once weekly for each week of cycle 1, and on the first day of cycles 4, 6, 8 and 10.
The investigators also evaluated polymorphisms in the Fc fragment of immunoglobulin G receptor IIa and IIIa (FcGR2A/FcGR3A).
One of the 66 patients never started treatment, leaving 65 for the response analysis.
As noted, the overall response rate was 95%, including 94% of 21 patients with FLIPI 0 or 1 disease, and 96% of 44 patients with FLIPI 2 or 3. There were no associations between FLIPI score and likelihood of achieving a complete response, and no associations between FcR polymorphism or change in angiogenic markers and either complete responses or PFS, Dr. Leonard said.
Complete responses, the primary endpoint, were seen in 15 of the 21 (71%) of patients with FLIPI 0-1, and in 32 of the 44 (73%) with FLIPI 2-3, for an overall complete response rate of 72%.
Partial responses occurred in 5 patients (23%) with FLIPI 0-1 and 10 patients (23%) with FLIPI 2-3, for an overall PR rate of 23%.
Respective rates of stable disease were 0, 2%, and 2%. One patient in each FLIPI group was not evaluated because of adverse events.
After a median follow-up of 5 years, the progression free survival rate was 70%.
The most common grade 3 or 4 adverse events were neutropenia, seen in 21% of patients, and infections, seen in 40% (including one grade 3 febrile neutropenia).
Grade 1-2 fatigue was reported by 51 patients, and grade 3 fatigue was reported by 4.
Other grade 3 or 4 events seen in more than 5% of patients included rash in 9%, and hyperglycemia, hypophosphatemia, or hypertension, each in 6% of patients.
Celgene and Genentech supported the study. Dr. Leonard has served as an adviser/consultant to Celgene and other companies.
AT 14-ICML
Key clinical point: The combination of lenalidomide and rituximab was highly active against previously untreated follicular lymphoma.
Major finding: The overall response rate was 95%; 5-year progression-free survival was 70%.
Data source: Open-label prospective study of lenalidomide-rituximab in 66 patients with previously untreated follicular lymphoma.
Disclosures: Celgene and Genentech supported the study. Dr. Leonard has served as an adviser/consultant to Celgene and other companies.
GALEN safe and effective in relapsed and refractory follicular lymphoma
LUGANO, SWITZERLAND – For patients with relapsed or refractory follicular lymphoma, a pairing of lenalidomide (Revlimid) and obinutuzumab (Gazyva) appeared to be especially useful among patients who had disease progression within 24 months, based on results from a Lymphoma Academic Research Organisation trial.
Among 86 patients who were enrolled in a phase II trial and were assessable for efficacy, overall response rates (ORR) with the combination therapy, nicknamed “GALEN,” were 80.2% by 1999 International Working Group criteria, and 74.4% according to the 2007 IWG criteria, reported Franck Morschhauser, MD, PhD, of the University of Lille, France.
The rationale for this combination is the known synergy between lenalidomide and rituximab in relapsed refractory non-Hodgkin lymphomas and in the frontline setting for patients with follicular lymphoma. Obinutuzumab, a follow-on to rituximab, is a unique type II glycoengineered monoclonal antibody directed against CD20, but with increased antibody-dependent cell-mediated cytotoxicity and increased direct cytotoxicity, compared with rituximab, he explained.
In the phase Ib part of the study, researchers settled on a dose of obinutuzumab 1000 mg and lenalidomide 20 mg. Obinutuzumab was administered on days 8, 15 and 22 and lenalidomide on days 1 to 21 of each 28 day cycle. Patients were evaluated for response after three cycles and at the end of induction (after completion of 4 to 6 cycles).
The maintenance phase consisted of obinutuzumab on day 1 of every other cycle beginning with cycle 1, and lenalidomide on days 1 through 22 for cycles 7 through 18. From cycles 19 through 24, obinutuzumab was given alone on the first day of every 56-day cycle.
The overall response rate (ORR) at the end of induction according to the IWG 1999 criteria, the primary endpoint, was 80.2%, including 39.5% complete or unconfirmed complete responses.
When the same patients were assessed according to 2007 IWG criteria, the ORR rate was slightly lower, at 74.4%, but the complete or unconfirmed complete response rate was slightly higher, at 44.2%.
An analysis of responses by time to relapse showed that the ORR among 24 patients with disease progression within 24 months was 70.8%, including 33.3% complete or unconfirmed complete responses by the 1999 criteria, and 66.7% with 54.2% complete or unconfirmed complete responses by the 2007 criteria.
