FDA Panel to Review Adcetris for Lymphoma Indications

The July 14 Oncologic Drugs Advisory Committee review of Seattle Genetics’ Adcetris for two rare lymphomas will indicate how the Food and Drug Administration and panel members will apply the general principles for accelerated approval that they enunciated during a February meeting.

Those principles include a desire for randomized trials to support accelerated approval and for confirmatory trials to be a work in progress when accelerated approval is granted.

The two proposed indications for Adcetris (brentuximab vedotin) are relapsed or refractory Hodgkin’s lymphoma and relapsed or refractory systemic anaplastic large cell lymphoma, both orphan indications.

Each indication is supported by one phase II single-arm trial, with the study for the other indication cited as supporting data.

During the February meeting, ODAC members suggested that single-arm trials are acceptable only for rare diseases and therapies with a pronounced treatment effect. They did not specify how high that effect must be.

In the case of Adcetris, of 102 relapsed or refractory Hodgkin’s lymphoma patients who had failed multiple lines of therapy, including autologous stem cell transplant, 73% achieved the primary end point of objective response after receiving brentuximab, according to an independent review facility. The median response duration was 6.7 months. In all, 32% of participants had complete remission, with a median duration of 20.5 months.

The FDA analysis of the phase II study of 58 patients with relapsed or refractory systemic ALCL found that 86% of participants achieved the primary end point of objective response, with a median duration of 12.6 months, including 57% with complete remissions with a median duration of 13.2 months.

That appears to be the home run that Office of Oncology Drug Products Director Richard Pazdur said he was looking for in single-arm trials for accelerated approval.

FDA briefing documents indicate that agency reviewers are comfortable with accelerated approval and that, in fact, that is the only option for Adcetris at this point.

However, in its explanation for the proposed voting question of whether Adcetris should be given accelerated or regular approval – or nonapproval – the FDA noted that the single-arm design and small size limit the benefit-to-risk analysis.

"Time-to-event [end points], such as progression-free survival or overall survival, cannot be adequately interpreted in a single-arm trial," and attribution of adverse events is not possible, the agency explained.

Despite being advised in prebiologic license application meetings that the antibody-drug conjugate would be reviewed for accelerated approval, Seattle Genetics is seeking full approval.

For both indications, the sponsor’s briefing materials state that progression-free survival was significantly superior for brentuximab, compared with the most recent prior therapy.

The firm maintains that "clinical benefit is established by the high overall response and complete remission rates as observed by independent review facility and the associated durability of these remissions, in addition to disease symptom resolution in the context of an acceptable safety profile."

But the FDA says that in the absence of a randomized controlled trial, "time-to-event analyses are not useful for regulatory purposes, nor is a progression-free survival analysis."

For Hodgkin’s lymphoma, the FDA phrases the question about approval with the words "for the treatment of patients with Hodgkin lymphoma who relapse after autologous stem cell transplant," which was the patient population studied in the pivotal trial. Seattle Genetics’ proposed indication is for the treatment of the general population of "patients with relapsed or refractory Hodgkin’s lymphoma."

The one discussion question for each indication centers on the FDA’s desire for confirmatory studies to be at least in the planning stage before an application for accelerated approval is filed.

If ODAC insists upon that requirement, the indication for anaplastic large-cell lymphoma could be derailed, as a confirmatory study is not in the works.

In its briefing document, the agency says it wants ODAC "to consider whether or not accelerated approval should be granted without an ongoing confirmatory trial" for that indication.

In the discussion question itself, the agency sounds more open minded, merely asking for a discussion of potential confirmatory studies, end points, and comparators.

Seattle Genetics is on firmer footing with the Hodgkin’s lymphoma indication, having already begun enrollment in a phase III, randomized, placebo-controlled trial in posttransplant patients. The primary end point is progression-free survival. The company expects to complete enrollment in 2012 and to have data in 2013 or 2014.

The agency will ask the committee to weigh in on whether PFS or overall survival is the most appropriate primary end point to demonstrate clinical benefit.

The FDA also is concerned that participants are not required to be in remission at the time of randomization. A risk-benefit assessment would be different in patients with no residual disease and in those with active disease, the FDA says, and asks for a discussion of whether the trial should be conducted only in those with no active disease.

The FDA’s focus on ensuring that the appropriate confirmatory trial is conducted comes in the wake of its proposed withdrawal of accelerated approval of Genentech’s Avastin because of the failure of its confirmatory studies.

Brentuximab vedotin is an antibody-drug conjugate consisting of an anti-CD30 monoclonal antibody and a small-molecule cytotoxin called monomethyl auristatin E (MMAE). The two are joined by a protease-cleavable linker. The antibody links to the surface of a CD30-expressing cancer cell, the conjugate is internalized to the cell, and the link between the antibody and drug is severed. This delivers the MAAE directly into malignant cells while bypassing normal cells.

The Adcetris Prescription Drug User Fee Act date is Aug. 30.

