Novartis’ Panobinostat Review Panel Could Scrutinize Survival Data
This article was originally published in The Pink Sheet Daily
Executive Summary
FDA’s Oncologic Drugs Advisory Committee is slated to meet on Nov. 6 to consider Novartis’ HDAC inhibitor panobinostat for relapsed multiple myeloma and may also look closely at dosing issues.
FDA’s upcoming advisory committee review of Novartis AG’s HDAC inhibitor panobinostat in relapsed/refractory multiple myeloma will be a test of a novel mechanism for the disease and may include careful analysis of survival data and dosing in relation to side effects.
The agency’s Oncologic Drugs Advisory Committee will consider the filing on Nov. 6. The application was supported by the pivotal PANORAMA I study of the drug in combination with Takeda Pharmaceutical Co. Ltd.’s Velcade (bortezomib) and dexamethasone versus Velcade/dexamethasone/placebo in 768 patients. Data were fully reported by Jesus San-Miguel of the Clínica Universidad de Navarra-CIMA in Pamplona, Spain, et. al in The Lancet Oncology in October.
Panobiniostat is one of a number of oncology drugs that Novartis feels have high potential and could drive the future after generics of the blockbuster leukemia drug Gleevec (imatinib) become available in 2015 and in the wake of other patent expirations (Also see "As Sun Sets On Gleevec, Novartis Looks To New Horizons In Oncology" - Pink Sheet, 19 Nov, 2012.).
Writing in an editorial in The Lancet Oncology accompanying trial results, Mayo Clinic’s S. Vincent Rajkumar noted that the PANORAMA I study is the “first to report on a new class of drugs with meaningful clinical activity in myeloma in nearly 15 years.”
“For the first time in myeloma we have a drug that shows a meaningful clinical benefit without having single-agent activity on its own,” emphasizing the “value of targeted treatment designed by good basic science and rationale. Although it is gratifying to have a drug from a new class, we are even more optimistic about the future,” Rajkumar said.
In the study, the drug demonstrated almost a four-month improvement in the progression-free survival primary endpoint (11.99 months versus 8.08 months). Data for overall survival, a secondary endpoint, are not yet mature, but at the time of this analysis, there was no significant difference between study arms. Overall response rate data were mixed. There was no significant difference in ORR 60.7% panobinostat vs. 54.6%, though there was a significantly higher complete and near complete response rate for patients on panibinostat (27.6% vs. 15.7%).
Rajkumar acknowledged that it is “puzzling that the proportion of patients who had an overall response did not differ between the two treatment groups.”
“Thus, the vast majority of patients who were refractory to the effects of proteasome inhibition probably did not benefit from the addition of panobinostat; rather, those who were sensitive to bortezomib had better quality of responses. This finding confirms the view that resistance to proteasome inhibitors is not only due to the presence of an alternative pathway, but is rather more fundamental and needs more study,” Rajkumar et. al. wrote.
Survival May Take Center Stage
Sagient Research analyst Robert Jeng is expecting OS to be an issue at the advisory committee meeting, especially after the recent failure of Amgen Inc.’s second-generation proteasome inhibitor Kyprolis (carfilzomib) to achieve the primary overall survival endpoint in the FOCUS refractory myeloma study.
Results were presented at the European Society of Medical Oncology meeting in September. Kyprolis was approved in 2012 and FOCUS – one of two Phase III studies – was designed according to guidance from the European Medicines Agency and was aimed at securing global approval (Also see "Onyx’s Myeloma Drug Kyprolis Fits ODAC’s View On Accelerated Approval" - Pink Sheet, 25 Jun, 2012.).
In the case of the PANORAMA I study of panobinostat, in which OS was the secondary endpoint, the “K-M [Kaplan-Meier] curve suggests only a separation at the median, but not really even a trend towards improved OS,” said Robert Jeng, Sagient Research analyst.
It seems likely that the data will be contrasted with results for Celgene Corp.’s second generation immunomodulator Pomalyst (pomalidomide). In the MM-003 study of relapsed myeloma, Pomalyst demonstrated a 4.6 month improvement in overall survival when used in combination with dexamethasone, though Jeng notes that trial involved a slightly different patient population.
However, Sagient analysts believe that panobinostat nevertheless has a high likelihood of getting approved – their BioMedTracker database suggests an 87% chance for success – due to the clinically meaningful improvement in PFS of 3.9 months.
Improvement in progression-free survival “might seem small,” Rajkumar said in his editorial, but “it will probably increase as we learn how to best use the drug, and optimise the dose and dosing schedule.”
‘Need For Monitoring And Dose Adjustment’
FDA’s committee meeting may also feature scrutiny about negative effects on quality of life, based on the comments in Rajkumar’s editorial. About one quarter of patients had severe Grade 3/4 side effects, or three times higher than the control group, he pointed out.
“This finding emphasizes the need for monitoring and dose adjustment of panobinostat, probably from the start of treatment,” Rajkumar wrote.
Rajkumar also expressed concern about the dosing schedule for bortezomib in the trial, as the drug was given intravenously twice-weekly, whereas a once-weekly subcutaneous dose is a newer and more preferred way of administering the drug with a much lower rate of peripheral neuropathy.
“I expect panobinostat to become an important component of myeloma treatment. However, it will probably be approved with a recommended dosing schedule that is not realistic,” Rajkumar wrote.
Most patients will probably be treated with a different schedule than the one on the prescribing label, he said.
ODAC’s review of panobinostat will take place the same day it considers another product with strong approval prospects – Rockwell Medical Inc.’s Triferic (ferric pyrophosphate citrate) for treating iron loss or iron deficiency in patients on dialysis for end-stage kidney disease, as a means of reducing the need for erythropoiesis stimulating agents (see related story, (Also see "Rock-Solid Triferic Heads Toward ODAC Review" - Pink Sheet, 9 Oct, 2014.)).