FDA Approves Panobinostat for Multiple Myeloma

Richard Pazdur, MD

The FDA has approved panobinostat (Farydak) in combination with bortezomib (Velcade) and dexamethasone for patients with multiple myeloma who receive prior treatment with bortezomib and an immunomodulatory (IMiD) agent, based on a prespecified subgroup analysis from the PANORAMA-1 trial.

The prespecified analysis looked specifically at 193 patients from the phase III study who were treated with bortezomib and an IMiD. In this population, the median progression-free survival (PFS) with the panobinostat combination was 10.6 months versus 5.8 months with placebo (HR = 0.52; 95% CI, 0.36-0.76). Additionally, the tumor shrinkage rate with panobinostat was 59% versus 41% with bortezomib and dexamethasone alone.

Panobinostat was approved with a Boxed Warning regarding severe diarrhea and severe and fatal cardiac events, arrhythmias and electrocardiogram (ECG) changes. As a result of these side effects, the drug has also been approved along with a Risk Evaluation and Mitigation Strategy (REMS).

“Farydak has a new mechanism of action that distinguishes it from prior drugs approved to treat multiple myeloma, making it a potentially attractive candidate agent for the treatment of multiple myeloma,” Richard Pazdur, MD, director of the Office of Hematology and Oncology Products in the FDA’s Center for Drug Evaluation and Research, said in a release. “Farydak’s approval is particularly important because it has been shown to slow the progression of multiple myeloma.”

The PANORAMA-1 study randomized 768 patients at a median age of 63 with relapsed or relapsed multiple myeloma to receive bortezomib and dexamethasone with panobinostat (n = 387) or placebo (n = 381). Treatment was administered in two 24-week phases.

In phase 1, panobinostat was administered orally at 20 mg 3 times a week for two weeks in a 3-week cycle. Bortezomib was administered intravenously at 1.3 mg/m² twice weekly for 2 weeks along with 20-mg dexamethasone. Patients who responded to therapy or had stable disease without grade 2 or higher adverse events in phase 1 continued to phase 2, where the bortezomib schedule was reduced to 2 doses every 3 weeks. Overall, 44% of patients in the panobinostat arm continued to phase 2 of treatment compared with 50% with placebo.

Study participants had been treated with 1-3 prior therapies, with 48% receiving at least two regimens. The most common prior treatments in the panobinostat arm were corticosteroids (89.7%), melphalan (80.1%), stem cell transplant (55.6%), thalidomide (53%), cyclophosphamide (47%), and bortezomib (43.7%).

Treatment with the 3-drug panobinostat regimen improved the primary endpoint of PDS by 3.9 months compared with bortezomib and dexamethasone alone. The median PFS by investigator assessment was 12 months in the panobinostat arm compared with 8.1 months with placebo (HR = 0.63; 95% CI, 0.52-0.76; P <.0001). By independent review, the median PFS was 9.9 months with panobinostat versus 7.7 months with placebo (HR = 0.69; 95% CI, 0.58-0.83).

By investigator assessment, the overall response rate (ORR) was 61% with panobinostat versus 55% in the placebo arm. The median duration of response with panobinostat was 13.1 versus 10.9 months with placebo. By independent review, the ORR was 64% with panobinostat and 54% with placebo. The complete response rate was 12% versus 7% and the duration of response was 11.8 versus 9.7 months, for panobinostat and placebo, respectively.

Prior to the approval, the FDA extended the review period for the HDAC inhibitor by 3 months following a 5-2 vote against the approval from the FDA’s Oncologic Drugs Advisory Committee (ODAC). The majority of concerns from the advisory panel related to long-term survival data and the side effect profile.

Serious adverse events (AEs) were more common with panobinostat versus placebo. The most common for panobinostat and placebo, respectively, were thrombocytopenia (7.3% vs 2.2%), diarrhea (11.1% vs 2.4%), fatigue (6.7% vs 1.6%), pneumonia (18.1% vs 14.2%), and sepsis (6% vs 3%).

New data presented at the 2014 ASH Annual Meeting shed light on the long-term benefits of the panobinostat combination. At this analysis, the median OS was 38.2 and 35.4 months, respectively, for the panobinostat and control arms (HR = 0.87; 95% CI, 0.70-1.07; P = .1783).

Among patients who completed treatment phase 1 only, the median PFS was 14.7 months in the panobinostat arm compared with 12.1 months in the control group. ORR was 85.2% versus 80.2%, respectively, with near complete response (nCR)/CR rates of 46.2% versus 25.0%. In phase 2, the median PFS was 17.6 months in the panobinostat arm compared with 15.6 months in the control group. The ORR was 88.2% versus 91.2%, respectively, with nCR/CR rates of 52.9% versus 38.2%.

A higher number of patients discontinued treatment in the panobinostat arm compared with placebo as a result of adverse events or consent withdrawal (34% vs 17%). However, 40% of patients in the placebo arm stopped therapy as a result of progression compared with 21% in the panobinostat arm.

In the overall PANORAMA 1 population, the most frequently reported grade 3/4 AEs in the panobinostat versus the placebo arm were thrombocytopenia (67.4% vs 31.4%), lymphopenia (53.2% vs 39.8%), neutropenia (34.5% vs 11.4%), and diarrhea (25.5% vs 8%). Toxicity resulted in treatment discontinuation in 36% and 20% of patients in the panobinostat and placebo arms, respectively. The all-cause death rate was 8% and 5%, respectively.

"Farydak represents an exciting agent with a new mechanism of action that is part of a promising class of drugs in this setting," study investigator Paul Richardson, MD, Clinical Program Leader and Director of Clinical Research, Jerome Lipper Multiple Myeloma Center at Dana-Farber Cancer Institute, said in a release. "Importantly, Farydak has been shown to improve progression-free survival in relapsed multiple myeloma patients who have received at least two prior regimens, including bortezomib and an IMiD, which is an area of particular unmet medical need."

Clinical trials continue to investigate the safety and efficacy of panobinostat across a variety of settings. A phase I/II study is exploring the combination of lenalidomide, bortezomib, and dexamethasone plus panobinostat as a treatment for transplant eligible newly diagnosed patients with multiple myeloma. Additionally, panobinostat is being explored in combination with other proteasome inhibitors, namely carfilzomib.