Onyx Pharmaceuticals' second-generation proteasome inhibitor Kyprolis (carfilzomib) has been approved for treating patients with multiple myeloma who have received at least 2 prior therapies.

Treatment options for patients with relapsed or refractory multiple myeloma broadened as the U.S. Food and Drug Administration (FDA) awarded accelerated approval for Onyx Pharmaceuticals' intravenous agent Kyprolis (carfilzomib) in July.

The second-generation proteasome inhibitor received clearance for treating patients with the disease who have received at least 2 prior therapies, including treatment with Velcade (bortezomib; Millennium Pharmaceuticals) and an immunomodulatory agent such as Celgene's Revlimid (lenalidomide) and Thalomid (thalidomide).

“We've seen treatment for multiple myeloma transformed over the past 12 to 15 years with the introduction of new agents,” says Richard Pazdur, MD, director of the Office of Hematology and Oncology Products in the FDA's Center for Drug Evaluation and Research. Those agents include Velcade as well as Revlimid and Thalomid. However, when these drugs are no longer effective, “this patient population has few if any other meaningful alternatives left to them,” he says.

Under the FDA's accelerated approval process, drugs that fill unmet medical needs in treating serious diseases are evaluated based on surrogate endpoints of clinical trials. After gaining such approvals, drug sponsors must continue with trials to confirm efficacy and safety.

The Kyprolis decision drew on a single-arm phase II trial reported in Blood, which demonstrated an overall response rate of 23% and median duration of response of 7.8 months in 266 patients.

“For a single-arm trial, the only endpoint we will accept is a response rate,” Pazdur points out. “We can't look at overall survival or progression-free survival, because they have the element of the natural history of the disease plus the therapeutic effect. In a single-arm trial, it also is very difficult to ascertain whether adverse effects are the result of the drug or the disease itself.”

Initial results are expected relatively soon from a follow-on randomized phase III trial examining treatment using Revlimid and dexamethasone versus those drugs plus Kyprolis in a similar patient population, with a primary endpoint of progression-free survival. That's one reason for the Oncologic Drugs Advisory Committee's near-unanimous recommendation for accelerated approval for Kyprolis, says Pazdur. Kyprolis also is in numerous other clinical trials, including some for patients with earlier stages of multiple myeloma.

Kyprolis is the third oncology drug to receive accelerated approval in the past year. The process has been controversial, particularly since December 2011, when the FDA revoked approval of Avastin (bevacizumab; Genentech) for treating advanced breast cancer, an indication that was given accelerated approval in 2008. “We do encourage the use of accelerated approvals,” says Pazdur. “There will be increased use of them, especially as we move to more targeted therapies, when we have a greater need to get effective therapies out to patients very early.”