The long wait is over. The Food and Drug Administration has approved ipilimumab – the first drug ever proven to prolong survival in stage IV melanoma – in a down-to-the wire decision announced by the agency on March 25.
The approved indication in unresectable and metastatic melanoma comes with a risk management plan addressing life-threatening toxicity associated with the new immunotherapy, as was seen in a pivotal clinical trial conducted in previously treated patients.
Ipilimumab is the first FDA-approved treatment "to clearly demonstrate that patients with metastatic melanoma live longer by taking this treatment," Dr. Richard Pazdur, director of the Office of Oncology Drug Products in the FDA's Center for Drug Evaluation and Research, noted in the announcement.
It is being marketed by Bristol-Myers Squibb under the trade name Yervoy. The approved dose is 3 mg/kg administered intravenously over 90 minutes every 3 weeks for a total of four doses.
That the FDA did not specify a line of therapy "is extremely important and … will open the floodgates to this drug," Dr. Jeffrey Sosman, Ingram Professor of Cancer Research, professor of medicine, and director of the melanoma program at Vanderbilt University, Nashville, said in an interview after the announcement.
"Most people with metastatic melanoma will see this drug," said Dr. Sosman, coauthor of the pivotal trial. The indication does not exclude untreated patients, he noted.
A monoclonal antibody administered intravenously, ipilimumab blocks cytotoxic T-lymphocyte antigen (CTLA-4), a molecule that the FDA said "may play a role in slowing down or turning off the body's immune system, affecting its ability to fight off cancerous cells … [and] may work by allowing the body's immune system to recognize, target, and attack cells in melanoma tumors." It is being studied in other cancers as well.
Approval was based on an international study of 676 patients with previously-treated unresectable stage III or IV melanoma whose disease had progressed. The study compared ipilimumab treatment with an experimental tumor vaccine (gp100), gp100 alone, and ipilimumab alone. Median overall survival was 10 months among those who received ipilimumab plus the vaccine, 10.1 months among those who received ipilimumab alone, and 6.4 months among those who received the vaccine alone (N. Engl. J. Med. 2010;363:711-23).
In the study, 10%-15% of patients on ipilimumab developed grade 3 or 4 immune-related adverse events, and 7 of the 14 deaths related to ipilimumab were associated with immune-related adverse events. The FDA approved the drug with a Risk Evaluation and Mitigation Strategy (REMS) to educate health care professionals about the risks of the drug, and a medication guide to explain the risks of treatment to patients.
On March 21, several days before ipilimumab was approved, drugmaker Bristol-Myers-Squibb announced that that it had met the primary end point, improvement in overall survival, in a separate phase III trial conducted in previously untreated patients. This study compared ipilimumab plus dacarbazine with dacarbazine alone. The company said it would submit an abstract with the results to the American Society of Clinical Oncology for presentation in June at ASCO's annual meeting.
Dr. Sosman pointed out that the second study used a higher dose of ipilimumab (10 mg/kg), an issue that will need to be addressed, since mg/kg is the FDA-approved dose.
He described the durability of response with ipilimumab as "very good." Those with a true response (5%-10%) "do extremely well."
Another group of patients who do extremely well technically have progression of disease - a well-known phenomenon with this drug, he said. "That's the group that actually gets the drug, their tumors seem to grow, but then they stabilize," so that at the end of the first 12 weeks of treatment, their scans show progression, but later scans show regression. This describes "a large group of patients who don't technically have a response, but have a durable stabilization of their disease," Dr. Sosman said.
The toxicities associated with ipilimumab are of a different nature than those of chemotherapy, he said. (The boxed warning states that severe immune-mediated reactions require permanent discontinuation of ipilimumab and treatment with systemic, high-dose corticosteroids.)
"Physicians will have to be enlightened in how to manage these patients," Dr. Sosman said. For example, diarrhea associated with ipilimumab therapy "can easily spiral out of control" and requires an aggressive response that includes colonoscopy to visualize the bowel, and steroid therapy.
Other significant toxicities include uveitis, hypophysitis that can be problematic despite hormone replacement, hepatitis, and, rarely, neurologic problems. "It's a real spectrum that you need to be very aware of and conscientious about following patients [and] patients have to be aware of what to look for," he said.