Bristol-Myers Squibb Company announced that the US Food and Drug Administration (FDA) has expanded the indication for Yervoy (ipilimumab) injection for intravenous use to now include the treatment of unresectable or metastatic melanoma in pediatric patients 12 years of age and older.
Yervoy was evaluated in two trials of pediatric patients: a dose-finding study in 33 patients aged two to 21 years with relapsed or refractory solid tumors and an open-label, single-arm trial in 12 adolescents (ages ranging from 12 to 16 years) with previously treated or untreated, unresectable Stage 3 or 4 malignant melanoma. The overall safety profile of Yervoy in children and adolescents was consistent with the safety profile in adults, and similarities in disease between adult and pediatric patients 12 years and older allow for extrapolation of data. Based on a population pharmacokinetic analysis, exposure in adolescents 12 years and older is comparable to that in adults for the approved dose of 3 mg/kg, administered intravenously over 90 minutes every three weeks for a total of four doses.
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.
“When my daughter was diagnosed with melanoma, our entire family was devastated,” said Brenda Busby, mother to a 12-year-old patient and pediatric programme coordinator, Melanoma Research Foundation. “As someone who has lived with the many challenges of pediatric cancer, I know how important it is for patients and their families who face metastatic melanoma to have access to new therapies.”
“Metastatic melanoma is extremely rare in children and adolescents, which makes it particularly difficult to investigate in clinical trials. Though designing clinical trials in small pediatric populations can be challenging, this group of investigators committed to bringing a new therapy to those in need,” said Lia Gore, MD, University of Colorado School of Medicine and Children’s Hospital of Colorado. “Ipilimumab’s approval represents the culmination of a long effort and gives physicians the ability to expand immuno-oncology – one of the most exciting areas of medicine – for the treatment of young adults with metastatic melanoma.”
The US FDA approval for Yervoy in patients 12 years and older with metastatic melanoma marks Bristol-Myers Squibb’s first pediatric indication for an immuno-oncology medicine. The expanded indication builds upon six years of experience with Yervoy, which has been used to treat more than 38,000 adult patients with metastatic melanoma since its first approval.
“Despite significant advancements in oncology research for adults in recent years, treatment options continue to be limited for pediatric patients with metastatic melanoma,” said Chris Boerner, PhD, president and head of US commercial operations, Bristol-Myers Squibb. “At Bristol-Myers Squibb, we are committed to providing meaningful support to the pediatric oncology community. This latest approval of Yervoy exemplifies our ongoing effort to expand the availability of therapies for younger cancer patients.”
As part of its commitment to children and adolescents with cancer, Bristol-Myers Squibb continues to explore pediatric applications for investigational oncology agents within its broad development program. In addition, Bristol-Myers Squibb supports organizations and initiatives focused on pediatric patients and their families.
Yervoy has been evaluated in a total of 45 pediatric patients across two clinical trials. The safety and effectiveness of Yervoy have been established in pediatric patients 12 years and older. The use of Yervoy in this age group is supported by evidence from adequate and well-controlled studies of Yervoy in adults and population pharmacokinetic data demonstrating that the exposure at a dose of 3 mg/kg in the pediatric and adult populations is comparable. In addition, the tumor biology and the course of advanced melanoma is sufficiently similar in adults and pediatric patients 12 years and older to allow extrapolation of data from adults to pediatric patients.
In a dose-finding trial, Yervoy was evaluated in 33 pediatric patients with relapsed or refractory solid tumors. Patients enrolled in the study ranged from two to 21 years of age, with a median age of 13 years, and 20 of the patients were 12 years of age or older. Yervoy was administered at doses of 1, 3, 5 and 10 mg/kg intravenously over 90 minutes every three weeks for four doses and then every 12 weeks thereafter until progression or treatment discontinuation.
Yervoy was also evaluated in an open-label, single-arm trial in 12 pediatric patients 12 years and older with previously treated or untreated, unresectable Stage 3 or 4 malignant melanoma. Patients received Yervoy 3 mg/kg (four patients) or 10 mg/kg (eight patients) intravenously over 90 minutes every three weeks for four doses.
Of the 17 patients 12 years of age and older with melanoma treated with Yervoy across both studies, two patients experienced objective responses, including one partial response that was sustained for 16 months.
The approved dose for Yervoy in pediatric patients with unresectable or metastatic melanoma is 3 mg/kg, administered intravenously over 90 minutes every three weeks for a total of four doses.
Based on a population pharmacokinetic analysis using available pooled data from 565 patients from four phase 2 adult studies (N=521) and two pediatric studies (N=44), body weight normalized clearance of Yervoy is comparable between adult and pediatric subjects.
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 US Food and Drug Administration (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.
Bristol-Myers Squibb remains committed to providing a comprehensive set of programs and services so that cancer patients who need our medicines can access them and expedite time to therapy.