April 7, 2011 — The prescribing information for ipilimumab (Yervoy, Bristol-Myers Squibb), the newly approved drug for unresectable and metastatic melanoma, includes a boxed warning stating that the product can cause severe and fatal immune-mediated adverse reactions.
These adverse reactions were highlighted recently in a safety warning issued by the US Food and Drug Administration, which has also put a Risk Evaluation and Mitigation Strategy (REMS) in place for the drug in conjunction with Bristol-Myers Squibb.
Because of the potential severity and relative novelty of these immune-mediated reactions, one melanoma expert has suggested that ipilimumab should only be administered by oncologists who are trained to use the drug and who work in medical center settings.
However, another expert disagrees. Ipilimumab is for use by community-based clinicians too, said Jedd Wolchok, MD, PhD, from Memorial Sloan-Kettering Cancer Center in New York City, who is one of the drug's investigators.
"I don't think using ipilimumab is beyond any oncologist," Dr. Wolchok told Medscape Medical News.
"Formal training" is not necessary, he noted, "but you must become familiar with the side effects and how they have been successfully managed."
The newly issued REMS is a good starting point for clinicians, suggested Dr. Wolchok.
The ipilimumab REMS is designed to help healthcare professionals identify the drug's serious risks early and provides an overview of the management of moderate and more severe immune-mediated adverse reactions.
"The REMS is geared to help the community oncologist use this drug safely," said Dr. Wolchok. "The REMS takes a typical black and white algorithm and makes it colorful, visually appealing, and more accessible."
Managing Life-Threatening Adverse Effects
Ipilimumab, which reportedly costs a staggering $120,000 for a 4-dose treatment, is the first drug proven to extend survival in metastatic melanoma.
In the pivotal MDX010-20 study of ipilimumab, patients receiving ipilimumab plus a peptide vaccine (glycoprotein 100) had a median survival of 10 months, compared with 6.4 months for patients receiving the vaccine alone (P < .001); patients receiving ipilimumab alone had a median survival nearly identical to the combination in the 3-group clinical trial (10.1 months; P < .003).
Results from this study were first presented at the 2010 annual meeting of the American Society of Clinical Oncology (ASCO), as reported previously by Medscape Medical News.
Vernon Sondak, MD, from the H. Lee Moffitt Cancer Center in Tampa, Florida, acting as the discussant of the study at the ASCO plenary session, said that the "serious potentially life-threatening complications" with ipilimumab require a committed multidisciplinary team to manage them.
Dr. Sondak was especially concerned about immune-mediated diarrhea. He said that this adverse effect was "not your [5-fluorouracil]/leucovorin diarrhea," and suggested that it might limit who can administer the drug. "A trained oncologist with an experienced team can manage the toxicity," he said at the time.
Dr. Wolchok disagrees with the suggestion that there is a limited pool of oncologists who can administer the new drug. "Taking care of the side effects of ipilimumab is not intellectually difficult," he said, adding that it is "not harder, just different" than taking care of chemotherapy adverse effects.
Quick action is one key to managing immune-mediated adverse events, Dr. Wolchok reported.
"If you waste time treating ipilimumab side effects like chemotherapy side effects, the patient can get very sick," he summarized.
Dr. Wolchok addressed Dr. Sondak's concern about diarrhea. Immune-mediated diarrhea can quickly progress to life-threatening enterocolitis, he said. At the beginning of the ipilimumab study, "a number of patients died" from this complication, he said. But the investigators realized the immune-mediated nature of the diarrhea and used systemic corticosteroids as effective treatment.
The REMS indicates that clinicians should advise patients to immediately report changes in bowel movements.
Clinicians are advised to withhold treatment in the event of moderate diarrhea (4 to 6 stools a day over baseline), which can include blood or mucus in stool and abdominal pain. If symptoms improve to mild severity or are resolved, treatment can resume. However, if symptoms continue for more than a week, systemic corticosteroids should be started (0.5 mg/kg per day of prednisone or equivalent).
The REMS also advises that corticosteroids be continued until improvement to mild severity or better, and be tapered as appropriate. Ipilimumab can be resumed if symptoms are mild or better and steroid dose is 7.5 mg prednisone equivalent or less.
Severe or life-threatening enterocolitis is another story. If this occurs, the drug should be permanently discontinued, clinicians are advised by the REMS. The symptoms of the condition include 7 or more stools a day over baseline, signs of bowel perforation, ileus, and fever. Ipilimumab should also be permanently discontinued when there is an inability to reduce the steroid dose to 7.5 mg prednisone equivalent or less per day.
The immune-mediated adverse events can involve any organ system, according to the REMS. The most common immune-mediated event was diarrhea in the MDX010-20 study (any grade; 27% to 31% of the 2 ipilimumab groups). The other most common immune-mediated adverse events are hepatitis, dermatitis (including toxic epidermal necrolysis), neuropathy, and endocrinopathy.
No Response, Then What?
"This is a powerful drug." That's how investigator Steven O'Day, MD, described ipilimumab when he presented the phase 3 study data at the 2010 ASCO meeting.
Dr. O'Day, who is from the University of Southern California Keck School of Medicine in Los Angeles, was discussing the severity of adverse reactions in some patients receiving the drug. But he might have used the same phrase in discussing efficacy in some patients.
Follow-up from the earliest cohort of patients who received ipilimumab shows that ongoing complete responses in some patients with metastatic melanoma can continue past 6 years, according to commentary published last year (N Engl J Med. 2010;363:779-781).
However, most patients with metastatic melanoma do not respond to the drug.
In the 676-patient MDX010-20 study, the "best overall response rate" (patients with a complete or partial response based on RECIST criteria) was limited to 10.9% of the ipilimumab recipients.
Unfortunately, at this time, there is no way of knowing which patients are likely to respond, said Dr. Wolchok, who is participating in research on biomarkers to identify patients who could benefit most from ipilimumab and other therapies.
The current dosing of ipilimumab calls for an induction course of 3 mg/kg of body weight administered intravenously over 90 minutes, once every 3 weeks, for a total of 4 treatments.
In the event that there is no response during this time, there is still hope that a response will be forthcoming, said Dr. Wolchok.
He explained that nonresponsive patients should be categorized as having progression that is either asymptomatic or symptomatic. In the case of asymptomatic patients (those whose scans reveal worsening disease but who do not feel worse), clinicians can continue to follow the patient carefully and repeat scans in 6 weeks or so. "The activity of ipilimumab may be delayed," he said.
Indeed, in a retrospective study of phase 2 ipilimumab data, 10% to 20% of patients looked "worse on the first scan" after treatment, but eventually showed evidence of a response — without further treatment, he said.
Furthermore, the overall survival of these patients is equal to that of early responders, he added.
Dr. Wolchok is a paid consultant to Bristol-Myers Squibb. Dr. O'Day reports serving in a consultant or advisory role for and receiving honoraria and research funding from Bristol-Meyers Squibb, and receiving research funding from Medarex. Dr. Sondak reports being a speakers bureau member and providing consulting and expert testimony for Merck/Schering-Plough; he is also on advisory panels for Bristol-Myers Squibb, Genzyme, GlaxoSmithKline, Pfizer, and Provectus.
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Cite this: Ipilimumab Is for Community-Based Oncologists Too, Says Expert - Medscape - Apr 07, 2011.