Panobinostat Combination Delays Disease Progression in Myeloma

Dr. Paul G. Richardson from the Dana-Farber Cancer Institute

Paul G. Richardson, MD

Combining the pan-deacetylase inhibitor panobinostat (LBH589) with bortezomib (Velcade) and dexamethasone delayed disease progression by 3.9 months over bortezomib and dexamethasone alone in patients with relapsed or relapsed and refractory multiple myeloma, according to results from the phase III PANORAMA 1 trial presented at the 2014 ASCO Annual Meeting.¹Novartis, which manufactures panobinostat, reported that based on the PANORAMA 1 data, the FDA has granted a priority review to the drug.

“These are the first phase III results to show meaningful clinical benefit and provide scientific support for adding LBH589 to bortezomib-based treatment for patients with relapsed or relapsed and refractory multiple myeloma and provide a strong rationale for the use of histone deacetylase inhibitors as part of the therapeutic armamentarium in this setting,” lead author Paul Richardson, MD, clinical program leader and director of Clinical Research at the Jerome Lipper Multiple Myeloma Center at Dana-Farber Cancer Institute, said in a press release.

The oral agent panobinostat is a pan-inhibitor of class I, II, and IV histone and non-histone deacetylase enzymes (HDACs/DACs). Panobinostat increases acetylation of proteins involved in multiple oncogenic pathways, inducing cancer cell death. In preclinical research in multiple myeloma, panobinostat was synergistic with bortezomib and dexamethasone.

PANORAMA 1 involved 768 patients (median age, 63 years) with relapsed or relapsed and refractory multiple myeloma. Approximately two-thirds of patients had relapsed multiple myeloma, with one-third having relapsed and refractory disease. 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. Previous treatments included bortezomib (43%), thalidomide (51%), and lenalidomide (20%). Twenty-five percent of patients had received both bortezomib and immunomodulatory agents. Approximately 57% of patients had autologous stem cell transplantation.

PANORAMA 1 had two treatment phases. In phase 1, patients were randomized to 20 mg of panobinostat (n = 387) or placebo (n = 381) three times per week plus IV bortezomib (1.3 mg/m²on days 1, 4, 8, and 11) during weeks 1 and 2 of eight 3-week cycles. Patients received 20 mg of oral dexamethasone on the same day and the day after bortezomib treatment.

Patients in each arm benefiting from the treatment could proceed to the second stage of the study. In treatment phase II, which consisted of four 42-day cycles, the panobinostat regimen remained constant, while the frequency of bortezomib and dexamethasone dosing was reduced.

Progression-free survival, assessed by modified EBMT criteria, was the primary endpoint of the study. Secondary endpoints included overall survival (OS), overall response rate (ORR), near complete/complete response (nCR/CR) rate, duration of response (DOR), and safety. An independent review committee confirmed PFS and ORR.

One hundred sixty-nine patients (43.7%) in the panobinostat arm and 192 patients (50.4%) in the placebo arm continued to treatment phase 2. In the panobinostat and placebo arms, respectively, the reason for discontinuing treatment after phase I was disease progression (21.2% vs 40.2%), adverse event(s) (33.6% vs 17.3%), subject withdrew consent (8.8% vs 4.7%), treatment duration completed (26.4% vs 26.8%), and death (5.4% vs 4.5%).

At a median follow-up of approximately 125 weeks, the study met its primary endpoint with a 37% decrease in the risk of disease progression in the panobinostat versus placebo arm (12 vs 8.1 months; 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, ORR was 60.7% versus 54.6% (P= .087), and nCR/CR was 27.6% versus 15.7% (P= .00006), respectively. Median DOR, 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.

&ldquo;Adverse events were predictable and generally manageable with supportive measures,&rdquo; Richardson said.

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.

In an interview withOncLive, myeloma expert Andrzej Jakubowiak, MD, PhD, said the PANORAMA 1 results build on the outcome of the phase III VANTAGE 088 trial,²in terms of demonstrating the efficacy of combining a proteasome inhibitor with an HDAC inhibitor in treating multiple myeloma.

In VANTAGE 088, bortezomib was combined with the HDAC-inhibitor vorinostat (Zolinza) in patients with nonrefractory multiple myeloma that was progressing. The combination produced a statistically significant improvement in PFS versus bortezomib alone; however, the actual PFS difference was less than 1 month, and the authors concluded that the clinical relevance of the PFS difference between the two cohorts was unclear.

Jakubowiak, who is a professor of Medicine and director of the Myeloma Program at the University of Chicago, said the PANORMA 1 results should add some clarity.

&ldquo;Both studies proved the same point, which is [that] combining a proteasome inhibitor with an HDAC inhibitor, to a lesser extent with vorinostat, and clearly with panobinostat, improved response rates, depth of response, and duration of response, which translated into progression-free survival superiority. So [this is a] very positive study, a very important study.&rdquo;

Novartis announced that additional results from PANORAMA 1 will be presented at future medical meetings this year, including an oral presentation at the 19th Congress of the European Hematology Association in June. The company also reported that additional global regulatory filings are planned.

References

1. Richardson PG, Hungria VTM, Yoon SS, et al. Panorama 1: A randomized, double-blind, phase 3 study of panobinostat or placebo plus bortezomib and dexamethasone in relapsed or relapsed and refractory multiple myeloma.J Clin Oncol. 2014;32:5s (suppl; abstr 8510).
2. Dimopoulos M, Siegel DS, Lonial S, et al. Vorinostat or placebo in combination with bortezomib in patients with multiple myeloma (VANTAGE 088): a multicentre, randomised, double-blind study.Lancet Oncol. 2013;14(11):1129-1140.

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