乌鸦传媒

CHICAGO -- Progression-free survival (PFS) in relapsed/refractory myeloma increased significantly in patients treated with a three-drug regimen that included panobinostat versus a two-drug regimen, a randomized trial showed.

Median PFS improved by about 4 months with the combination of panobinostat, bortezomib (Velcade), and dexamethasone as compared with placebo, bortezomib, and dexamethasone. The progression benefit was consistent across patient subgroups.

Data were too immature for a definitive survival analysis, but preliminary results showed a 3- to 4-month difference in favor of the panobinostat arm, Paul Richardson, MD, of Dana-Farber Cancer Institute in Boston, reported here at the meeting.

"The results confirm the efficacy of panobinostat, bortezomib, and dexamethasone observed in heavily pretreated, bortezomib-refractory patients," said Richardson. "Panobinostat, bortezomib, and dexamethasone was associated with a higher rate of diarrhea, fatigue, and thrombocytopenia, but the adverse events were predictable and generally manageable with supportive measures."

A pan-histone deacetylase (HDAC) inhibitor, panobinostat increases protein acetylation affecting multiple oncogenic pathways. In preclinical models of multiple myeloma, panobinostat, bortezomib, and dexamethasone demonstrated synergistic activity, said Richardson. Phase I and II studies showed that the combination led to durable responses in patients with relapsed/refractory myeloma, including bortezomib-refractory disease.

The accumulation of favorable data led to a randomized, phase III comparison of bortezomib and dexamethasone with or without panobinostat in patients with relapsed/refractory myeloma.

Known as PANORAMA 1, the trial consisted of two stages. During the first stage, patients were randomized to eight 21-day cycles of bortezomib-dexamethasone plus panobinostat or placebo. Patients who obtained clinical benefit during the first stage received an additional four cycles of randomized therapy, administered every 42 days.

The primary endpoint was PFS, and the key secondary endpoint was overall survival. Other secondary endpoints included overall response rate, the rate of near-complete/complete response, time to relapse, time to progression, and quality of life.

Investigators at 215 centers in 34 countries initially randomized 768 patients who had received as many as three prior regimens. Prior bortezomib therapy was not an exclusion factor.

Two-thirds of the patients had relapsed disease and the rest had refractory-relapsed myeloma. Almost 60% of the study population had undergone stem-cell transplantation, more than 40% had prior bortezomib exposure, and more than 70% had received thalidomide and/or lenalidomide (Revlimid).

Richardson reported that 361 patients entered the second stage of the trial, 169 in the panobinostat arm and 192 in the placebo arm. The most common reason for not continuing to the second stage were adverse events in the panobinostat arm (33.6%) and disease progression in the placebo group (40.2%). About one-quarter of patients in each group completed the first stage but did not obtain clinical benefit.

The panobinostat group had a median PFS (both stages combined) of 12.0 months versus 8.1 months in the placebo group, a difference that represented a 37% reduction in the hazard for progression (P<0.0001).

Subgroup analyses showed a consistent benefit with panobinostat by race/ethnicity, sex, age, clinical stage, and cytogenetic risk group.

Analysis of overall survival showed a median of 33.64 months in the panobinostat group and 30.39 months in the placebo group, a difference that represented a nonsignificant 13% reduction in the hazard. Richardson said a final survival analysis will occur after 415 events, approximately 100 more than observed in the interim data.

Evaluation of other secondary endpoints showed a significant difference only for the proportion of patients who achieved a near-complete or complete response: 27.6% with panobinostat and 15.7% with placebo (P=0.00006).

Adverse events occurred more often in the panobinostat arm, especially diarrhea (25.5% grade 3/4) and asthenia/fatigue (23.9%).

Hematologic toxicity also occurred more often with panobinostat. Almost every patient had thrombocytopenia in the panobinostat arm, which was grade 3/4 in two-thirds of cases. Half of the patients treated with panobinostat had grade 3/4 lymphopenia, and one-third had grade 3/4 neutropenia. The rate of febrile neutropenia was 1% with panobinostat and 0.5% in the placebo group.

The results are intriguing because of the background of panobinostat in myeloma, said Sagar Lonial, MD, of Emory University in Atlanta.

"This is the first time we have taken a drug that has little or no single-agent activity and demonstrated a combination effect in a phase III study," Lonial told 乌鸦传媒. "In the myeloma world, we can take drugs that may not work by themselves but that may make other drugs better. That's very encouraging."

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