The FDA has scheduled an ODAC advisory hearing to discuss the NDA for panobinostat in combination with bortezomib and dexamethasone for patients with multiple myeloma who have received at least one prior therapy.
Alessandro Riva, MD
The FDA has scheduled an ODAC advisory hearing to discuss the new drug application (NDA) for panobinostat (LBH589) in combination with bortezomib (Velcade) and dexamethasone for the treatment of patients with multiple myeloma who have received at least one prior therapy. The meeting will be held on November 6, 2014.
The FDA initially granted a priority review designation to the NDA for panobinostat in May 2014, based on data from the phase III PANORAMA-1 trial. Under the priority review program, the FDA is scheduled to make a decision on the drug in November 2014. In the phase III PANORAMA-1 study, combining the pan-deacetylase inhibitor panobinostat with bortezomib and dexamethasone improved progression-free survival (PFS) by 37% over bortezomib and dexamethasone alone in patients with relapsed or relapsed and refractory multiple myeloma.
"The majority of people living with multiple myeloma eventually will stop responding to treatment or relapse, which underscores the need for new treatment options," Alessandro Riva, MD, the global head of Novartis Oncology Development and Medical Affairs, said in a statement when results from the PANORAMA-1 study were published inLancet Oncologyin September.
The PANORAMA-1 study enrolled 768 patients at a median age of 63 with relapsed or relapsed multiple myeloma. Patients with bortezomib- and primary-refractory disease were excluded from the trial. Study participants had been treated with one to three prior therapies, with 48% receiving at least two regimens.
Patients in the study were randomized to 20 mg of panobinostat (n = 387) or placebo (n = 381) in a 21 day cycle. Panobinostat was administered orally on days 1, 3, 5, 8, 10, and 12. Intravenous bortezomib was administered at 1.3 mg/m2 on days 1, 4, 8, 11 and 20-mg dexamethasone was given on days 1, 2, 4, 5, 8, 9, 11, and 12.
At a median follow-up of approximately 125 weeks, the median PFS was 11.99 months with panobinostat versus 8.08 months with bortezomib and dexamethasone alone (HR = 0.63; 95% CI, 0.52-0.76;P<.0001). The final OS data for the trial are not yet mature. At an interim analysis, median OS was 33.64 and 30.39 months in the panobinostat and placebo arms, respectively (HR = 0.87; 95% CI, 0.69-1.10).
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.
"The PANORAMA-1 results provide strong evidence of the potential impact LBH589 could have for the multiple myeloma community," Riva said. "We are committed to working with regulatory authorities to make this treatment available to patients as soon as possible."
The most frequently reported grade 3/4 adverse events 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.
"There was a higher proportion of GI toxicities in the panobinostat arm compared to the placebo arm, which where mostly manageable," Andrzej Jakubowiak, MD, PhD, professor of medicine, director, Myeloma Program, University of Chicago Medicine, said in an interview withTargeted Oncologywhen the data were presented at the 2014 ASCO Annual Meeting. "There was a higher rate also of thrombocytopenia and other hematological toxicities; again, overall manageable, and was eventually no impact on superior outcomes."