Elsevier Global Medical News and "The Pink Sheet" are published by Elsevier.

The July 14 Oncologic Drugs Advisory Committee review of Seattle Genetics’ Adcetris for two rare lymphomas will indicate how the Food and Drug Administration and panel members will apply the general principles for accelerated approval that they enunciated during a February meeting.

Those principles include a desire for randomized trials to support accelerated approval and for confirmatory trials to be a work in progress when accelerated approval is granted.

The two proposed indications for Adcetris (brentuximab vedotin) are relapsed or refractory Hodgkin’s lymphoma and relapsed or refractory systemic anaplastic large cell lymphoma, both orphan indications.

Each indication is supported by one phase II single-arm trial, with the study for the other indication cited as supporting data.

During the February meeting, ODAC members suggested that single-arm trials are acceptable only for rare diseases and therapies with a pronounced treatment effect. They did not specify how high that effect must be.

In the case of Adcetris, of 102 relapsed or refractory Hodgkin’s lymphoma patients who had failed multiple lines of therapy, including autologous stem cell transplant, 73% achieved the primary end point of objective response after receiving brentuximab, according to an independent review facility. The median response duration was 6.7 months. In all, 32% of participants had complete remission, with a median duration of 20.5 months.

The FDA analysis of the phase II study of 58 patients with relapsed or refractory systemic ALCL found that 86% of participants achieved the primary end point of objective response, with a median duration of 12.6 months, including 57% with complete remissions with a median duration of 13.2 months.

That appears to be the home run that Office of Oncology Drug Products Director Richard Pazdur said he was looking for in single-arm trials for accelerated approval.

FDA briefing documents indicate that agency reviewers are comfortable with accelerated approval and that, in fact, that is the only option for Adcetris at this point.

However, in its explanation for the proposed voting question of whether Adcetris should be given accelerated or regular approval – or nonapproval – the FDA noted that the single-arm design and small size limit the benefit-to-risk analysis.

"Time-to-event [end points], such as progression-free survival or overall survival, cannot be adequately interpreted in a single-arm trial," and attribution of adverse events is not possible, the agency explained.

Despite being advised in prebiologic license application meetings that the antibody-drug conjugate would be reviewed for accelerated approval, Seattle Genetics is seeking full approval.

For both indications, the sponsor’s briefing materials state that progression-free survival was significantly superior for brentuximab, compared with the most recent prior therapy.

The firm maintains that "clinical benefit is established by the high overall response and complete remission rates as observed by independent review facility and the associated durability of these remissions, in addition to disease symptom resolution in the context of an acceptable safety profile."

But the FDA says that in the absence of a randomized controlled trial, "time-to-event analyses are not useful for regulatory purposes, nor is a progression-free survival analysis."

For Hodgkin’s lymphoma, the FDA phrases the question about approval with the words "for the treatment of patients with Hodgkin lymphoma who relapse after autologous stem cell transplant," which was the patient population studied in the pivotal trial. Seattle Genetics’ proposed indication is for the treatment of the general population of "patients with relapsed or refractory Hodgkin’s lymphoma."

The one discussion question for each indication centers on the FDA’s desire for confirmatory studies to be at least in the planning stage before an application for accelerated approval is filed.

If ODAC insists upon that requirement, the indication for anaplastic large-cell lymphoma could be derailed, as a confirmatory study is not in the works.

In its briefing document, the agency says it wants ODAC "to consider whether or not accelerated approval should be granted without an ongoing confirmatory trial" for that indication.

In the discussion question itself, the agency sounds more open minded, merely asking for a discussion of potential confirmatory studies, end points, and comparators.

Seattle Genetics is on firmer footing with the Hodgkin’s lymphoma indication, having already begun enrollment in a phase III, randomized, placebo-controlled trial in posttransplant patients. The primary end point is progression-free survival. The company expects to complete enrollment in 2012 and to have data in 2013 or 2014.

The agency will ask the committee to weigh in on whether PFS or overall survival is the most appropriate primary end point to demonstrate clinical benefit.

The FDA also is concerned that participants are not required to be in remission at the time of randomization. A risk-benefit assessment would be different in patients with no residual disease and in those with active disease, the FDA says, and asks for a discussion of whether the trial should be conducted only in those with no active disease.

The FDA’s focus on ensuring that the appropriate confirmatory trial is conducted comes in the wake of its proposed withdrawal of accelerated approval of Genentech’s Avastin because of the failure of its confirmatory studies.

Brentuximab vedotin is an antibody-drug conjugate consisting of an anti-CD30 monoclonal antibody and a small-molecule cytotoxin called monomethyl auristatin E (MMAE). The two are joined by a protease-cleavable linker. The antibody links to the surface of a CD30-expressing cancer cell, the conjugate is internalized to the cell, and the link between the antibody and drug is severed. This delivers the MAAE directly into malignant cells while bypassing normal cells.

The Adcetris Prescription Drug User Fee Act date is Aug. 30.

Elsevier Global Medical News and "The Pink Sheet" are published by Elsevier.