ORR among the 64 patients with disease progression after more than 24 months was 83.9% with 41.9% complete or unconfirmed complete responses by 1999 criteria, and 77.4% with 40.3% complete or unconfirmed complete responses by 2007 criteria. The differences between the groups with disease progression within 24 months and later relapse groups were not significant.
A subanalysis by refractory status, however, showed that the 63 nonrefractory patients fared significantly better, with 87.3% ORR and 41.3% complete or unconfirmed complete responses by 1999 criteria, and 81.0% with 49.2% complete or unconfirmed complete response rate by 2007 determinations, compared with respective rates among 23 refractory patients of 60.9%/34.8% complete or unconfirmed complete response rate and 56.5% with 30.4% complete or unconfirmed complete responses (P = .0212 by 1999 criteria, and P = .022 by 2007 criteria).
After a median follow-up of 18 months, 1-year progression-free survival (PFS) among all patients was 75.5%, and 1-year overall survival (OS) was 88.8%.
There were no significant differences in either progression-free survival or overall survival by time to relapse. Although there appeared to be a nonsignificant trend toward worse outcomes among patients with refractory vs. nonrefractory disease, there was a significantly lower 1-year overall survival rate among refractory patients, at 71.5% compared with 95% for nonrefractory patients (censored logrank P = .0098).
Dr. Morschhauser said that the combination had no unexpected toxicities. Hematologic toxicities of grade 3 or greater included neutropenia in 28.4%, thrombocytopenia in 11.4%, and anemia and lymphopenia in 3.4% each.
The most common nonhematologic toxicities of all grades included infections in 62.5% of patients (grade 3 or greater in 6.8%), and asthenia in 52.3% of patients (grade 3 or greater in 2.3%). The only other grade 3 or greater toxicities were peripheral neuropathy in 1.1%, and infusion related rash in 3.4%.
Additional follow-up will be need for evaluation of the full impact of maintenance on outcomes, he added.
The study was funded by Celgene and Roche. Dr. Morschhauser disclosed receiving honoraria from and serving on advisory boards for both companies.
LUGANO, SWITZERLAND – For patients with relapsed or refractory follicular lymphoma, a pairing of lenalidomide (Revlimid) and obinutuzumab (Gazyva) appeared to be especially useful among patients who had disease progression within 24 months, based on results from a Lymphoma Academic Research Organisation trial.
Among 86 patients who were enrolled in a phase II trial and were assessable for efficacy, overall response rates (ORR) with the combination therapy, nicknamed “GALEN,” were 80.2% by 1999 International Working Group criteria, and 74.4% according to the 2007 IWG criteria, reported Franck Morschhauser, MD, PhD, of the University of Lille, France.
The rationale for this combination is the known synergy between lenalidomide and rituximab in relapsed refractory non-Hodgkin lymphomas and in the frontline setting for patients with follicular lymphoma. Obinutuzumab, a follow-on to rituximab, is a unique type II glycoengineered monoclonal antibody directed against CD20, but with increased antibody-dependent cell-mediated cytotoxicity and increased direct cytotoxicity, compared with rituximab, he explained.
In the phase Ib part of the study, researchers settled on a dose of obinutuzumab 1000 mg and lenalidomide 20 mg. Obinutuzumab was administered on days 8, 15 and 22 and lenalidomide on days 1 to 21 of each 28 day cycle. Patients were evaluated for response after three cycles and at the end of induction (after completion of 4 to 6 cycles).
The maintenance phase consisted of obinutuzumab on day 1 of every other cycle beginning with cycle 1, and lenalidomide on days 1 through 22 for cycles 7 through 18. From cycles 19 through 24, obinutuzumab was given alone on the first day of every 56-day cycle.
The overall response rate (ORR) at the end of induction according to the IWG 1999 criteria, the primary endpoint, was 80.2%, including 39.5% complete or unconfirmed complete responses.
When the same patients were assessed according to 2007 IWG criteria, the ORR rate was slightly lower, at 74.4%, but the complete or unconfirmed complete response rate was slightly higher, at 44.2%.
An analysis of responses by time to relapse showed that the ORR among 24 patients with disease progression within 24 months was 70.8%, including 33.3% complete or unconfirmed complete responses by the 1999 criteria, and 66.7% with 54.2% complete or unconfirmed complete responses by the 2007 criteria.
