New four- and five-year survival data for YERVOY®

Bristol-Myers Squibb Company today announced four- and five-year survival rates based on long-term follow up from Phase 3 and Phase 2 YERVOY® (ipilimumab) clinical trials inpatients with treatment-naïve and previously-treated metastatic melanoma. The data were presented at the ESMO 2012 Congress (European Society for MedicalOncology). (Abstract #1127 and 1116.)

In the Phase 3 trial (024), patients who had not previously received treatment for metastatic melanoma (n=502) were randomised to receive either the investigational dose of YERVOY 10 mg/kg in combination with dacarbazine (DTIC, 850 mg/m2) or DTIC alone. Long-term follow-up from this study demonstrated that treatment with YERVOY plus DTIC resulted in a four-year survival rate of 19.0% compared to 9.6% for DTIC alone. Additionally, the overall survival data appeared relatively stable between years three and four for patients treated with YERVOY plus DTIC (21.2% at three years and 19.0% at four years). The three and four-year survival rates for patients treated with placebo plus DTIC were 12.1% and 9.6%, respectively.

In three Phase 2 trials (007 [n=115], 008 [n=155] and 022 [n=217]) in which five-year follow-up data are available through a rollover study (025), patients received YERVOY at 0.3mg/kg, 3.0mg/kg or 10mg/kg. No comparator treatment arms were included in these studies. In treatment-naïve patients, the five-year estimated survival rates ranged from 38% to 49%, which was unchanged from the four-year rates. In previously-treated patients, the five-year estimated survival rates (12% to 28%) were relatively stable compared to the rates at four years (14% to 28%).

For patients who were alive after four years and who continue on therapy in study 024, few new immune-related adverse events occurred beyond two years of treatment. Overall safety data from these investigational studies have been previously presented.(1-4) The types of adverse events (AEs) attributed to YERVOY in these studies were generally mechanism (immune)-based. YERVOY can result in severe and fatal immune-related adverse reactions due to T-cell activation and proliferation. Adverse events associated with YERVOY were managed with protocol-specific guidelines, including the administration of systemic corticosteroids, dose interruption/discontinuation and/or other immunosuppressants.

“Metastatic melanoma is one of the most aggressive forms of cancer with a historical five-year survival rate of less than 10% in patients with distant metastasis.(5) Results from these investigational studies showed a prolonged survival benefit with YERVOY at four and five years for some patients,” said Celeste Lebbe, MD, Professor of Dermatology, Hôpital Saint-Louis. “These results add to the growing body of long-term survival data seen in some patients treated with YERVOY and further our understanding of the potential of this immunotherapy in the treatment of metastatic melanoma.”

About Study 024

Study 024 is a multi-national, randomised, double-blind Phase 3 study that evaluated the safety and efficacy of YERVOY (10 mg/kg) plus DTIC (850 mg/m2) versus DTIC alone in treatment naive patients with Stage III unresectable or Stage IV metastatic melanoma. Patients who received prior adjuvant therapy were allowed in the trial.  Patients were randomly assigned in a 1:1 ratio to receive either YERVOY plus DTIC (n=250) or DTIC plus placebo (n=252) at Weeks 1, 4, 7, 10 followed by DTIC alone every 3 weeks through Week 22 (induction phase). If drug intolerance or progressive disease (PD) was noted during Weeks 12-24, treatment was discontinued. At Week 24, patients who had stable disease (SD) or an objective response (OR) during induction with no dose-limiting toxicity could enter a maintenance phase in which they received placebo or YERVOY every 12 weeks until PD, drug intolerance or end of study. The primary endpoint of study 024 was overall survival. Results from study 024, which included three-year follow-up data, were originally published in the New England Journal of Medicine and presented at the American Society of Clinical Oncology Annual Meeting in 2011.

