Bristol-Myers’ melanoma immunotherapy expected to take the spotlight at ASCO

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Bristol-Myers Squibb’s (NYSE:BMY) cancer drug ipilimumab is expected to demonstrate durable responses in a limited subset of patients with second-line melanoma, a number of oncologists told Pharmawire. The agent will also be effective as a monotherapy, some noted.

Results from a Phase III study of ipilimumab in patients with previously-treated advanced melanoma have been selected for presentation in a Plenary Session at the American Society of Clinical Oncology (ASCO) on Sunday, June 6. Ipilimumab, an immunotherapy, targets a molecule on T-cells (CTLA-4) in order to sustain the body’s immune response on cancer cells.

This trial compared ipilimumab alone to ipilimumab in combination with a melanoma peptide vaccine to the vaccine alone in patients with previously treated unresectable Stage III or IV Melanoma.

Results presented last year at ASCO from three Phase II studies showed a two-year survival rate ranging from 30 to 42 percent in patients treated with ipilimumab. The two-year survival rate ranged from 29.8 to 41.8 percent in patients who received ipilimumab (10 mg/kg).

Thus far, ipilimumab has been very promising and while it has only demonstrated modest patient response rates, there is a prolonged response at one to two years, noted Dr Jeffrey Weber, director of the Donald A. Adam Comprehensive Melanoma Research Center. When patients do respond to treatment with ipilimumab, their disease stays in remission for a long time, he said.

It is clear that approximately 10 percent of patients respond to ipilimumab and these patients have demonstrated tumor shrinkage that appears to be durable, said Dr Keith Flaherty, director of developmental therapeutics at Massachusetts General Hospital. The tumors appear to stay the same size in a fair number of patients. He noted that there are also an additional percentage of patients who -- while they do not demonstrate tumor shrinkage -- do benefit from treatment due to better immune system surveillance.

While only a small portion of patients benefit, those that do have shown long-term survival benefits, said Dr Claire Verschraegen, director of protocol specific research support and clinical research and translational therapeutics at the University of New Mexico Cancer Center. It is still unclear which subset of patients is responding better, as there did not appear to be any correlation with LDH status, she said. LDH is an enzyme that is present in the blood that has been shown to be negatively correlated with survival in melanoma patients. The duration seen with ipilimumab would be the main selling point for the agent if it receives FDA approval, Verschraegen added.

Furthermore, she said that if approved, ipilimumab would be the standard of care for patients with metastatic disease. However, the remaining question is whether it could be the standard of care for patients with bulky tumors, she added.

The FDA looks for a durable response, according to Dr Anna Pavlick, an associate professor of medical oncology at New York University School of Medicine. Ipilimumab should not be “written off,” she said, adding that she believes the agent will receive approval.

BMS declined to comment for this article.

Dr Antoni Ribas, a medical oncologist and investigator at the University of California, Los Angeles, noted that duration is a key issue since it is difficult to demonstrate that the 10 percent of patients that do respond to ipilimumab is better than would be expected with chemotherapy. It is difficult to determine which patients will respond, similar to IL-2, he noted. IL-2 is one of two agents approved for the treatment of metastatic melanoma

The durability of response is important, agreed Dr Aaron Mansfield, a melanoma researcher at the Mayo Clinic. Overall the complete response rates were low, he noted. There is a heterogeneity to patients’ tumors, which has made it difficult to predict response to an immunotherapy such as ipilimumab, he said.

“I think ipilimumab is going to be the first agent we’re going to see as possibly useful [with a biomarker] within the next 12 months,” said Dr Nicholas Vogelzang, chair and medical director of developmental therapeutics at Comprehensive Cancer Centers of Nevada. Plexxikon and other developers of BRAF inhibitors are also likely to shortly follow ipilimumab, in response to the current state of biomarkers and companion diagnostics in melanoma.

Despite Pfizer’s (NYSE:PFE) decision to halt a late-stage trial of tremelimumab in 2008 after poor results compared to chemotherapy, ipilimumab is definitely still moving forward, said Vogelzang. Earlier this year, Pfizer partnered with Debiopharm to continue development of tremelimumab, and the Phase III study will use a biomarker to select patients considered likely to respond to the drug. Tremelimumab is also an immunotherapy that works like ipilimumab.

While HLA-0201 patients were selected for the ipilimumab study because of the vaccine arm, Dr Mario Sznol, an oncologist at the Yale Cancer Center, said that the results will also be applicable to the HLA negative population. HLA positive patients represent approximately 50% of the Caucasian population, he noted.

Since there is no standard of care for second line patients, it is acceptable that the active arm was compared to vaccine, said Ribas. “The current systemic treatments for melanoma are so poor, the current first option is still always to consider surgery,” Mammen added. The only other FDA approved medication is interferon alfa-2b but it is “certainly not a great medication, and the response rates are pretty poor overall,” noted Dr Joshua Mammen, assistant professor of general surgery at University of Kansas Hospital. Other options include biochemotherapy, or using agents that modulate the immune system, he said.

Ipilimumab appears to work as a monotherapy and other immunotherapies have shown single agent activity in melanoma, said Sznol. However, a combination might be a better approach, he said. Since immunotherapies such as ipilimumab act specifically to activate the immune system when chemotherapy is non-specific, there is little logic behind the combination, said Ribas.

Yet Mansfield explained that if chemotherapy works, immunotherapy could be added to deal with microscopic disease.

Dr Roy Beveridge, an oncologist who is an investigator for a number of melanoma agents in development, and executive vice president and medical director for US Oncology, said despite the number of failures in melanoma, there is a renewed interest in this space due to recent data. “There’s going to be a ton of stuff presented at ASCO that will be very interesting,” he said.

With melanoma, it’s a much less predictable disease in the metastatic setting, with some patients presenting very aggressive disease, while others have very slow progression, Beveridge said. “This has been one of the historical issues with melanoma trials. There are a wide variety of responses, with what you think is a similar patient cohort,” he explained.

This is where biomarkers will hopefully play more of a role, as almost every pharmaceutical company is trying to link its drug to a biomarker, he said. Companies are exploring this area in part because the FDA has said they have to, Beveridge said, but realistically there aren’t that many great biomarkers and most of them were found in a serendipitous manner.

Regarding potential side effects, Vogelzang said that there are no significant toxicity problems associated with this agent, but some patients reported significant diarrhea, unusual immunologic responses and other toxicities. “They are strange, but not life threatening,” he said. Ipilimumab also has the advantage of being potentially active in the BRAF wild type patients – since all the other agents targeting BRAF do not work in this patient group very well, Vogelzang noted.

If the expectations for this trial are met, and are indeed positive - then that will be a game changer in melanoma, Flaherty added. The FDA may only need one positive Phase III trial for approval – despite the fact that the company is running two trials – due to the need for new treatments, he noted.

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