The existence of a fully enrolled, Phase III confirmatory trial helped seal the deal for an FDA advisory committee endorsement of Onyx Pharmaceuticals Inc.’s investigational multiple myeloma drug Kyprolis (carfilzomib) June 20.

The Oncologic Drugs Advisory Committee voted 11-0, with one abstention, that carfilzomib had a favorable risk/benefit assessment for treatment of patients with relapsed and refractory multiple myeloma who have received at least two prior lines of therapy, including a proteasome inhibitor and an immunomodulatory agent.

Onyx is seeking accelerated approval for the proteasome inhibitor based upon a single-arm, 266-patient Phase II study. The overall response rate in the study was 22.9%, with a median duration of response of 7.8 months.

Committee members said they were encouraged by the evidence of clinical activity seen in the single-arm study, and carfilzomib’s safety profile appeared acceptable for a drug intended for use in a heavily pretreated patient population that has few viable therapeutic options.

Several panelists pointed to Onyx’s current and planned confirmatory trials as a reason why they felt confident in recommending accelerated approval now on the basis of single-arm study rather than the preferred randomized design.

Given the difficulty encountered by some sponsors in conducting and completing confirmatory trials for drugs receiving accelerated approval, ODAC has supported requiring sponsors to conduct two post-approval confirmatory trials, rather than one, and said such trials should be ongoing or in the final stage of development at the time accelerated approval is granted Also see "Accelerated And Accompanied: Oncology Drugs Should Use Randomized Trials, FDA Panel Says" - Pink Sheet, 8 February, 2011..

“I feel that this application fulfilled the criteria for what we should see for accelerated approval – an unmet need, a drug with, I felt given the setting, a good response rate and certainly a very good duration of response,” committee chairman Wyndham Wilson, National Cancer Institute, said. “The toxicity profile was really very reasonable given the degree of prior therapy here.”

The fact that the 792-patient, randomized ASPIRE confirmatory trial has been fully enrolled “is in Onyx’s favor,” Wilson added.

A second confirmatory trial is expected to start enrolling soon.

“I think it’s important that there is a Phase III trial that’s ongoing and one that’s due to start,” committee member Ralph Freedman, M.D. Anderson Cancer Center, agreed.

Committee member Deborah Armstrong, Johns Hopkins University, said she believed the clinical responses seen in the single-arm Phase II trial “are real and, probably even more important, are meaningful in this population.”

With one confirmatory trial having completed accrual and a second study planned in an earlier treatment setting, “I don’t know that we’ll actually get true confirmation in this population ever, but I think based on what’s available for these patients … this is definitely improving the therapeutic armamentarium.”

The panel’s positive recommendation significantly bolsters the chances that FDA will grant accelerated approval by the July 27 user fee date rather than awaiting results from one or more confirmatory trials.

Comparisons To The Velcade Experience

Onyx’s reliance upon a single-arm study was a risky regulatory strategy given the expressed preference of ODAC and FDA for randomized trials to support accelerated approval whenever possible, with an exception made for small patient populations or where drug activity is high.

FDA’s briefing documents released ahead of the meeting suggested that Onyx might not be able to meet the latter hurdle, given that the ORR was “only” 22% and there were serious cardiac, pulmonary and hepatic toxicities seen in the pivotal trial. The document pointed to the limitations of a single-arm study both in terms of demonstrating benefit over other available therapies in a relapsed/refractory population and in determining whether the adverse events are drug-related Also see "Safety Concerns Weigh On Onyx’s Carfilzomib In Multiple Myeloma" - Pink Sheet, 18 June, 2012..

However, the agency’s briefing documents were more negative in tone than were FDA senior officials’ comments at the meeting, particularly those of Office of Hematology and Oncology Products Director Richard Pazdur.

Pazdur acknowledged the shortcomings of single-arm trials but sought to put the carfilzomib data into perspective as it related to the only other proteasome inhibitor approved for relapsed/refractory multiple myeloma. Millennium Pharmaceuticals Ltd.’s Velcade (bortezomib) received accelerated approval in 2003; it later converted to regular approval.

“One of the things that we had confidence in is … the response rate that’s being presented here is quite similar to what we saw with bortezomib; in fact it’s in a more refractory disease population,” Pazdur said. “Bortezomib went on in confirmatory trials to show clinical benefit.”

Unlike other applications for accelerated approval based upon single-arm trials, “we already have a ... completely enrolled randomized study, so it gives us a lot of confidence in this,” he said.

The fully enrolled, Phase III ASPIRE study is being conducted under a Special Protocol Assessment. The randomized trial is testing a combination of lenalidomide (Celgene Corp.’s Revlimid) and dexamethasone, with or without carfilzomib, in 792 relapsed multiple myeloma patients who received one to three prior therapies. The primary endpoint is progression-free survival, and a final analysis is expected in mid-2014.

Onyx recently announced plans for a second confirmatory study, ENDEAVOR, which is slated to begin enrolling patients in mid-2012. The study will evaluate the combination of carfilzomib and low-dose dexamethasone against a bortezomib/dexamethasone combination.

The company also has an ongoing study, FOCUS, aimed at gaining global approval. The randomized trial is comparing carfilzomib to corticosteroids and optional low-dose cyclophosphamide in relapsed/refractory patients who have received three or more lines of therapy. The primary efficacy endpoint is overall survival. More than half of the targeted 302 patients had been enrolled as of March 2012; final analysis is projected for mid-2014.

Onyx’s Kyprolis Sails Through FDA Panel, Boosted By Confirmatory Trial Plans

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