The combination of DTIC with YERVOY is not an FDA approved-regimen. In addition, study 024 was not designed to compare the safety and efficacy of the FDA-approved monotherapy dose of 3mg/kg for unresectable or metastatic melanoma vs. the investigational dose of 10 mg/kg. Bristol-Myers Squibb is conducting a head-to-head Phase 3 study comparing the safety and efficacy of the currently-approved dose of 3 mg/kg versus 10mg/kg as monotherapy in patients with previously-treated or treatment naïve unresectable or metastatic melanoma. This study rapidly accrued patients and completed enrolment in just over four months.

Study 025 is a rollover Phase 2 study that includes patients from three trials who only received YERVOY: CA184-008, a single-arm study of YERVOY 10mg/kg in previously treated patients (n=155); CA184-022, a dose-ranging study in which previously treated patients were randomised to receive YERVOY at 0.3mg/kg (n=73), 3 mg/kg (n=72), or 10 mg/kg (n=72) with crossover from lower doses to 10 mg/kg allowed in patients whose disease progressed; and CA184-007, a randomised study of YERVOY 10 mg/kg with or without prophylactic budesonide in treatment-naïve (n=53) and previously treated patients (n=62). Treatment was administered every three weeks for up to four doses, at which point eligible patients could receive re-induction or maintenance YERVOY every 12 weeks starting at week 24. The analysis reported overall survival with updated last known alive date or death based on data collected through March 2012.

Melanoma is a form of skin cancer characterised by the uncontrolled growth of pigment-producing cells (melanocytes) located in the skin. Metastatic melanoma is the deadliest form of the disease, and occurs when cancer spreads beyond the surface of the skin to other organs, such as the lymph nodes, lungs, brain or other areas of the body. Some cancer cells can actively evade surveillance by the immune system, allowing tumours to survive. Melanoma is mostly curable when treated in its early stages.

However, in its late stages, the average survival rate is just six months with a 1-year mortality rate of 75%, making it one of the most aggressive forms of cancer. These rates are based on a meta-analysis of 42 Phase 2 trials of more than 2,100 previously-treated and treatment-naïve patients with Stage IV metastatic melanoma conducted by multiple cooperative groups from 1975-2005. The incidence of melanoma has been increasing for at least 30 years. The median age at diagnosis for melanoma is 57 and the median age at death is 67.

About YERVOY

On 25 March 2011, the US Food and Drug Administration (FDA) approved ipilimumab 3 mg/kg for the treatment of patients with unresectable (inoperable) or metastatic melanoma in the US. On 13 July 2011, the EU approved ipilimumab 3mg/kg for the treatment of adult patients with previously-treated unresectable or metastatic melanoma.

YERVOY, which is a recombinant, human monoclonal antibody, is the first FDA-approved cancer immunotherapy that blocks the cytotoxic T-lymphocyte antigen-4 (CTLA-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. The mechanism of action of ipilimumab’s effect in patients with melanoma is indirect, possibly through T-cell mediated anti-tumour immune responses.

1. Weber J, Thompson JA, Hamid O, et al. A randomized, double-blind, placebo-controlled, phase II study comparing the tolerability and efficacy of ipilimumab administered with or without prophylactic budesonide in patients with unresectable stage III or IV melanoma. Clin Cancer Res 2009;15:5591-5598.
2. Wolchok JD, Neyns B, Linette G, et al. Ipilimumab monotherapy in patients with pretreated advanced melanoma: a randomised, double-blind, multicentre, phase 2, dose-ranging study. Lancet Oncol 2010;11:155-164.
3. O’Day SJ, Maio M, Chiarion-Sileni V, et al. Efficacy and safety of ipilimumab monotherapy in patients with pretreated advanced melanoma: a multicentre, single-arm, phase II study. Ann Oncol 2010;21:1712-1717.
4. Thomas L, Wolchok JD, Garbe C, et al. Safety of ipilimumab in patients (pts) with untreated, advanced melanoma alive beyond 2 years: Results from a phase III study. J Clin Oncol. 2012;30(15s): abstract 8512.
5. National Comprehensive Cancer Network (NCCN) Web site. “NCCN Clinical Practice Guidelines in Oncology (NCCNGuidelines): Melanoma.” Available at: http://www.nccn.org/professionals/physician_gls/pdf/melanoma.pdf   Accessed on September 19, 2012.