FDA Gives Thumbs Up to Carfilzomib for Multiple Myeloma

Roxanne Nelson

June 21, 2012

June 21, 2012 — The Oncologic Drugs Advisory Committee of the US Food and Drug Administration (FDA) has voted to unanimously recommend the accelerated approval of carfilzomib (Onyx Pharmaceuticals) for the treatment of patients with relapsed or refractory multiple myeloma.

When asked whether the risk/benefit assessment is favorable for carfilzomib in the treatment of patients with relapsed or refractory multiple myeloma who have received at least 2 previous lines of therapy, including a proteasome inhibitor and an immunomodulatory agent, the panel voted 11 to 0, with 1 abstention.

The positive response was largely based on the urgent need for more therapeutic options in this population.

Patients with end-stage multiple myeloma who have been heavily pretreated have few, if any, viable options, said advisory panel member Mikkael Sekeres, MD, MS, associate professor of medicine at the Cleveland Clinic Taussig Cancer Institute in Ohio. "Today, we voted to make one option available to them. The response rate was acceptable for this population, and safety was also acceptable," he said.

"My great hope is that the potentially confirmatory study shows a magnitude of progression-free survival at least as good as we're seeing today and an overall survival advantage," he added.

There is no standard of care and we need additional novel agents in this disease, said Kenneth Anderson, MD, director of the Jerome Lipper Multiple Myeloma Center and LeBow Institute for Myeloma Therapeutics at the Dana-Farber Cancer Institute in Boston, Massachusetts.

"We have unmet medical needs and we have patients who are relapsed. In that setting, patients live only a very short time — in the order of 6 to 10 months," said Dr. Anderson, who was not a panel member. "In addition, patients start with morbidities such as neuropathy; during the course of therapy, this can limit our ability to use available agents."

Clinical Data

Carfilzomib is a second-generation proteasome inhibitor. It consists of an epoxyketone pharmacophore attached to a tetrapeptide backbone. In vitro studies have shown that it maintains activity against tumor cells that have become resistant to bortezomib (Velcade), the only currently approved proteasome inhibitor.

The efficacy and safety of carfilzomib has been demonstrated in 4 phase 2 studies that involved 526 patients and a safety database that involved 768 patients enrolled in phase 1 and phase 2 studies.

The pivotal trial central to the New Drug Application is a multicenter single-group phase 2 study known as 003A1. It was designed to evaluate carfilzomib in patients with relapsed or refractory myeloma with limited therapeutic options, and enrolled patients who had been exposed to available antimyeloma agents and who were refractory to their last line of therapy.

The 003A1 trial enrolled 266 patients and was conducted at more than 30 sites in Canada and the United States. Patients received intravenous carfilzomib 20 mg/m² over 2 to 10 minutes on days 1, 2, 8, 9, 15, and 16 in cycle 1, with escalation to 27 mg/m² in subsequent cycles, as tolerated, for up to twelve 28-day cycles.

Upon completion, continued carfilzomib therapy was offered in extension study 010.

The primary efficacy end point was overall response rate, determined by an Independent Review Committee. For all treated patients, the overall response rate was 22.9%. The median duration of response was 7.8 months. Response was maintained for at least 6 months in 62% of responders and at least 12 months in 27% of responders.

Concern About Toxic Effects

There is concern about severe toxic effects, including death, associated with this agent. In a briefing document prepared for the advisory committee, the FDA cautioned that because carfilzomib produced an overall response rate of only 22% in the primary efficacy study, "it may not provide an advantage over available therapy."

Cardiac toxicity contributed to the discontinuation of carfilzomib in the study, the FDA pointed out in the briefing document. There were also significant pulmonary and, to a lesser extent, hepatic toxic effects, in addition to adverse effects associated with carfilzomib infusion that need further characterization, according to the document. Because the pathogenesis of these toxic effects is not understood, "the risks of carfilzomib may not outweigh its benefits."

Several of the panel members expressed concern about toxicity and efficacy. James Neaton, PhD, from the University of Minnesota School of Health in Minneapolis, abstained from voting, explaining that this is not his area of expertise. However, he said that he is very "nervous about the outcome" as it was assessed in this study, about being able to reliably address risk/benefit."

Michael Menefee, MD, assistant professor of hematology and oncology at the Mayo Clinic in Jacksonville, Florida, explained that he is also nervous about study, for some of the same reasons cited by Dr. Neaton. However, he voted yes, stating that "I do think this drug is beneficial to this patient population given the limited therapeutic options available." He noted that there are mechanisms in place to rescind approval if safety issues persist.

Some of the panel members stated that carfilzomib offers a clinical benefit with an acceptable safety profile; others noted that the risk profile is more neutral rather than negative.

Jane Zones, PhD, a former board member of Breast Cancer Action, believes that the benefit outweighs the risk, but feels that the data are "soft."

"I am looking forward to seeing the phase 3 data," she said. "I know it is difficult to carry out this kind of research in this population, but I would like to see something that is a little more solid."

Ongoing Phase 3 Trials

There are 2 ongoing phase 3 trials. The 009-ASPIRE trial is intended to provide confirmatory evidence of the clinical benefit of carfilzomib (20/27 mg/m²) and support the expansion of the product-label indication for the combination of carfilzomib, lenalidomide, and dexamethasone in patients with relapsed multiple myeloma. The primary end point is progression-free survival, and the target enrollment of 780 patients was achieved earlier this year. It is expected that the final analysis will be available in mid-2014.

The 011-FOCUS trial, which was designed in accordance with recommendations from the European Medicines Agency, is comparing carfilzomib (20/27 mg/m²) and a corticosteroid agent plus oral cyclophosphamide. The primary efficacy end point is overall survival, target enrollment is 302 patients, and the final analysis is expected in mid-2014.

In addition, other studies are exploring use of the drug in a first-line setting in patients newly diagnosed with multiple myeloma. Interim data from one such study, presented a few days ago at the European Hematology Association annual meeting, as reported by Medscape Medical News, showed a very high response rate. Carfilzomib in combination with lenalidomide (Revlimid) plus dexamethasone induced a stringent complete response in 61% of patients after 8 cycles.

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