CHICAGO - Use of Bristol Myers-Squibb's immunotherapy ipilimumab will entail extensive, careful medical management in light of adverse events that can be severe and in a small number of patients fatal, experts said at an American Society of Clinical Oncology presentation detailing positive Phase III results in metastatic melanoma.

Though the trial was the first to ever show a survival benefit in metastatic melanoma and should provide strong support for approval, a closer look at the data revealed some practical challenges ahead - chiefly the need for close monitoring for immune-related adverse events.

Key findings from the Phase III '020 study of the cytotoxic T lymphocyte antigen 4 (CTLA-4) inhibitor with and without an experimental vaccine in 676 patients with stage III/IV metastatic melanoma were presented at the plenary session of the American Society of Clinical Oncology annual meeting in Chicago June 6, and also published online in the New England Journal of Medicine.

The trial is a major milestone in melanoma drug development. During the discussion of the results at the plenary session, Vernon Sondak of the Moffitt Cancer Center called it the first light at the end of the dark tunnel that has characterized metastatic melanoma therapy, where nothing has been approved since IL-2 over a decade ago. First-line therapy for metastatic melanoma has questionable value over supportive care, and there is no established second-line option, he stressed.

In contrast to that void, the ipilimumab trial showed a four-month increase in overall survival.

The three-arm study tested ipilimumab plus the experimental glycoprotein 100 vaccine (403 patients) against monotherapy with ipilimumab and placebo (137 patients), and the gp100 vaccine with placebo (136 patients).

Median overall survival was 10.1 months for patients who received ipilimumab alone, 10 months for those on ipilimuman plus the gp100 vaccine, and only 6.4 months for those who got the vaccine without the drug. The survival rate of those taking ipilimumab at one year was 46 percent compared to 25 percent for those in the vaccine arm. The rates at two years were 24 percent for ipilimumab and 14 percent for the vaccine respectively. The combination therapy arm lagged slightly behind the ipilimumab alone rates: 44 percent at 12 months and 22 percent at 24 months.

Ipilimumab worked regardless of the severity of disease, said lead investigator Steven O'Day, chief of research and director of the melanoma program at The Angeles Clinic and Research Institute in Los Angeles. Patients enrolled in the study had progressed on at least one and in many cases two treatments. Multiple metastases were common.

Committed multidisciplinary medical team is needed

But one known downside of CTLA4 inhibitors is the possibility for serious side effects as the immune system revs up. In this trial, the drug was generally well tolerated, but immune-related side effects were common and could be fatal.

The overall rate of severe adverse events (Grade 3 to 4) was 17 percent in the ipilimumab/vaccine arm compared to 23 percent in the ipilimumab-alone arm and 11.4 percent in the vaccine arm.

Furthermore, investigators reported treatment-related death rates of 2.1 in the ipilimumab/vaccine arm, 3 percent for ipilimumab alone and 1.5 percent for the vaccine alone.

The most important side effects were immune-related, occurring at all grades in 58 percent in the ipilimumab/vaccine arm, compared to 61 percent for ipilimumab alone and 31 percent for the vaccine alone.

Immune-related adverse events most commonly occurred in four sites: skin, the GI tract, the endocrine system, and the liver. The most frequent auto-immune event was diarrhea, which occurred at any grade in 27 to 31 percent of the patients in the ipilimumab arms, the NEJM paper notes.

More severe immune-related adverse events necessitated treatment with corticosteroids. Effects in the GI tract were the most important in terms of morbidity and death. Common causes of death were colitis and bowel obstruction.

In light of the toxicity, a committed multidisciplinary medical team is needed to manage use of the drug, Sondak emphasized. "Trained oncologists, an experienced team, can manage this toxicity if they are careful and thorough," he said.

The need for monitoring and management will add to the costs of care with ipilimumab, however, assuming it gains approval.

Unanswered questions, future research direction

The study results included some surprising findings on efficacy, in that the role of the gp100 vaccine was not additive to the effect. Adding the vaccine to ipilimumab actually slightly reduced the benefit. Median survival and overall survival at 12 months were lower for the combination arm than for ipilimumab alone, though the ipilimumab and ipilimumab/vaccine arms of the study outperformed the vaccine-alone control arm on all endpoints. But the vaccine actually dampened the benefits of ipilimumab, reducing best overall response rates and progression-free survival, but not negatively affecting overall survival.

"It's an interesting finding," said O'Day in an interview at the meeting. "Why ipilimumab did not do as well with the vaccine as by itself is not exactly clear." Sondak also raised that issue during the plenary as an open question.

"Since it didn't improve survival or help with any of the other endpoints, I don't think there is a role for gp100," O'Day said. "There is a clear message that ipilimumab monotherapy is the superior arm of the study."

Ipilimumab with and without the vaccine did not improve median progression-free survival, but did boost it after longer course treatment. The results reinforce the need for an overall survival endpoint in trials of cancer immunotherapy, investigators and industry sources say. PFS is not a reliable endpoint in melanoma and is particularly not suitable for immunotherapy treatment for melanoma, O'Day said.

"At this point the gold standard is [overall] survival," O'Day said.

Looking forward, O'Day told "The Pink Sheet" DAILY that further research is needed to identify biomarkers to predict response. A subset of 20 percent to 30 percent of patients did particularly well on ipilimumab treatment.

Future research will also be needed to test combinations of therapies that could push survival rates even higher than what was seen in the '020 study. Combining with Roche/Plexikkon's PLX-4032, for example, is a particularly appealing idea for investigators.

"Obviously we need to combine with other [investigational] agents. But the reality is that it's hard to get combination studies going until something is on the market," O'Day said.

- Emily Hayes (e.hayes@elsevier.com)

Ipilimumab Boosts Survival, But With Adverse Events That Need Strict Oversight

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