CHICAGO—Although the large Phase III MDX010-20 trial of ipilimumab in advanced melanoma is closed, a principal investigator says there will be sufficient supplies of the experimental drug for compassionate use at centers of excellence for melanoma in the United States.
Given the survival benefit just reported for ipilimumab, researchers familiar with the trial said they expect patients with advanced melanoma will be calling their physicians asking for the drug.
“Bristol-Myers Squibb has told me they have adequate supplies of the drug for patients eligible for its compassionate-use trial,” principal investigator Steven O‘Day, MD, Chief of Research and Director of the Melanoma Program at The Angeles Clinic and Research Institute in Santa Monica, California, said at a news conference at the ASCO Annual Meeting here.
The study was also published online in the New England Journal of Medicine on the same day as the ASCO report (www.nejm.orgJune 5, 2010 [10.1056/NEJMoa1003466]) with F. Stephen Hodi, MD, of Dana-Farber Cancer Institute as first author and Dr. O‘Day as co-principal investigator.
The impressive news in these reports was that ipilimumab as first-line therapy showed an improvement in overall survival in patients with metastatic melanoma, the first drug to clearly do so in 30 years.
The trial was conducted at 75 sites in 13 countries.
Ipilimumab is a human antibody directed against CTLA-4 on the surface of T cells. CTLA-4 is a brake on the T cell, and blocking this brake accelerates and potentiates the T cell resulting in attack on and death of cancer cells.
The double-blind, placebo-controlled trial of 676 pre-treated patients, all HLA0201 positive, randomly selected patients to receive ipilimumab plus placebo (37 patients); ipilimumab plus the peptide vaccine gp100 (403 patients); or gp100 plus placebo (136 patients).
The ipilimumab regimen was 3 g/kg every three weeks for four doses. The regimen for gp100 was 1 mg every three weeks for four doses.
Patients receiving ipilimumab plus gp100 had a median survival of 10 months, compared with 6.4 months for patients receiving the vaccine alone.
Ipilimumab also showed significant increases in survival at 12 months (46% vs 25% for gp100 alone) and 24 months (24% vs 14% respectively).
Dr. O’Day said ipilimumab (regularly referred to in the news conference as “ipi”) is in a new class of targeted T cell antibodies with potential applications in melanoma and other cancers.
The news conference’s moderator, melanoma researcher Lynn M. Schuchter, MD, Professor of Medicine and Chief of Hematology/Oncology at the University of Pennsylvania, said the results were very significant findings: “We have not had any therapy that has prolonged survival in patients with Stage IV melanoma, period,” she said. “So to show in this randomized, large clinical trial this kind of benefit is really a step forward.
“The other important point is that patients tolerated this well, so we were able to see benefit without a lot of toxicity.”
That said, there were 14 deaths in this trial, approximately half of them immune related.
“This is a powerful drug,” Dr. O’Day said. Ten to 15 percent of immune-related adverse effects were Grade 3 and required immunosuppressive therapy with steroids. “Steroids were quite successful in the vast majority of patients, and they did not affect efficacy,” Dr. O’Day said.
Dr. Schucter said oncologists would like to see bigger and better responses, “but this is an important first step and we’re going to be able to build on these results with other combinations of immunotherapy, and maybe take this to earlier stages of disease.”
Dr. Schucter said there was a lot of enthusiasm at this meeting about molecularly targeted therapy in melanoma, and a lot of interest in combining the approach Dr. O’Day has taken.
“So this is really an optimistic time for our patients with advanced melanoma, to see this first step forward and this first evidence of survival benefit, it’s really important and it’s going to be a great benefit to our patients.”
It was Dr. Schucter who commented that patients hearing about the results—and now, of course, the information has been extensively covered in the media—would be asking for this drug even though it is not approved.
Dr. O’Day said, “I feel like I’m presenting this not only for myself and for my co-investigators, but also for clinicians who have worked in this disease over many decades as we faced great disappointment—but finally, we’re getting good news.”
Discussant: ‘Long Dark Tunnel’
The Discussant for Dr. O’Day’s plenary presentation, Vernon Sondak, MD, Chair of the Department of Cutaneous Oncology at H. Lee Moffitt Cancer Center, was equally enthusiastic.
“Physicians who treat melanoma have felt like they were in a long dark tunnel, with no documented improvement in survival over the past 30 years, no new FDA approved drugs since IL-2 was approved over a decade ago, first-line therapy of questionable value over supportive care, and no established second line therapy at all,” he said.
But Dr. Sondak also warned of ipilimumab’s side effects, saying treatment with ipilimumab requires a committed multidisciplinary team to manage them.