Date: 2016-10-08
Type of information: Presentation of results at a congress
phase: 3
Announcement: presentation of results at the European Society for Medical Oncology (ESMO) 2016 Congress
Company: BMS (USA - NY)
Product: Yervoy® (ipilimumab)
Action
mechanism: monoclonal antibody/immune checkpoint inhibitor . Cytotoxic T-lymphocyte antigen-4 (CTLA-4) is a negative regulator of T-cell activation. Ipilimumab binds to CTLA-4 and blocks the interaction of CTLA-4 with its ligands, CD80/CD86. Blockade of CTLA-4 has been shown to augment T-cell activation and proliferation, including the activation and proliferation of tumor infiltrating T-effector cells. Inhibition of CTLA-4 signaling can also reduce T-regulatory cell function, which may contribute to a general increase in T-cell responsiveness, including the anti-tumor immune response. On March 25, 2011, the FDA approved Yervoy® 3 mg/kg monotherapy for patients with unresectable or metastatic melanoma. Yervoy is approved for unresectable or metastatic melanoma in more than 50 countries. There is a broad, ongoing development program in place for Yervoy spanning multiple tumor types.
Disease: stage III melanoma patients at high risk of recurrence following complete surgical resection
Therapeutic area: Cancer - Oncology - Rare diseases
Country:
Trial
details: CA184-029 (EORTC 18071), a study initiated in 2008 by the European Organization for Research and Treatment of Cancer (EORTC), is a Phase 3, double-blind, placebo-controlled randomized trial evaluating the efficacy and safety of Yervoy® 10 mg/kg in the adjuvant setting for high-risk stage III melanoma. The independently-run trial involved 99 centers across 19 countries from the EORTC’s pan-European network and specialized infrastructure. The trial enrolled eligible patients, which included those ?18 years of age who underwent complete resection of stage III cutaneous melanoma (excluding lymph node metastasis ?1 mm or in-transit metastasis). In the trial, patients were randomized to receive Yervoy® 10 mg/kg (n=475) or placebo (n=476) as an intravenous infusion every 3 weeks for 4 doses, followed by Yervoy® 10 mg/kg or placebo every 12 weeks from Week 24 to Week 156 (three years), or until documented disease recurrence or unacceptable toxicity. Yervoy® was studied across a broad range of patient characteristics, including patients with stage IIIa with lymph node >1 mm (20%), IIIb (44%) or IIIc with no in-transit metastases (36%); 42% had ulcerated primary lesions, and 58% had macroscopic lymph node involvement.
Latest
news: * On October 8, 2016, BMS announced superior efficacy with Yervoy® 10 mg/kg versus placebo on all survival endpoints in the Phase 3 trial CA184-029 (EORTC 18071) evaluating stage III melanoma patients who are at high risk of recurrence following complete surgical resection. In the study, Yervoy® compared with placebo significantly improved overall survival (OS) (HR=0.72 [95.1% CI: 0.58-0.88; p=0.001]), a secondary endpoint, with five-year OS rates at 65.4% in the Yervoy® group and 54.4% in the placebo group. Distant metastasis-free survival (DMFS), a secondary endpoint, was also significantly improved versus placebo (HR=0.76 [95.8% CI: 0.64-0.92; p=0.002]) and had five-year DMFS rates of 48.3% and 38.9% in the Yervoy and placebo groups, respectively. In this updated five-year analysis, the recurrence-free survival (primary endpoint) benefit observed previously with Yervoy® was maintained (HR=0.76 [95% CI: 0.64-0.89; p<0.001). The safety profile remained consistent with the initial analysis, with no new deaths or safety signals. The most common grade 3/4 immune-related adverse events in the Yervoy group were gastrointestinal (16.1%), hepatic (10.8%), and endocrine (7.9%). These data were featured during the 2016 European Society for Medical Oncology Congress Press Program and simultaneously published in The New England Journal of Medicine. CA184-029 (EORTC 18071), a study initiated in 2008 by the European Organization for Research and Treatment of Cancer (EORTC), is a Phase 3, double-blind, placebo-controlled randomized trial evaluating the efficacy and safety of Yervoy® 10 mg/kg in the adjuvant setting for high-risk stage III melanoma. In the study, Yervoy® significantly improved RFS, the primary endpoint, versus placebo across all patient groups. Updated five-year results demonstrated RFS remained significantly longer for Yervoy® versus placebo, with a median RFS of 27.6 months (95% CI: 19.3-37.2) versus 17.1 months (95% CI: 13.6-21.6), respectively (HR=0.76; 95% CI: 0.64-0.89; p<0.001). Yervoy® also demonstrated a significant improvement in OS, a secondary endpoint of the study, with a 28% reduction in the risk of death versus placebo (HR=0.72 [95% CI: 0.58-0.88; p=0.001]) and an estimated five-year OS rate of 65.4% (95% CI: 60.8-69.6) for Yervoy versus 54.4% (95% CI: 49.7-58.9) for placebo. In addition, Yervoy® showed a 24% reduction in the risk of developing distant metastases versus placebo (HR=0.76 [95.8% CI: 0.64-0.92; p=0.002]), with an estimated five-year DMFS rate of 48.3% with Yervoy® versus 38.9% with placebo. The median DMFS was 48.3 months with Yervoy® versus 27.5 months with placebo. The safety profile of Yervoy® based on this updated analysis was consistent with previously reported findings from CA184-029 (EORTC 18071). In those initial findings, five patient deaths occurred due to drug-related adverse events (AE); no new deaths have since been reported. Among the 471 patients who received Yervoy®, 465 (98.7%) experienced an AE of any grade, and 255 patients (54.1%) experienced a grade 3 or 4 AE, whereas among 474 placebo-treated patients, 432 (91.1%) experienced an AE of any grade, and 124 patients (26.2%) experienced a grade 3 or 4 AE. Immune-related AEs were more frequent with Yervoy than with placebo. The most common grade 3/4 immune-related AEs in the Yervoy group were gastrointestinal (16.1%), hepatic (10.8%), and endocrine (7.9%). The median time to onset of on-study grade 2-5 immune-related AEs ranged from 4.0 weeks (skin immune-related adverse events) to 13.1 weeks (neurological immune-related adverse events). Endocrine grade 2-4 immune-related AEs resolved in 51.5% of patients, and median time to resolution was 54.3 weeks. The majority (82-97%) of all other grade 2-4 immune-related AEs resolved, and median time to resolution ranged from 4.0 to 8.0 weeks.