ORR among the 64 patients with disease progression after more than 24 months was 83.9% with 41.9% complete or unconfirmed complete responses by 1999 criteria, and 77.4% with 40.3% complete or unconfirmed complete responses by 2007 criteria. The differences between the groups with disease progression within 24 months and later relapse groups were not significant.
A subanalysis by refractory status, however, showed that the 63 nonrefractory patients fared significantly better, with 87.3% ORR and 41.3% complete or unconfirmed complete responses by 1999 criteria, and 81.0% with 49.2% complete or unconfirmed complete response rate by 2007 determinations, compared with respective rates among 23 refractory patients of 60.9%/34.8% complete or unconfirmed complete response rate and 56.5% with 30.4% complete or unconfirmed complete responses (P = .0212 by 1999 criteria, and P = .022 by 2007 criteria).
After a median follow-up of 18 months, 1-year progression-free survival (PFS) among all patients was 75.5%, and 1-year overall survival (OS) was 88.8%.
There were no significant differences in either progression-free survival or overall survival by time to relapse. Although there appeared to be a nonsignificant trend toward worse outcomes among patients with refractory vs. nonrefractory disease, there was a significantly lower 1-year overall survival rate among refractory patients, at 71.5% compared with 95% for nonrefractory patients (censored logrank P = .0098).
Dr. Morschhauser said that the combination had no unexpected toxicities. Hematologic toxicities of grade 3 or greater included neutropenia in 28.4%, thrombocytopenia in 11.4%, and anemia and lymphopenia in 3.4% each.
The most common nonhematologic toxicities of all grades included infections in 62.5% of patients (grade 3 or greater in 6.8%), and asthenia in 52.3% of patients (grade 3 or greater in 2.3%). The only other grade 3 or greater toxicities were peripheral neuropathy in 1.1%, and infusion related rash in 3.4%.
Additional follow-up will be need for evaluation of the full impact of maintenance on outcomes, he added.
The study was funded by Celgene and Roche. Dr. Morschhauser disclosed receiving honoraria from and serving on advisory boards for both companies.
LUGANO, SWITZERLAND – For patients with relapsed or refractory follicular lymphoma, a pairing of lenalidomide (Revlimid) and obinutuzumab (Gazyva) appeared to be especially useful among patients who had disease progression within 24 months, based on results from a Lymphoma Academic Research Organisation trial.
Among 86 patients who were enrolled in a phase II trial and were assessable for efficacy, overall response rates (ORR) with the combination therapy, nicknamed “GALEN,” were 80.2% by 1999 International Working Group criteria, and 74.4% according to the 2007 IWG criteria, reported Franck Morschhauser, MD, PhD, of the University of Lille, France.
The rationale for this combination is the known synergy between lenalidomide and rituximab in relapsed refractory non-Hodgkin lymphomas and in the frontline setting for patients with follicular lymphoma. Obinutuzumab, a follow-on to rituximab, is a unique type II glycoengineered monoclonal antibody directed against CD20, but with increased antibody-dependent cell-mediated cytotoxicity and increased direct cytotoxicity, compared with rituximab, he explained.
In the phase Ib part of the study, researchers settled on a dose of obinutuzumab 1000 mg and lenalidomide 20 mg. Obinutuzumab was administered on days 8, 15 and 22 and lenalidomide on days 1 to 21 of each 28 day cycle. Patients were evaluated for response after three cycles and at the end of induction (after completion of 4 to 6 cycles).
The maintenance phase consisted of obinutuzumab on day 1 of every other cycle beginning with cycle 1, and lenalidomide on days 1 through 22 for cycles 7 through 18. From cycles 19 through 24, obinutuzumab was given alone on the first day of every 56-day cycle.
The overall response rate (ORR) at the end of induction according to the IWG 1999 criteria, the primary endpoint, was 80.2%, including 39.5% complete or unconfirmed complete responses.
When the same patients were assessed according to 2007 IWG criteria, the ORR rate was slightly lower, at 74.4%, but the complete or unconfirmed complete response rate was slightly higher, at 44.2%.
An analysis of responses by time to relapse showed that the ORR among 24 patients with disease progression within 24 months was 70.8%, including 33.3% complete or unconfirmed complete responses by the 1999 criteria, and 66.7% with 54.2% complete or unconfirmed complete responses by the 2007 criteria.
