The European Commission has approved panobinostat (Farydak) in combination with bortezomib (Velcade) and dexamethasone for adult patients with relapsed/refractory multiple myeloma following prior treatment with bortezomib and an immunomodulatory (IMiD) agent.
The decision, which was based on a subanalysis of the phase III PANORAMA-1 trial, makes panobinostat the first HDAC inhibitor to gain approval in the European Union. In the pivotal trial, the addition of panobinostat to bortezomib and dexamethasone improved progression-free survival (PFS) by 7.8 months in a subgroup of 147 patients. Panobinostat is approved in the United States and Japan for similar indications in previously treated multiple myeloma.
"With the approval of Farydak in the European Union, we hope to address critically important treatment needs faced by the multiple myeloma community-disease progression and treatment resistance," Bruno Strigini, president, Novartis Oncology, said in a statement. "This milestone, the approval of a first in its class treatment option for patients in need of new therapies, is the result of more than 13 years of dedicated research, which has helped us better understand the development 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 of the study, 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%).
In data from the subanalysis that were presented at the 20th Congress of the European Hematology Associated, the median PFS was 12.5 months in patients treated with panobinostat versus 4.7 months with placebo (HR = 0.47; 95% CI, 0.31-0.72). Additionally, the panobinostat combination demonstrated a higher overall response rate compared with placebo (58.9% vs 39.2%). The complete response (CR) or near CR rate with panobinostat was 21.9% compared with 8.1% for placebo.
In the subpopulation of patients, the most common grade 3/4 non-hematologic AEs with panobinostat versus placebo, respectively, included diarrhea (33.3% vs 15.1%), asthenia/fatigue (26.4% vs 13.7%), and peripheral neuropathy (16.7% vs 6.8%). The most frequent grade 3/4 hematologic adverse events were thrombocytopenia (68.1% vs 44.4%, respectively), lymphopenia (48.6% versus 49.3%), and neutropenia (40.3% versus 16.4%).
"Farydak is a welcome advance for people living with relapsed and/or refractory multiple myeloma in Europe," Philippe Moreau, MD, Department of Hematology, Centre Hospitalier Universitaire de Nantes, France, said in a statement. "Patients with multiple myeloma often relapse or stop responding to treatments; Farydak offers a new mechanism of action, which may improve the effectiveness of response to standard-of-care treatment in patients."
Data on overall survival (OS) from the PANORAMA-1 trial are not yet mature. However, an early assessment showed a trend toward improved survival. In 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
In February 2015, the FDA approved panobinostat in combination with bortezomib and dexamethasone for patients with multiple myeloma following treatment with 2 prior therapies, including bortezomib and an IMiD. This approval was based on a subpopulation of 193 patients, in which bortezomib and an IMiD had been administered along with a median of 2 prior therapies.
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.
Einsele H, Richardson P, Hungria V, et al. Subgroup Analysis by Prior Treatment Among Patients with Relapsed or Relapsed and Refractory Multiple Myeloma in the PANORAMA 1 Study of Panobinostat or Placebo Plus Bortezomib and Dexamethasone. Presented at: 20th Congress of the European Hematology Association (EHA) Vienna, Austria, 2015. Abstract #S102.