Datamonitor: ASCO 2010 - ipilimumab achieves breakthrough in 'long dark tunnel' of metastatic melanoma

At this year's American Society of Clinical Oncology meeting, Bristol-Myers Squibb presented data for its monoclonal antibody ipilimumab in metastatic melanoma. Research and development in this area has been underwhelming over the past few years and, despite its high rate of adverse events, ipilimumab represents a breakthrough in the treatment of metastatic melanoma.

At the 2010 meeting of the American Society of Clinical Oncology (ASCO 2010), Dr Steven O' Day presented data from a Phase III study exploring the use of ipilimumab (MDX-010; Bristol-Myers Squibb) and MDX-1379 (gp100 peptide vaccine; Bristol-Myers Squibb) in previously treated unresectable stage III or stage IV melanoma.

Ipilimumab is a fully human monoclonal antibody directed towards cytotoxic T-lymphocyte antigen-4 (CTLA-4), a protein that is expressed on T-cells, slowing down the activation of these cells. Blocking this antigen helps to stimulate the expansion of T-cell populations, potentially increasing tumor-directed immune responses. MDX-1379, meanwhile, is a standardized therapeutic cancer vaccine consisting of two glycoprotein-100 (gp100) melanoma peptides that form part of an antigen normally found on the surface of melanocytes and melanoma tumor cells.

This study enrolled 576 previously treated patients with unresectable stage III/IV melanoma who were positive for the human leukocyte antigen HLA-A*0201. These patients were randomized to one of three arms: ipilimumab plus placebo, ipilimumab plus MDX-1379 or MDX-1379 plus placebo. The dosing schedule for ipilimumab was 3mg/kg every three weeks for four doses, while the dosing schedule for MDX-1379 was 1mg every three weeks for four doses. The primary endpoint was overall survival (OS) in the ipilimumab plus MDX-1379 arm compared to the single-agent MDX-1379 arm.

Median OS in patients receiving ipilimumab plus MDX-1379 was 10.0 months, compared to 6.4 months in patients receiving MDX-1379 alone. However, there was no significant difference in OS between the ipilimumab plus MDX-1379 combination arm and the single-agent ipilimumab arm, where median OS was 10.1 months. This suggests that the peptide vaccine has minimal activity in this patient population. Progression free survival (PFS) was similar across all three arms, at 2.9 months in the single-agent ipilimumab arm, 2.8 months in the combination arm and 2.8 months in the single-agent MDX-1370 arms. The best overall response rates in these three treatment arms were 10.9%, 5.7% and 1.5%, respectively.

Dr O' Day reported that adverse events were consistent with earlier studies of ipilimumab. The rate of grade 3/4 drug-related adverse events was 17.4% in the ipilimumab and MDX-1379 combination arm and 22.9% in the ipilimumab single-agent arm, significantly higher than in the MDX-1379 single-agent arm. The most common grade 3/4 events in the ipilimumab arms included fatigue, diarrhea and colitis. The rate of treatment-related deaths was 2.1% in the combination arm and 3.1% in the ipilimumab single-agent arm, while immune-related deaths occurred in 1.3% and 1.5% of patients in these two arms, respectively.

Discussing the results of the study, Dr Vernon Sondak put these data in the context of the exceptionally poor outcomes of clinical trials in metastatic melanoma in recent years, likening the situation to a "long dark tunnel". There has not been a FDA approval in this indication since Proleukin (aldesleukin; Prometheus) in 1998, while no standard treatment option exists for second-line patients. Dr Sondak commended the design of the study, pointing out that it included a "very representative patient population" for this indication. He also considered MDX-1379 to be an appropriate comparator, given that there is no standard salvage regimen in metastatic melanoma and that outcomes with this vaccine were in line with a meta-analysis of previous trials of other agents in this setting. The main area for concern highlighted by Dr Sondak was the high rate of adverse events with ipilimumab, which will require management by "a highly committed, multidisciplinary team". However, Dr Sondak asserted that these adverse events are manageable, provided a "careful and thorough" approach is taken.

As the first agent to demonstrate a survival benefit in metastatic melanoma, these data represent an important and much-needed breakthrough in this indication and are likely to earn ipilimumab its first approval. Bristol-Myers Squibb anticipates filing for approval of ipilimumab in advanced melanoma by the end of 2010. Nevertheless, some physicians will view the agent cautiously given the common occurrence of adverse events and the low overall response rate, which make the risk-benefit ratio high. Assuming this agent reaches the market, Bristol-Myers Squibb will need to place great emphasis on educating physicians (particularly community-based physicians) about the optimal management of adverse events as part of its detailing in order to maximize uptake.

Bristol-Myers Squibb is already seeking to maximize the commercial potential of ipilimumab in melanoma through label expansions. A Phase III trial of ipilimumab in combination with dacarbazine in the first-line setting is underway and is due for completion before the end of 2010. Given the encouraging efficacy already shown in the second-line, the results of this study will be eagerly anticipated and could see the next important advance in treatment of melanoma.

Related research:

Datamonitor: Stakeholder Opinions: Melanoma - Future treatment will be based on individual tumor gene expression signatures:
http://www.reports-research.com/studien/stakeholder-opinions-melanoma-future-treatment-will-based-individual-tumor-gene-expression-signatures-p-77408.html

Business Insights: The Cancer Market Outlook To 2014: Competitive landscape, market size, pipeline analysis and growth opportunities:
http://www.reports-research.com/studien/cancer-market-outlook-2014-competitive-landscape-market-size-pipeline-analysis-growth-opportunities-p-69533.html

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