ORR among the 64 patients with disease progression after more than 24 months was 83.9% with 41.9% complete or unconfirmed complete responses by 1999 criteria, and 77.4% with 40.3% complete or unconfirmed complete responses by 2007 criteria. The differences between the groups with disease progression within 24 months and later relapse groups were not significant.
A subanalysis by refractory status, however, showed that the 63 nonrefractory patients fared significantly better, with 87.3% ORR and 41.3% complete or unconfirmed complete responses by 1999 criteria, and 81.0% with 49.2% complete or unconfirmed complete response rate by 2007 determinations, compared with respective rates among 23 refractory patients of 60.9%/34.8% complete or unconfirmed complete response rate and 56.5% with 30.4% complete or unconfirmed complete responses (P = .0212 by 1999 criteria, and P = .022 by 2007 criteria).
After a median follow-up of 18 months, 1-year progression-free survival (PFS) among all patients was 75.5%, and 1-year overall survival (OS) was 88.8%.
There were no significant differences in either progression-free survival or overall survival by time to relapse. Although there appeared to be a nonsignificant trend toward worse outcomes among patients with refractory vs. nonrefractory disease, there was a significantly lower 1-year overall survival rate among refractory patients, at 71.5% compared with 95% for nonrefractory patients (censored logrank P = .0098).
Dr. Morschhauser said that the combination had no unexpected toxicities. Hematologic toxicities of grade 3 or greater included neutropenia in 28.4%, thrombocytopenia in 11.4%, and anemia and lymphopenia in 3.4% each.
The most common nonhematologic toxicities of all grades included infections in 62.5% of patients (grade 3 or greater in 6.8%), and asthenia in 52.3% of patients (grade 3 or greater in 2.3%). The only other grade 3 or greater toxicities were peripheral neuropathy in 1.1%, and infusion related rash in 3.4%.
Additional follow-up will be need for evaluation of the full impact of maintenance on outcomes, he added.
The study was funded by Celgene and Roche. Dr. Morschhauser disclosed receiving honoraria from and serving on advisory boards for both companies.
AT 14-ICML
Key clinical point: A combination of lenalidomide and obinutuzumab was safe and effective in patients with relapsed/refractory follicular lymphoma.
Major finding: The overall response rate according to 1999 International Working Group criteria was 80.2%, including 39.5% CR/CRu.
Data source: Single-arm phase II study with 86 patients evaluable for efficacy and 88 evaluable for safety.
Disclosures: The study was funded by Celgene and Roche. Dr. Morschhauser disclosed receiving honoraria from and serving on advisory boards for both companies.
Biosimilar rituximab approved in Europe
The European Commission (EC) has approved the Sandoz biosimilar rituximab (Rixathon®) for use in the European Economic Area.
Rixathon is approved for all indications of the reference medicine, MabThera®, including follicular lymphoma, diffuse large B-cell lymphoma, chronic lymphocytic leukemia, and immunologic diseases such as rheumatoid arthritis, granulomatosis with polyangiitis, and microscopic polyangiitis.
This approval allows Rixathon to be marketed in the member states of the European Union and Iceland, Liechtenstein, and Norway, members of the European Free Trade Association.
The approval “represents a big win for patients in Europe with blood cancers or immunological diseases,” according to Carol Lynch, global head of Biopharmaceuticals at Sandoz.
“Rixathon will be one of the 5 major launches we plan in the next 4 years,” she said.
Earlier in the year, the European Medicines Agency’s Committee for Medicinal Products for Human Use had recommended marketing authorization for Rixathon.
The EC based its approval on a comprehensive development program generating analytical, preclinical, and clinical data. Clinical studies included ASSIST-RA and ASSIST-FL.
ASSIST-RA demonstrated that the biosimilar product has equivalent pharmacokinetic and pharmacodynamic profiles to the reference medicine, with no clinically meaningful differences in safety, tolerability, or immunogenicity in patients with rheumatoid arthritis.
ASSIST-FL was a phase 3 study confirming efficacy and safety. The study met its primary endpoint of equivalence in overall response rate between the biosimilar product and the reference medicine after 6 months.
ASSIST-FL also confirmed the comparable safety profiles of the 2 medicines.
Sandoz is a division of the Swiss pharmaceutical company Novartis. MabThera is a registered trademark of F. Hoffmann-La-Roche AG.
Another Sandoz biosimilar rituximab has been approved in the EU as Riximyo® under a duplicate marketing authorization.
The European Commission (EC) has approved the Sandoz biosimilar rituximab (Rixathon®) for use in the European Economic Area.
