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Encouraging Results for Panobinostat from PANORAMA1: A Phase 3 Clinical Trial

Value-Based Care in Myeloma - Multiple Myeloma
Caroline Helwick

The recently published results of the multicenter, randomized, double-blind Panobinostat Oral in Multiple Myeloma 1 (PANORAMA1) clinical trial suggest that patients with relapsed or refractory multiple myeloma may derive benefit from the new class of histone deacetylase (HDAC) inhibitors (San-Miguel JF, et al. Lancet Oncol. 2014;15:1195-1206).

“Their study is the first to report on a new class of drugs with meaningful clinical activity in myeloma in nearly 15 years,” pointed out Vincent Rajkumar, MD, Professor of Medicine at the Mayo Clinic, Rochester, MN, in an editorial accompanying the article.

Panobinostat is a potent, oral HDAC inhibitor that has shown synergistic antitumor activity when combined with bortezomib (Velcade) and dexamethasone (Decadron). HDAC inhibitors could help overcome the acquired resistance to proteasome inhibitors, such as bortezomib, by blocking the aggresome pathway, which is an escape route for myeloma cells as they evade the ubiquitin proteasome pathway, Dr Rajkumar said.

“Although the improvement in progression-free survival might seem small, it will probably increase as we learn how best to use the drug and optimize the dose and dosing schedule,” Dr Rajkumar maintained. “The benefit of panobinostat might be even greater than that reported in this study.”

Key Findings from PANORAMA1

The PANORAMA1 trial enrolled 768 patients from 215 centers in 34 countries. All patients had relapsed or refractory multiple myeloma, although patients with disease refractory to bortezomib were excluded. The patients were randomized to panobinostat or to placebo, both in combination with bortezomib and dexamethasone, for a maximum of 12 cycles. Patients were followed for a median of approximately 6 months.

Median progression-free survival (PFS), the primary end point, was significantly longer in the panobinostat group (11.99 months) than in the placebo group (8.08 months), with a 27% reduction in the risk of disease progression (P <.001). The 2-year PFS rates were 20.6% in the panobinostat group and 8.4% in the placebo group.

For patients who achieved a complete response or near-complete response, the median PFS times were 19.38 months in the panobinostat group and 15.21 months in the placebo group. The addition of panobinostat also led to longer median duration of response and longer time to first progression, relapse, or death from myeloma.

The investigators deemed this activity in the panobinostat arm “clinically relevant and significant,” and noted that efficacy in the placebo arm was similar to that seen in historical controls. The effect was consistent across all subgroups, “suggesting benefit irrespective of previous treatment or baseline characteristics,” including the previous number of treatments and previous treatment with bortezomib.

The overall survival data were not mature, but at the time of this analysis, the median survival times were 33.64 months with panobinostat and 30.39 months with placebo. Although this 13% risk reduction was not significant (P = .26), significantly more complete or near-complete responses were seen in the panobinostat group than in the placebo group (27.6% vs 15.7%, respectively; P = .006).

According to Dr Rajkumar, the similar overall response rates but greater deep response rates with panobinostat suggest a differential sensitivity to the drug. Patients whose disease is refractory to proteasome inhibitors probably did not benefit from the addition of panobinostat, whereas patients with disease sensitivity to bortezomib had higher-quality responses, he suggested.

Serious adverse events were reported by 60% of patients receiving panobinostat versus 42% of patients receiving placebo. Neuropathy was not increased in the experimental group, but the triple combination of panobinostat, bortezomib, and dexamethasone was associated with more diarrhea, thrombocytopenia, asthenia, and fatigue. Dr Rajkumar suggested that dose adjustments and monitoring may therefore be important when panobinostat is used in the clinic.

San-Miguel and colleagues noted in their article that the results with panobinostat are better than the results seen with another HDAC inhibitor, vorinostat (Zolinza), which when added to bortezomib did not produce a clinically relevant increase in PFS (<1 month). “Panobinostat is a pan-deacetylase inhibitor with more potent in vitro inhibitory activity than vorinostat,” the investigators pointed out.

They concluded that PANORAMA1 is the first phase 3 clinical trial to show a benefit for a 3-drug versus a 2-drug combination in patients with relapsed and/or refractory myeloma.

“Our results are noteworthy within the context of the existing treatment landscape….This combination provides an important new platform for combining agents in this setting, and the toxicity profile is expected to improve with the use of subcutaneous bortezomib given once per week,” they suggested.

Dr Rajkumar agreed that subcutaneous bortezomib once weekly will ameliorate the neurotoxicity of this regimen, and this approach is likely to be used in the clinic.

“I expect panobinostat to become an important component of myeloma treatment,” he concluded.

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Last modified: May 20, 2015
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