By: Tari Awipi, Ph.D. Associate Consultant, Clinical & Scientific Assessment, Kantar Health and Arnold DuBell, Ph.D., M.B.A., Senior Consultant, Clinical & Scientific Assessment, Kantar Health
The CDK 4/6 inhibitor Ibrance® (palbociclib, Pfizer) burst onto the scene in February 2015 with its original approval from the U.S. Food and Drug Administration (FDA) for treatment of newly diagnosed HR+/HER2- breast cancer. This accelerated approval, based on the Phase II PALOMA-1 trial, was contingent on a post-marketing Phase III trial, PALOMA-2. Yesterday the positive results of PALOMA-2 were presented at the American Society for Clinical Oncology (ASCO) annual meeting and confirmed the 10-month improvement in progression-free survival (PFS) (10.2 months versus 20.2 months, HR 0.49, p=0.0004) in patients with HR+/HER2- advanced breast cancer reported in PALOMA-1.1,2
As it was partly confirmatory, PALOMA-2 had a similar design. In PALOMA-2, 666 previously untreated HR+/HER2- breast cancer patients were randomized to Ibrance or Ibrance plus letrozole or placebo plus letrozole. Similar to PALOMA-1, the addition of Ibrance was associated with a 10.3-month improvement in PFS (investigator-assessed medians: 24.8 months versus 14.5 months; HR 0.58, p=0.0004). Independent central review suggested a similar benefit (30.5 months versus 19.3 months, HR 0.65, p=0.0005). In the intent-to-treat population, Ibrance improved the objective response (42% versus 35%, OR 1.40, p=0.031) and the clinical benefit rate (85% versus 70%, OR 2.39, p<0.0001). Overall survival data were not presented. Ibrance primarily increased the incidence of Grade 3-4 neutropenia (66% versus 1%) and leucopenia (25% versus 0%). This is represented in the minor increase in the adverse event-associated treatment discontinuation rate (9.7% versus 5.9%). One factor that was highlighted in both the presentation and the discussion was that the data from the Phase III PALOMA-2 trial were strongly consistent with the data from the Phase II PALOMA-1 trial (see table below). This consistency confirms not only the statistically significant efficacy benefit for Ibrance but also the strong clinical relevance of this efficacy benefit.
|Trial Design||Phase II, open-label||Phase III, placebo control|
|Patients on Study||165||666|
|Median PFS (months)||20.2 versus 10.2 months
(10 month improvement)
|24.8 versus 14.5 months
(10.3 month improvement)
|ORR (ITT)||43% versus33%||42% versus 35%|
|CBR (ITT)||81% versus 58%||85% versus 70%|
|Source: (1) Finn, Lancet Oncol, 2015; (2) Finn, Abstract 507, ASCO 2016|
A third study, PALOMA-3, compared Ibrance in combination with Faslodex® (fulvestrant, AstraZeneca) in patients who had already progressed on endocrine therapy and also published strong positive safety and efficacy data.3 The results of this trial were the basis for Ibrance’s FDA label extension to include the treatment of patients in the second-line setting in February 2016. In all three trials, neutropenia was affected the most by the addition of Ibrance.
Since its 2015 accelerated approval, Ibrance has already gained strong utilization in the U.S. and is already the most utilized regimen as first-line therapy for postmenopausal HR+ metastatic breast cancer patients, with approximately 30% utilization.4 These strong new data will support conversion of accelerated approval in the United States and regulatory filings for Ibrance in the first-line setting elsewhere. While Ibrance currently enjoys first-in-class status (at least in the first-line setting) it may soon face more competition from two other CDK 4/6 inhibitors in this space. The first is Eli Lilly’s abemaciclib. It has two ongoing Phase III trials: MONARCH 2 (NCT02107703), which is comparing Faslodex with or without abemaciclib in 630 HR+/HER2- patients, and MONARCH 3 (NCT02246621), which is comparing the activity of non-steroidal aromatase inhibitors with or without abemaciclib in 450 HR+/HER2- patients. Abemaciclib received a boost at this year’s ASCO annual meeting with presentation of positive results from its MONARCH 1 Phase II trial. MONARCH-1 found that single-agent abemaciclib was active in refractory metastatic HR+/HER2- patients with a 19.7% objective response rate (ORR), a six-month median PFS and a 17.7-month median overall survival (OS). Toxicities were more of a concern, with diarrhea (19.7%), fatigue (12.9%), neutropenia (26.9%) and leucopenia (27.7%) being common Grade 3-4 toxicities.5 Eli Lilly’s agent had already received Breakthrough Therapy Status in October 2015. The second competitor in the first-line setting is Novartis’ ribociclib, which is being evaluated in three trials: MONALEESA-2 (NCT01958021; letrozole with or without ribociclib in 667 HR+ postmenopausal patients), MONALEESA-3 (NCT02422615; Faslodex with or without ribociclib in 660 HR+ men or postmenopausal women) and MONALEESA-7 (NCT02278120; hormone therapy with or without ribociclib in 660 premenopausal patients).
Moreover, Afinitor® (everolimus, Novartis) is currently approved for use in postmenopausal women with advanced HR+ breast cancer in combination with exemestane after relapse on letrozole or anastrozole, based on the results of the BOLERO-2 trial.6 Novartis had attempted other trials in both the first-line and relapsed settings. BOLERO-1, which evaluated Afinitor plus Herceptin and paclitaxel in HR+/HER2+ patients, failed to reach its PFS primary endpoint.7 Afinitor did meet the primary endpoint in the BOLERO-3 trial,8 which evaluated the efficacy of adding Afinitor to Herceptin and vinorelbine to Herceptin pretreated patients; however, the PFS benefit was small (HR 0.78), and Novartis has not yet filed for regulatory approval since the trial’s 2014 data publication. Other agents are being evaluated in late-stage trials for relapsed patients. These include buparlisib (PI3K inhibitor, Novartis), alpelisib (PI3Kα inhibitor, Novartis), taselisib (PI3Kα inhibitor, Genentech/Roche) and entinostat (histone deacetylase inhibitor, Syndax). If successful in the relapsed setting, these agents could also become competition to Ibrance in the first-line setting.
In spite of the future competition, Ibrance solidified its current position for use as a first-line treatment option with the results from PALOMA-2 and made it harder for competitors to dislodge its preferential status in this setting. With the extremely positive data presented at ASCO 2016, Ibrance can truly spread its wings and soar.
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