Rixathon is approved for all indications of the reference medicine, MabThera®, including follicular lymphoma, diffuse large B-cell lymphoma, chronic lymphocytic leukemia, and immunologic diseases such as rheumatoid arthritis, granulomatosis with polyangiitis, and microscopic polyangiitis.
This approval allows Rixathon to be marketed in the member states of the European Union and Iceland, Liechtenstein, and Norway, members of the European Free Trade Association.
The approval “represents a big win for patients in Europe with blood cancers or immunological diseases,” according to Carol Lynch, global head of Biopharmaceuticals at Sandoz.
“Rixathon will be one of the 5 major launches we plan in the next 4 years,” she said.
Earlier in the year, the European Medicines Agency’s Committee for Medicinal Products for Human Use had recommended marketing authorization for Rixathon.
The EC based its approval on a comprehensive development program generating analytical, preclinical, and clinical data. Clinical studies included ASSIST-RA and ASSIST-FL.
ASSIST-RA demonstrated that the biosimilar product has equivalent pharmacokinetic and pharmacodynamic profiles to the reference medicine, with no clinically meaningful differences in safety, tolerability, or immunogenicity in patients with rheumatoid arthritis.
ASSIST-FL was a phase 3 study confirming efficacy and safety. The study met its primary endpoint of equivalence in overall response rate between the biosimilar product and the reference medicine after 6 months.
ASSIST-FL also confirmed the comparable safety profiles of the 2 medicines.
Sandoz is a division of the Swiss pharmaceutical company Novartis. MabThera is a registered trademark of F. Hoffmann-La-Roche AG.
Another Sandoz biosimilar rituximab has been approved in the EU as Riximyo® under a duplicate marketing authorization.
The European Commission (EC) has approved the Sandoz biosimilar rituximab (Rixathon®) for use in the European Economic Area.
Rixathon is approved for all indications of the reference medicine, MabThera®, including follicular lymphoma, diffuse large B-cell lymphoma, chronic lymphocytic leukemia, and immunologic diseases such as rheumatoid arthritis, granulomatosis with polyangiitis, and microscopic polyangiitis.
This approval allows Rixathon to be marketed in the member states of the European Union and Iceland, Liechtenstein, and Norway, members of the European Free Trade Association.
The approval “represents a big win for patients in Europe with blood cancers or immunological diseases,” according to Carol Lynch, global head of Biopharmaceuticals at Sandoz.
“Rixathon will be one of the 5 major launches we plan in the next 4 years,” she said.
Earlier in the year, the European Medicines Agency’s Committee for Medicinal Products for Human Use had recommended marketing authorization for Rixathon.
The EC based its approval on a comprehensive development program generating analytical, preclinical, and clinical data. Clinical studies included ASSIST-RA and ASSIST-FL.
ASSIST-RA demonstrated that the biosimilar product has equivalent pharmacokinetic and pharmacodynamic profiles to the reference medicine, with no clinically meaningful differences in safety, tolerability, or immunogenicity in patients with rheumatoid arthritis.
ASSIST-FL was a phase 3 study confirming efficacy and safety. The study met its primary endpoint of equivalence in overall response rate between the biosimilar product and the reference medicine after 6 months.
ASSIST-FL also confirmed the comparable safety profiles of the 2 medicines.
Sandoz is a division of the Swiss pharmaceutical company Novartis. MabThera is a registered trademark of F. Hoffmann-La-Roche AG.
Another Sandoz biosimilar rituximab has been approved in the EU as Riximyo® under a duplicate marketing authorization.
BLA for CAR T-cell therapy granted priority review
The US Food and Drug Administration (FDA) has accepted for priority review the biologics license application (BLA) for axicabtagene ciloleucel (formerly KTE-C19), a chimeric antigen receptor (CAR) T-cell therapy.
Kite Pharma, Inc. is seeking approval for axicabtagene ciloleucel as a treatment for patients with relapsed or refractory, aggressive non-Hodgkin lymphoma (NHL) who are ineligible for autologous stem cell transplant.
The FDA grants priority review to applications for products that may provide significant improvements in the treatment, diagnosis, or prevention of serious conditions.
The agency’s goal is to take action on a priority review application within 6 months of receiving it, rather than the standard 10 months.
The FDA has set a review deadline of November 29, 2017, for the axicabtagene ciloleucel BLA.
