CHICAGO The investigational agent ipilimumab showed activity against all stages of advanced metastatic melanoma, but was also associated with colitis and diarrhea that were not controlled by oral prophylaxis with the anti-inflammatory budesonide, investigators reported at the annual meeting of the American Society of Clinical Oncology.
"Ipilimumab, which in my opinion is an active drug in melanoma, is associated with autoinflammatory side effects, so-called immune-related adverse events," said Dr. Jeffrey S. Weber of the H. Lee Moffitt Cancer Center and Research Institute in Tampa, Fla.
The hypothesis of the study, funded by Bristol-Myers Squibb, joint developer of the monoclonal antibody ipilimumab, was that prophylactic oral budesonide (Entocort EC), an anti-inflammatory approved for treatment of Crohn's disease, might reduce the rate of grade 2 or greater gastrointestinal immune-related adverse events associated with ipilimumab therapy.
The idea did not pan out and the study did not reach its primary end point, although it did meet several of the secondary end points of melanoma control in both previously treated and treatment-naïve patients, reported Dr. Weber, who shares a patent with the University of Southern California and Bristol-Myers Squibb/Medarex.
Budesonide was chosen because it is a controlled-release oral steroid with minimal systemic corticosteroid exposure, Dr. Weber noted.
The primary end point of the study was diarrhea of grade 2 severity or greater among patients receiving 10 mg/kg of ipilimumab and either placebo or budesonide.
Secondary end points included best overall response rate per modified World Health Organization criteria, disease control rate (a composite of complete and partial response rates and stable disease), overall and 1-year survival, and biologic and pharmacokinetic parameters.
Budesonide was administered at a dose of 9 mg/day during ipilimumab induction every 3 weeks in four cycles over 12 weeks, after which budesonide was tapered. A total of 58 patients received the monoclonal antibody plus budesonide, and 57 received ipilimumab plus placebo.
The authors found that grade 2 or greater diarrhea occurred in 19 of the 58 (32.83%) of patients on budesonide, and 20 of 57 (35.1%) of those on placebo; the difference was not statistically significant, Dr. Weber said.
Objective tumor response to ipilimumab was seen in both the budesonide and control arms, at 15.8% and 12.1% of patients, respectively. Response rates were similar among previously treated and treatment-naïve patients, and in patients with stage M1a, M1b, and M1c disease. At the time of the analysis, 24 months, median overall survival had not been reached. The 1-year survival rate was similar in both groups, at 58.8% among patients on budesonide, and 59.1% of controls.
A Kaplan-Meier estimate for overall survival suggested that at about 20 months the survival rate for previously untreated patients would be 67.2%, and the rate for treatment-experienced patients would be 48.8%.
Among patients with melanoma metastatic to brain, two had a partial response, three had stable disease, one had disease progression, and one patient's status was unknown. Of these patients, one survived less than 6 months after being started on ipilimumab, four lived between 6 and 9 months, and seven were still alive from 10.4 to 19.4 months, the point of most recent follow-up.
Central nervous system adverse events related to ipilimumab were reported in two patients, with grade 2 headache and grade 1 dizziness. Immune-related adverse events were the most common toxicities seen with ipilimumab; 40% were grade 3 or 4 events. There were no bowel perforations or treatment-related deaths.
"My conclusion as to the secondary end points is that ipilimumab showed significant efficacy with an excellent estimated median overall survival in patients who got or did not receive prophylactic budesonide, previously treated or untreated patients, patients at all M stages, and including the 50% who had M1c disease," Dr. Weber said.