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In what was described as a very difficult decision, ODAC voted 5-2 against the accelerated approval of the HDAC inhibitor panobinostat in combination with bortezomib and dexamethasone as a treatment for patients with multiple myeloma who have received at least one prior therapy.
Deborah Armstrong, MD
In what was described as a very difficult decision, the FDA’s Oncologic Drugs Advisory Committee (ODAC) voted 5-2 against the accelerated approval of the HDAC inhibitor panobinostat (Farydak) in combination with bortezomib (Velcade) and dexamethasone as a treatment for patients with multiple myeloma who have received at least one prior therapy.
By voting against the approval of the drug, the committee asserted that the benefits of the panobinostat combination did not outweigh the risks. The new drug application was based on data from the phase III PANORAMA-1 trial. By investigator-assessed criteria, the addition of panobinostat to bortezomib and dexamethasone improved progression-free survival (PFS) by 3.9 months compared with bortezomib and dexamethasone alone. By independent review, panobinostat improved PFS by 2.2 months, according to the FDA.
Novartis submitted the new drug application (NDA) for panobinostat in early 2014. In May, the FDA granted the application a priority review designation. The ODAC advisory meeting was established in October.
"The problem I see here, is that the therapy has a PFS benefit but there's nothing else to hang our hat on," Deborah Armstrong, MD, ODAC chairperson and an associate professor of oncology at the Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins, said during the meeting. "I think we struggle when we don't see an overall survival benefit."
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). 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 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. The final OS data for the trial are not yet mature. At an interim analysis, median OS was 33.6 and 30.4 months in the panobinostat and placebo arms, respectively (HR = 0.87; 95% CI, 0.69-1.10; P = .2586).
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%).
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.
"First, this was a very difficult decision because I think this agent does have some activity in this disease and can be useful in this disease," James E. Liebmann, MD, ODAC panelist from the UMass Memorial Medical Center, said after casting a vote against the approval. "I think the toxicity outweighed the marginal benefit in progression-free survival. I hope that the drug is not given up on."
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.
ECG changes following treatment occurred in 64% of patients treated with panobinostat versus 42% with placebo. New T-wave changes were 40% and 18% and ST-segment depressions were 22% and 4%, for panobinostat and placebo, respectively. QT prolongation was similar in both arms.
"PFS was not the question, there's clearly a benefit," Richard Pazdur, MD, director of the Office of Hematology and Oncology Products in the FDA’s Center for Drug Evaluation and Research, said during the event. "The question is what is the magnitude of benefit and does it warrant the toxicity."
The FDA is not required to follow the recommendations of ODAC; however, the agency rarely goes against the committee. The FDA is scheduled to make a decision regarding the approval of panobinostat later this month.