FDA approved BMS’s Yervoy

U.S. Food and Drug Administration (FDA) has approved BMS’s Yervoy (ipilimumab) 10 mg/kg for the adjuvant treatment of patients with cutaneous melanoma with pathologic involvement of regional lymph nodes of more than 1 mm who have undergone complete resection including total lymphadenectomy.

BMS explained in anouncement issued on Thursday that this approval is based on clinical data from a pivotal Phase 3 trial, CA184-029 (EORTC 18071), which demonstrated Yervoy 10 mg/kg significantly improved recurrence-free survival (RFS) vs. placebo in this setting, with a 25 percent reduction in the risk of recurrence or death. The median RFS was 26 months (95% CI: 19, 39) for Yervoy vs. 17 months (95% CI: 13, 22) for placebo (hazard ratio [HR]=0.75; 95% CI: 0.64, 0.90; p<0.002). Yervoy is the first and only FDA-approved immune checkpoint inhibitor in the adjuvant treatment for fully resected Stage III melanoma (lymph node >1 mm).

Resectable, Stage III melanoma represents 5 percent, or approximately 3,100 cases, of all new melanoma cases diagnosed annually. This stage of melanoma can be aggressive, with a 60 percent risk of recurrence after surgery. Despite the risk of disease recurrence among Stage III melanoma patients following resection, there are limited treatment options available to help reduce the risk of recurrence after surgery, said the company.

“The science of Immuno-Oncology is rapidly advancing, and we are proud to be the first to demonstrate the potential of an immune checkpoint inhibitor in the adjuvant setting, an earlier stage of the disease, where patients urgently need new medicines,” said Michael Giordano, M.D., senior vice president, head of Development, Oncology, Bristol-Myers Squibb.

“The approval of Yervoy for the treatment of adjuvant melanoma underscores our scientific leadership in Immuno-Oncology, with a commitment to further developing our I-O agents – Yervoy and Opdivo – across multiple tumor types and at many stages of disease.”

BMS added that Yervoy is associated with a Boxed Warning and can result in severe to fatal immune-mediated adverse reactions. These immune-mediated reactions may involve any organ system; however, the most common severe immune-mediated adverse reactions are enterocolitis, hepatitis, dermatitis (including toxic epidermal necrolysis), neuropathy, and endocrinopathy. Please see below for additional Important Safety Information, including Boxed WARNING regarding immune-mediated adverse reactions.

This Phase 3 trial, CA184-029 (EORTC 18071), is a cooperative group study initiated in 2008 by the European Organization for Research and Treatment of Cancer (EORTC) evaluating the 10 mg/kg dose in the adjuvant setting. With the goal of advancing treatment options for the adjuvant treatment of melanoma, Bristol-Myers Squibb is working with the Eastern Cooperative Oncology Group (ECOG) and is conducting an ongoing study to investigate other dosing options for Yervoy in the adjuvant setting.

“Today’s approval is an important step in our commitment to bring our Immuno-Oncology pipeline to earlier lines of cancer treatment and to make new options available quickly while we continue to build upon our scientific understanding and develop even better solutions,” continued Giordano.

“Bristol-Myers Squibb has broad development programs in the adjuvant setting across multiple tumors, including the ongoing studies of Opdivo and of Yervoy in adjuvant melanoma.”

To help ensure patient access to Yervoy in the adjuvant setting at the 10 mg/kg dose, Bristol-Myers Squibb is offering a new patient assistance program – the Adjuvant Patient Program for Melanoma. Through this program, eligible patients who have been prescribed Yervoy 10 mg/kg for the adjuvant treatment of fully resected Stage III melanoma (lymph node >1 mm), whether insured or uninsured, may receive Yervoy 10 mg/kg free of charge for the duration of treatment, which may be up to three years. More information about the program is available from BMS Access Support by calling 1-800-861-0048 or by visiting http://www.bmsaccesssupport.com.

The randomized, double-blind Phase 3 trial, CA184-029 (EORTC 18071), demonstrated that Yervoy 10 mg/kg (n=475) significantly improved RFS vs. placebo (n=476) in patients with resected Stage IIIa (lymph node >1 mm), IIIb and IIIc (with no in-transit metastases) histologically confirmed cutaneous melanoma. The median RFS was 26 months (95% CI: 19, 39) for Yervoy vs. 17 months (95% CI: 13, 22) for placebo (HR=0.75; 95% CI: 0.64, 0.90; p<0.002). 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 (3 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. The primary endpoint was RFS, defined as the time between the date of randomization and the date of first recurrence or death, as assessed by the Independent Review Committee, said the company.

In patients who received Yervoy 10 mg/kg (n=471), severe to fatal immune-mediated adverse reactions were reported, and included enterocolitis (16%), hepatitis (11%), endocrinopathy (8%), hypopituitarism (7%), dermatitis (4%), neuropathy (1.7%), hyperthyroidism (0.6%), meningitis (0.4%), primary hypothyroidism (0.2%), myocarditis (0.2%), pericarditis (0.2%), pneumonitis (0.2%), and uveitis (0.2%). The most common adverse reactions were rash (50%), diarrhea (49%), fatigue (46%), pruritus (45%), headache (33%), weight loss (32%), nausea (25%), pyrexia (18%), colitis (16%), decreased appetite (14%), vomiting (13%), and insomnia (10%). Yervoy was discontinued for adverse reactions in 52% of patients.

BMS About Yervoy

Yervoy is a recombinant, human monoclonal antibody that binds to the cytotoxic T-lymphocyte-associated antigen-4 (CTLA-4). CTLA-4 is a negative regulator of T-cell activity. Yervoy 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 in more than 40 countries. There is a broad, ongoing development program in place for Yervoy spanning multiple tumor types.

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