Alessandro Riva, MD
The FDA has extended the review period for panobinostat (LBH589) in combination with bortezomib (Velcade) and dexamethasone for patients with previously treated multiple myeloma by 3 months, placing a new decision date in early 2015.
The extension to the review period follows a 5-2 vote against the approval of the novel HDAC inhibitor by the FDA’s Oncologic Drugs Advisory Committee (ODAC) in early November. Novartis submitted the new drug application (NDA) for panobinostat in early 2014. In May, the FDA granted the application a priority review designation.
"We are committed to working with the FDA as they continue to review the LBH589 NDA," Alessandro Riva, MD, the global head of Oncology Development and Medical Affairs at Novartis Oncology, said in a press release. "Multiple myeloma remains an incurable cancer where patients who have relapsed or become resistant to available therapies need new treatment options."
The regulatory submission was based on a 3.9-month extension in progression-free survival (PFS) experienced by patients enrolled in the phase III PANORAMA-1 trial in the panobinostat arm compared with bortezomib and dexamethasone alone. In this trial, the most common grade 3/4 adverse events with panobinostat versus without were thrombocytopenia (56.7% vs 24.7%), diarrhea (25.4% vs 7.8%), and fatigue (24.6% vs 12.6%).
In an FDA review of the data, the agency established a PFS of 2.2 months. Upon review of the data, in addition to findings from the earlier phase II PANORAMA-2 trial that explored panobinostat, ODAC came to the conclusion that the risks associated with the addition of panobinostat to bortezomib and dexamethasone were not outweighed by the benefits. However, when describing the reasoning behind their vote, panelists expressed that the decision was very difficult.
Although the FDA is not required to follow the recommendations of ODAC, the agency rarely goes against the committee.
In the PANORAMA-1 study, 768 patients at a median age of 63 with relapsed or relapsed multiple myeloma were randomized to receive bortezomib and dexamethasone with panobinostat (n = 387) or placebo (n = 381). Study participants had been treated with 1-3 prior therapies, with 48% receiving at least two regimens.
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.
In the panobinostat arm, 44% of patients continued to phase 2 of treatment compared with 50% with placebo. 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.
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 by the FDA, the median PFS was 9.9 months with panobinostat versus 7.7 months with placebo.
In the panobinostat and placebo arms, the objective response rate was 60.7% versus 54.6% (P = .087) and near complete/complete response was 27.6% versus 15.7% (P = .00006), respectively. Median duration of response, time to response, and time to progression, were 13.1 versus 10.9 months, 1.5 versus 2 months, and 12.7 versus 8.5 months, respectively.
Novartis submitted additional data to the FDA in September 2014 for OS. At this point, the median with panobinostat was 38.2 versus 35.4 months with placebo (HR = 0.87; 95% CI, 0.70-1.07; P = .1783). This analysis followed 86.5% of the required events.
The FDA noted that deaths within 30 days of treatment occurred more frequently in the panobinostat arm compared with placebo (8% vs 5.1%). Death as a result of disease progression within the first 30 days following treatment was also higher with panobinostat (7% vs 3.5%).
The most frequently reported (>10%) grade 3/4 adverse events in the panobinostat versus the placebo arm were thrombocytopenia (56.7% vs 24.7%), diarrhea (25.4% vs 7.8%), fatigue (24.6% vs 12.6%), neutropenia (23.8% vs 8.1%), and hypokalemia (19.2% vs 6.5%), according to FDA review.
Grade 3/4 events occurred in 96% of patients treated with panobinostat versus 82% with placebo. Non-fatal serious adverse events occurred in 60% of patients with panobinostat versus 42% with placebo. The most common serious adverse events were pneumonia, diarrhea, thrombocytopenia, and sepsis.
"HDAC inhibitors are of great interest in myeloma, we've had a quite large focus in this area for many years," Kenneth C. Anderson, MD, program director and chief of the Division of Hematologic Neoplasias at the Dana-Farber Cancer Institute and the Giant of Cancer Care in Multiple Myeloma, said in an interview with OncLive before the ODAC hearing. "I do hope most sincerely that this agent is approved. There are no histone deacetylase inhibitors approved in multiple myeloma, so this would be a first in class novel agent. As is true with all medicines, once a drug is approved, they are explored in other ways other doses and other combinations then would otherwise be possible."