Nick Mulcahy

June 06, 2011

June 6, 2011 (Chicago, Illinois) — The immunotherapy ipilimumab (Yervoy, Bristol-Myers Squibb) is effective as first-line therapy in melanoma, increasing the number of patients who can benefit from the drug, which has just been approved for use as second-line therapy.

The data on first-line use come from a phase 3 international multicenter study of 502 patients, which was presented here at the American Society of Clinical Oncology (ASCO®) 2011 Annual Meeting, and published online June 5 in the New England Journal of Medicine to coincide with the presentation.

Ipilimumab in combination with dacarbazine improved overall survival in patients with previously untreated metastatic melanoma, compared with dacarbazine plus placebo, said senior author Jedd Wolchok, MD, from Memorial Sloan-Kettering Cancer Center in New York City, at a press conference.

The drug was recently approved by the US Food and Drug Administration as second-line therapy for patients with advanced melanoma, based on a study of previously treated patients presented at ASCO last year.

Notably, the study dose of 10 mg/kg body weight used in this study was higher than that used in the 2010 study, said Dr. Wolchok.

Overall survival was significantly longer in the ipilimumab group than in the placebo group (11.2 vs 9.1 months; hazard ratio [HR] for death, 0.72; P < .001), Dr. Wolchok and his coauthors report. The ipilimumab group had higher survival rates than the placebo group at 1 year (47.3% vs 36.3%), 2 years (28.5% vs 17.9%), and 3 years (20.8% vs 12.2%). The 3-year results are "very mature," explained Dr. Wolchok.

The survival data were less than expected but not discouraging, suggested an expert not involved in the study.

The improvement was "not what we had hoped," Kari Kendra, MD, from Ohio State University in Columbus, told Medscape Medical News. But, she added, the data "still demonstrate that the combination of chemotherapy with [ipilimumab] can enhance survival."

Dr. Wolchok also reported that drug-related, grade 3/4 adverse events occurred in 50.6% of patients treated with ipilimumab plus dacarbazine, compared with 11.6% treated with dacarbazine and placebo.

However, on the bright side of the adverse events data, no drug-related deaths or gastrointestinal perforations occurred in the ipilimumab group. In the previous major study of ipilimumab, there were 7 treatment-related deaths.

"The ability to manage the toxicities associated with [ipilimumab] has improved," said Dr. Kendra. "Clinicians need to be aware of the differences in the supportive care necessary when using biologic agents, compared to that used with chemotherapeutic agents."

Recently, Dr. Wolchok told Medscape Medical News that the potential need for supportive care should not discourage community-based clinicians from prescribing ipilimumab, which is the first-ever drug proven to extend survival in metastatic melanoma and costs a reported $127,000 for a 4-dose treatment.

Tumor Response Details

Dr. Wolchok highlighted tumor response in the 2 different treatment groups at the press conference.

The rate of disease control — a complete or partial response or stable disease — did not differ significantly between the ipilimumab and placebo groups (33.2% vs 30.2%; P = .41).

However, the rate of best overall response (i.e., a complete or partial response) was significantly better in the ipilimumab group than in the placebo group (15.2% vs 10.3%; P = .09).

However, one expert looked at the matter differently.

"Some of these responses are complete and durable over years, something we have not seen in metastatic melanoma, said Petra Rietschel, MD, PhD, from the Montefiore Einstein Center for Cancer Care in the Bronx, New York, who is a former fellow at Memorial Sloan-Kettering. She also noted that ipilimumab has at least one advantage over another agent for metastatic melanoma — vemurafenib — which received high praise at ASCO this year. "Vemurafenib has higher response rates, but the responses are not as durable; resistance seems to develop," she pointed out.

Indeed, at the press conference, Dr. Wolchok stressed that the median duration of response among patients with a complete or partial response was 19.3 months (95% confidence interval [CI], 12.1 to 26.1) in the ipilimumab group and 8.1 months (95% CI, 5.19 to 19.8) in the placebo group (P = .03).

"This sustained response is very characteristic of ipilimumab as an immunotherapy," said Dr. Wolchok.

Prolonged survival has occurred in some patients who have now been followed for 4 years, report the study authors.

Especially Poor Prognosis for Many

More than 50% of the patients in the study had M1c disease, which indicates the presence of visceral metastases, elevated lactate dehydrogenase levels (LDH), or both, say the authors. Also, more than 35% had baseline elevations in LDH levels. Both of these characteristics are "associated with poor survival," they write.

Dr. Kendra agreed with the authors.

"The interesting feature in this population is the percentage of patients with an elevated LDH. An elevated LDH is a poor prognostic factor in patients with melanoma," she said. "I look forward to seeing the data with the combination on a population with a normal LDH."

Study Design

In the study, patients were randomized equally to receive either ipilimumab plus dacarbazine (850 mg/m2) or dacarbazine plus placebo at weeks 1, 4, 7, and 10, followed by dacarbazine alone every 3 weeks through to week 22 (induction phase).

Treatment was discontinued if toxic effects associated with the drug or progressive disease were noted during weeks 12 to 24.

Discontinuation due to a drug-related adverse event was reported in 89 of the 247 patients in the ipilimumab group who received at least 1 dose of the study drug (36.0%), and in 10 of the 251 patients in the placebo group who received at least 1 dose of the study drug (4.0%), write the authors.

However, the most frequent reason for discontinuation of the study drug across the entire study was disease progression (in 46.2% of patients in the ipilimumab group and 77.3% in the placebo group), they also report.

At week 24, a maintenance phase began, in which patients received placebo or ipilimumab every 12 weeks until progression of the disease, the development of toxic effects, or the end of the study. Only patients with stable disease or an objective response during the induction phase who did not have a dose-limiting adverse event were eligible to enter the maintenance phase.

At least 1 maintenance dose was administered to 43 patients in the ipilimumab group (17.2%) and 53 in the placebo group (21.0%), report the authors.

Adverse Events

Adverse events of all grades for which there was a higher incidence in the ipilimumab group than in the placebo group included elevation of alanine aminotransferase levels (33.2% vs 5.6%), elevation of aspartate aminotransferase levels (29.1% vs 5.6%), diarrhea (36.4% vs 24.7%), pruritus (29.6% vs 8.8%), and rash (24.7% vs 6.8%).

The elevated aminotransferase levels were "probably due to the pairing with dacarbazine," said Dr. Wolchok. In their paper, the study authors note that dacarbazine is "known to cause hepatoxic effects when used as a monotherapy."

Notably, the study findings for adverse events are different than those seen in previous studies of ipilimumab, the authors say. These include the rates of diarrhea (4% in this study vs 11% in the previous studies) and of colitis (2% vs 5%).

Treatment for immune-related adverse events was common in the study. "The proportion of patients who received glucocorticoids or other immunosuppressant agents after the emergence of high-grade immune-mediated hepatitis was 80.8% (63 of 78 patients, including 5 patients who received mycophenolate mofetil) in the ipilimumab–dacarbazine group and 33.3% (2 of 6 patients) in the dacarbazine group," write the authors.

The study was sponsored by Bristol-Myers Squibb. Jedd D. Wolchok reports serving as a consultant/advisory for Bristol-Myers Squibb. Some of the coauthors report financial relationships with industry, including Roche, or are employees of Roche.

N Engl J Med. Published online June 5, 2011. Abstract

American Society of Clinical Oncology (ASCO®) 2011 Annual Meeting: Abstract LBA5. Presented June 6, 2011.

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