Kantar Health Blog

Panobinostat leads the way for novel MOAs in multiple myeloma

by Neesha Suvarna | Jun 2, 2014
Neesha Suvarna

By Len Kusdra and Neesha Suvarna

To date, the field of myeloma therapy has been dominated by proteasome inhibitors and immunomodulators (IMiDs). The past two years had two new entrants into the relapsed/refractory setting: Kyprolis® (carfilzomib, Onyx/Amgen), a proteasome inhibitor that was approved in 2012, and Pomalyst® (pomalidomide, Celgene) a second-generation IMiD approved in 2013. Both agents were approved for patients that had received two prior therapies, including Velcade® (bortezomib, Millennium/Takeda) and an immunomodulator; in the case of Kyprolis the immunomodulator was either thalidomide or Revlimid® (Celgene). The future of myeloma seems promising, with multiple novel targeted therapies that are currently in development; one of these reported data at ASCO 2014.  

Panobinostat (LBH589) is a novel, multitargeted pan-deacetylase inhibitor developed by Novartis. In a Phase Ib trial, panobinostat in combination with Velcade plus dexamethasone (Veldex) was well-tolerated and achieved a 62% clinical benefit rate (six PR and two MR) in patients who were refractory to prior Velcade-based therapy.[1] This formed the basis of a randomized Phase III trial (PANORAMA-1; NCT01023308) that evaluated panobinostat plus VelDex versus placebo plus VelDex in 768 previously treated patients with relapsed/refractory multiple myeloma.[2] The trial was designed in two parts and conducted in 215 centers across 35 countries (including Europe and Asia). In treatment phase 1 (TP1), patients received oral panobinostat at 20 mg or placebo three times a week in combination with  Velcade at  1.3 mg/mon Days 1 and 4 and oral dexamethasone at 20 mg on Days 1-2 and Days 4-5 each week, in a  “two-week-on/one-week-off” schedule. Patients who achieved response in TP1 had the option to proceed to treatment phase 2 (TP2), whereby the panobinostat schedule was maintained but Velcade and dexamethasone administration was reduced to once per weekly cycle. The primary endpoint was progression-free survival (PFS), with response assessed by modified European group for blood and marrow transplantation (EBMT) score. Other endpoints included overall survival (OS), overall response rate (ORR), complete response/near complete response rate (CR/nCR) rate, duration of response (DOR), time to progression (TTP) and safety.  

Eligible patients were randomized to the panobinostat/VelDex arm (n=387) or the VelDex-alone arm (n=381). The trial accrued patients who had relapsed on prior therapies, and the majority of patients had received prior Velcade (43.7% in panobinostat/VelDex arm versus 42.3% in VelDex arm). About one-quarter of the patients in each arm had received prior Velcade and IMiD (24.3% in panobinostat/VelDex arm versus 26% in VelDex arm). The trial met its primary endpoint and demonstrated a 3.9-month PFS improvement with panobinostat/VelDex compared to VelDex alone (12 months versus 8.1 months; p<0.0001; HR 0.63, 95% CI: 0.52-0.76). Subgroup analysis also demonstrated that the efficacy was better in patients who had received prior Velcade regimens (almost 40% of the patients). Numerical improvements in ORR were observed in the panobinostat/VelDex arm (60.7%) compared to the VelDex arm (54.6%); however, this trend did not approach significance. At the interim analysis for OS (134 events), there was a trend to OS benefit, but no significance was reached (mOS was 33.64 months in panobinostat/VelDex arm versus 30.39 months in VelDex arm); full survival analyses are expected after 415 events are reached. Significant improvements were also observed in CR/nCR rate in the panobinostat/VelDex arm compared to the VelDex arm (27.6% versus 15.7%; p=0.00006). The panobinostat/VelDex arm showed about a three-month improvement in mDOR (13.1 versus 10.9 months) and TTP (12.7 months versus 8.5 months).

Of concern is the toxicity profile observed with panobinostat plus VelDex. Nearly 67.4% of patients receiving panobinostat/VelDex had Grade 3-4 thrombocytopenia compared to 31.4% in the VelDex-alone arm. In addition, Grade 3-4 diarrhea and fatigue were high in panobinostat compared to the VelDex arm (diarrhea: 25.5% versus 8%; fatigue: 23.9% versus 11.9%). Treatment-related deaths were also higher in the panobinostat/Veldex combination (2.9%) compared to the VelDex arm (1.9%). 

According to Kantar Health surveys, physicians prefer the first-generation proteasome inhibitors (Thalidomide and Velcade) and IMiD (Revlimid) in the first- or second-line setting, whereas the second-generation proteasome inhibitors and IMiDs are preferred in the third-line setting.[3]  The second-line setting has no established standard of care, so it will be interesting to see how panobinostat will be positioned. Cross-trial comparison of these three agents suggests that panobinostat plus VelDex has better efficacy compared with Pomalyst or Kyprolis. However, it is important to note that the efficacy in the table below compares Kyprolis monotherapy or Pomalyst/Dex to three-drug combination.  It is also equally important to note that the trials for Pomalyst and Kyprolis enrolled patients who had received three or more prior lines of therapy, unlike the panobinostat trial that primarily accrued patients receiving only one prior line of therapy.

 Table 1: Cross-trial comparison of the efficacy of panobinostat/VelDex versus Pomalyst or Kyprolis in relapsed/refractory myeloma patients

Regimen

ORR (%)

mPFS (Mos)

OS (Mos)

Pomalyst + LoDex[4]

31%

4.0

12.7

Krypolis[5]

23.7%

3.7

15.6

Panobinostat + VelDex

61%

12.0

N.D.

Another point that was noted by the discussant for the Panorama presentation was that it included a large percentage of patients who had received prior Velcade therapy, and a subgroup analysis noted that efficacy was better in prior Velcade-treated patients in the panobinostat arm compared with the control arm. This may contrast with the other agents that did not note such differential efficacy benefit.

The second-line setting is heavily contested with both Kyprolis and Pomalyst in pivotal trials that would support their adoption into the second-line setting if they were positive. Also under investigation are two unique targets: elotuzumab (CS-1 antibody, Abbvie/BMS/Ono) and daratumumab (CD38 antibody, Genmab, J&J). More immediately, Kyprolis is challenging VelDex in second-line therapy with the pivotal trial ENDEAVOR that will compare Kyprolis plus Dex versus VelDex (endpoint PFS) and Pomalyst in combination with VelDex versus VelDex in OPTIMISMM trial. If they reach the PFS endpoint both trials will provide major competition to panobinostat based on their adoption and familiarity with physicians in the relapsed/refractory setting. The pivotal ELOQUENT-2 trial also will compare elotuzumab plus RevDex versus RevDex alone based on clinical activity demonstrated in Phase I/II trials. Daratumumab is still in early clinical development, and no pivotal trials have been initiated to date. Time will tell whether the novel mechanism of action provided by panobinostat will be enough to garner physician excitement and to overlook the toxicity of this agent in relapsed/refractory multiple myeloma patients.



[1] Mateos, Abstract 8030, ASCO 2010

[2] Richardson, Abstract 8051, ASCO 2014

[3] Kantar Health, CancerMPact® Treatment Architecture United States and Western Europe, accessed June 1, 2014.

[4] San Miguel, Lancet Oncol, 2013

[5] Siegel, Blood, 2012

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