Updated results from the PANORAMA 1 trial: OS of patients with relapsed MM treated with panobinostat plus bortezomib and dexamethasone

In November 2016 the final Overall Survival (OS) analysis of the phase 3 PANORAMA 1 trial - to examine the efficacy of panobinostat in combination with bortezomib and dexamethasone - was published in Lancet Haematology. The study design and results from the interim analysis are detailed in a previous MMHub article.

Key Findings:

• Final OS was calculated after 415 events; 53% (204 of 387) of those receiving panobinostat had died, vs 55% (211 of 381) receiving the placebo
• Median OS (ITT population):
  • Panobinostat = 40.3 months (95% CI 35.0–44.8)
  • Placebo = 35.8 months (95% CI 29.0–40.6); HR = 0.94; 95% CI 0.78–1.14; P=0.54
• In the sub-group analysis of OS, particular benefit of panobinostat vs placebo was seen in two sub-groups:
  • Pts with Asian ethnicity 9.7-month benefit (HR = 0.77; 95% CI 0.54–1.10)
  • Pts with RRMM 11.1-month benefit (HR = 0.74; 0.55–1.01)
• In the sub-population that received at least two previous drug treatments:
  • Median OS = 25.5 months (95% CI 19.6–34.3) panobinostat vs 19.5 months (14.1–32.50) placebo; HR = 1.01 (95% CI 0.68–1.50)  
• Pts receiving new drug at the end of treatment (ITT population) = 38% panobinostat vs 49% placebo
• Pts receiving subsequent immunomodulatory treatment = 20% panobinostat vs 29% placebo
• At least one serious AE was reported for: 60% panobinostat vs 42% placebo
• Commonly observed AE’s (observed in >20% in either treatment group) included thrombocytopenia, lymphopenia, neutropenia, diarrhea, fatigue, and leucopenia

Although no significant difference was observed in median OS between the two treatment groups, this was attributed to several factors, such as the placebo group being more likely to receive other treatments, a lack of control over subsequent anti-myeloma treatments, and different access to drugs between treatment centers. In addition, improved OS of patients due to availability of novel drugs, and a high rate of discontinuation in the panobinostat group (possibly due to the twice-weekly intravenous dosing, which could be limited to once a week without affecting efficacy) also contributed. In conclusion, the OS benefit of panobinostat with bortezomib and dexamethasone was modest, but optimization of the treatment regimen may pave the way for prolonged treatment and improved outcomes in future trials of patients with RRMM.

Abstract

Background:

Panobinostat plus bortezomib and dexamethasone significantly increased median progression-free survival compared with placebo plus bortezomib and dexamethasone in the phase 3 PANORAMA 1 trial. Here, we present the final overall survival analysis for this trial.

Methods:

PANORAMA 1 is a randomised, placebo-controlled, double-blind, phase 3 trial of patients with relapsed or relapsed and refractory multiple myeloma with one to three previous treatments. Patients were randomly assigned (1:1) to receive panobinostat (20 mg orally) or placebo, with bortezomib (1·3 mg/m² intravenously) and dexamethasone (20 mg orally), over two distinct treatment phases. In treatment phase 1 (eight 3-week cycles), patients received: panobinostat or placebo on days 1, 3, 5, 8, 10, and 12; bortezomib on days 1, 4, 8, and 11; and dexamethasone on days 1, 2, 4, 5, 8, 9, 11, and 12. During treatment phase 2 (four 6-week cycles with a 2 weeks on, 1 week off schedule), panobinostat or placebo was given three times a week, bortezomib was administered once a week, and dexamethasone was given on the days of and following bortezomib administration. The primary endpoint was progression-free survival; overall survival was a key secondary endpoint. This study is registered at ClinicalTrials.gov, NCT01023308.

Findings:

Between Jan 21, 2010, and Feb 29, 2012, 768 patients were enrolled into the study and randomly assigned to receive either panobinostat (n=387) or placebo (n=381), plus bortezomib and dexamethasone. At data cutoff (June 29, 2015), 415 patients had died. Median overall survival was 40·3 months (95% CI 35·0–44·8) in those who received panobinostat, bortezomib, and dexamethasone versus 35·8 months (29·0–40·6) in those who received placebo, bortezomib, and dexamethasone (hazard ratio [HR] 0·94, 95% CI 0·78–1·14; p=0·54). Of patients who had received at least two previous regimens including bortezomib and an immunomodulatory drug, median overall survival was 25·5 months (95% CI 19·6–34·3) in 73 patients who received panobinostat, bortezomib, and dexamethasone versus 19·5 months (14·1–32·5) in 74 who received placebo (HR 1·01, 95% CI 0·68–1·50).

Interpretation:

The overall survival benefit with panobinostat over placebo with bortezomib and dexamethasone was modest. However, optimisation of the regimen could potentially prolong treatment duration and improve patients' outcomes, although further trials will be required to confirm this.