The July 14 Oncologic Drugs Advisory Committee review of Seattle Genetics' Adcetris for two rare lymphomas will indicate how FDA and panel members will apply the general principles for accelerated approval 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 (Also see "FDA Will Make Advisory Committee Review Of Accelerated Approvals An Annual Event" - Pink Sheet, 14 February, 2011.).

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 (Also see "Seattle Genetics Files Antibody-Drug Conjugate BLA; Late August Approval Possible" - Pink Sheet, 28 February, 2011.).

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 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 endpoint of objective response after receiving brentuximab, per an independent review facility. The median response duration was 6.7 months. Thirty-two percent of participants had complete remission, with a median duration of 20.5 months.

FDA analysis of the Phase II study of 58 patients with relapsed or refractory systemic ALCL found 86% of participants achieved the primary endpoint 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 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 non-approval, FDA notes that the single-arm design and small size limits the benefit to risk analysis.

"Time-to-event endpoints, 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 notes.

Despite being advised in pre-BLA 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 to 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 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, FDA phrases the question about approval as: "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."

Status Of Confirmatory Trials

The one discussion question for each indication centers on FDA's desire for confirmatory studies to at least be in the planning stage prior to filing an application for accelerated approval.

If ODAC insists on 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, endpoints 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 post-transplant patients. The primary endpoint is progression-free survival. The company expects 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 endpoint to demonstrate clinical benefit.

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

FDA's focus on ensuring the appropriate confirmatory trial is conducted comes in the wake of its proposed withdrawal of accelerated approval of Genentech's Avastin for breast cancer, due to the failure of its confirmatory studies to confirm the magnitude of benefit initially seen (Also see "New Avastin Breast Cancer Study Proposal Not Enough To Save Current Claim, ODAC Concludes" - Pink Sheet, 29 June, 2011.).

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 CD-30-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 by-passing normal cells.

Seattle Genetics is partnered on brentuximab outside the U.S. and Canada with Takeda Pharmaceutical through the latter's oncology company, Millennium. The Japanese pharma paid $60 million up front and agreed to cover 50% of costs to obtain the ex-U.S. commercial rights (Also see "Takeda Partners With Seattle Genetics On Lymphoma Candidate In Pivotal Trials" - Pink Sheet, 15 December, 2009.).

The Adcetris PDUFA date is Aug. 30.

-Cathy Dombrowski (c.dombrowski@elsevier.com )

[Editor's note: This story has been modified to better describe the problems related to Avastin's accelerated approval.]

Adcetris Review Gives ODAC Chance To Apply Principles On Accelerated Approval

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