Axicabtagene ciloleucel also has breakthrough therapy designation from the FDA as a treatment for diffuse large B-cell lymphoma, transformed follicular lymphoma, and primary mediastinal B-cell lymphoma.
ZUMA-1 trial
The BLA for axicabtagene ciloleucel is supported by data from the phase 2 ZUMA-1 trial, which enrolled 111 patients with relapsed/refractory B-cell NHL.
After a single infusion of axicabtagene ciloleucel, the objective response rate was 82%. At a median follow-up of 8.7 months, 44% of patients were still in response, which included 39% of patients in complete response.
The most common grade 3 or higher adverse events were anemia (43%), neutropenia (39%), decreased neutrophil count (32%), febrile neutropenia (31%), decreased white blood cell count (29%), thrombocytopenia (24%), encephalopathy (21%), and decreased lymphocyte count (20%).
There were 3 deaths during the trial that were not due to disease progression. Two of these deaths were deemed related to axicabtagene ciloleucel.
The US Food and Drug Administration (FDA) has accepted for priority review the biologics license application (BLA) for axicabtagene ciloleucel (formerly KTE-C19), a chimeric antigen receptor (CAR) T-cell therapy.
Kite Pharma, Inc. is seeking approval for axicabtagene ciloleucel as a treatment for patients with relapsed or refractory, aggressive non-Hodgkin lymphoma (NHL) who are ineligible for autologous stem cell transplant.
The FDA grants priority review to applications for products that may provide significant improvements in the treatment, diagnosis, or prevention of serious conditions.
The agency’s goal is to take action on a priority review application within 6 months of receiving it, rather than the standard 10 months.
The FDA has set a review deadline of November 29, 2017, for the axicabtagene ciloleucel BLA.
Axicabtagene ciloleucel also has breakthrough therapy designation from the FDA as a treatment for diffuse large B-cell lymphoma, transformed follicular lymphoma, and primary mediastinal B-cell lymphoma.
ZUMA-1 trial
The BLA for axicabtagene ciloleucel is supported by data from the phase 2 ZUMA-1 trial, which enrolled 111 patients with relapsed/refractory B-cell NHL.
After a single infusion of axicabtagene ciloleucel, the objective response rate was 82%. At a median follow-up of 8.7 months, 44% of patients were still in response, which included 39% of patients in complete response.
The most common grade 3 or higher adverse events were anemia (43%), neutropenia (39%), decreased neutrophil count (32%), febrile neutropenia (31%), decreased white blood cell count (29%), thrombocytopenia (24%), encephalopathy (21%), and decreased lymphocyte count (20%).
There were 3 deaths during the trial that were not due to disease progression. Two of these deaths were deemed related to axicabtagene ciloleucel.
The US Food and Drug Administration (FDA) has accepted for priority review the biologics license application (BLA) for axicabtagene ciloleucel (formerly KTE-C19), a chimeric antigen receptor (CAR) T-cell therapy.
Kite Pharma, Inc. is seeking approval for axicabtagene ciloleucel as a treatment for patients with relapsed or refractory, aggressive non-Hodgkin lymphoma (NHL) who are ineligible for autologous stem cell transplant.
The FDA grants priority review to applications for products that may provide significant improvements in the treatment, diagnosis, or prevention of serious conditions.
The agency’s goal is to take action on a priority review application within 6 months of receiving it, rather than the standard 10 months.
The FDA has set a review deadline of November 29, 2017, for the axicabtagene ciloleucel BLA.
Axicabtagene ciloleucel also has breakthrough therapy designation from the FDA as a treatment for diffuse large B-cell lymphoma, transformed follicular lymphoma, and primary mediastinal B-cell lymphoma.
ZUMA-1 trial
The BLA for axicabtagene ciloleucel is supported by data from the phase 2 ZUMA-1 trial, which enrolled 111 patients with relapsed/refractory B-cell NHL.
After a single infusion of axicabtagene ciloleucel, the objective response rate was 82%. At a median follow-up of 8.7 months, 44% of patients were still in response, which included 39% of patients in complete response.
The most common grade 3 or higher adverse events were anemia (43%), neutropenia (39%), decreased neutrophil count (32%), febrile neutropenia (31%), decreased white blood cell count (29%), thrombocytopenia (24%), encephalopathy (21%), and decreased lymphocyte count (20%).
There were 3 deaths during the trial that were not due to disease progression. Two of these deaths were deemed related to axicabtagene ciloleucel.