The July 14 Oncologic Drugs Advisory Committee review of Seattle Genetics’ Adcetris for two rare lymphomas will indicate how the Food and Drug Administration and panel members will apply the general principles for accelerated approval that they enunciated during a February meeting.

Those principles include a desire for randomized trials to support accelerated approval and for confirmatory trials to be a work in progress when accelerated approval is granted.

The two proposed indications for Adcetris (brentuximab vedotin) are relapsed or refractory Hodgkin’s lymphoma and relapsed or refractory systemic anaplastic large cell lymphoma, both orphan indications.

Each indication is supported by one phase II single-arm trial, with the study for the other indication cited as supporting data.

During the February meeting, ODAC members suggested that single-arm trials are acceptable only for rare diseases and therapies with a pronounced treatment effect. They did not specify how high that effect must be.

In the case of Adcetris, of 102 relapsed or refractory Hodgkin’s lymphoma patients who had failed multiple lines of therapy, including autologous stem cell transplant, 73% achieved the primary end point of objective response after receiving brentuximab, according to an independent review facility. The median response duration was 6.7 months. In all, 32% of participants had complete remission, with a median duration of 20.5 months.

The FDA analysis of the phase II study of 58 patients with relapsed or refractory systemic ALCL found that 86% of participants achieved the primary end point of objective response, with a median duration of 12.6 months, including 57% with complete remissions with a median duration of 13.2 months.

That appears to be the home run that Office of Oncology Drug Products Director Richard Pazdur said he was looking for in single-arm trials for accelerated approval.

FDA briefing documents indicate that agency reviewers are comfortable with accelerated approval and that, in fact, that is the only option for Adcetris at this point.

However, in its explanation for the proposed voting question of whether Adcetris should be given accelerated or regular approval – or nonapproval – the FDA noted that the single-arm design and small size limit the benefit-to-risk analysis.

"Time-to-event [end points], such as progression-free survival or overall survival, cannot be adequately interpreted in a single-arm trial," and attribution of adverse events is not possible, the agency explained.

Despite being advised in prebiologic license application meetings that the antibody-drug conjugate would be reviewed for accelerated approval, Seattle Genetics is seeking full approval.

For both indications, the sponsor’s briefing materials state that progression-free survival was significantly superior for brentuximab, compared with the most recent prior therapy.

The firm maintains that "clinical benefit is established by the high overall response and complete remission rates as observed by independent review facility and the associated durability of these remissions, in addition to disease symptom resolution in the context of an acceptable safety profile."

But the FDA says that in the absence of a randomized controlled trial, "time-to-event analyses are not useful for regulatory purposes, nor is a progression-free survival analysis."

For Hodgkin’s lymphoma, the FDA phrases the question about approval with the words "for the treatment of patients with Hodgkin lymphoma who relapse after autologous stem cell transplant," which was the patient population studied in the pivotal trial. Seattle Genetics’ proposed indication is for the treatment of the general population of "patients with relapsed or refractory Hodgkin’s lymphoma."

The one discussion question for each indication centers on the FDA’s desire for confirmatory studies to be at least in the planning stage before an application for accelerated approval is filed.

If ODAC insists upon that requirement, the indication for anaplastic large-cell lymphoma could be derailed, as a confirmatory study is not in the works.

In its briefing document, the agency says it wants ODAC "to consider whether or not accelerated approval should be granted without an ongoing confirmatory trial" for that indication.

In the discussion question itself, the agency sounds more open minded, merely asking for a discussion of potential confirmatory studies, end points, and comparators.

Seattle Genetics is on firmer footing with the Hodgkin’s lymphoma indication, having already begun enrollment in a phase III, randomized, placebo-controlled trial in posttransplant patients. The primary end point is progression-free survival. The company expects to complete enrollment in 2012 and to have data in 2013 or 2014.

The agency will ask the committee to weigh in on whether PFS or overall survival is the most appropriate primary end point to demonstrate clinical benefit.

The FDA also is concerned that participants are not required to be in remission at the time of randomization. A risk-benefit assessment would be different in patients with no residual disease and in those with active disease, the FDA says, and asks for a discussion of whether the trial should be conducted only in those with no active disease.

The FDA’s focus on ensuring that the appropriate confirmatory trial is conducted comes in the wake of its proposed withdrawal of accelerated approval of Genentech’s Avastin because of the failure of its confirmatory studies.

Brentuximab vedotin is an antibody-drug conjugate consisting of an anti-CD30 monoclonal antibody and a small-molecule cytotoxin called monomethyl auristatin E (MMAE). The two are joined by a protease-cleavable linker. The antibody links to the surface of a CD30-expressing cancer cell, the conjugate is internalized to the cell, and the link between the antibody and drug is severed. This delivers the MAAE directly into malignant cells while bypassing normal cells.

The Adcetris Prescription Drug User Fee Act date is Aug. 30.

Elsevier Global Medical News and "The Pink Sheet" are published by Elsevier.