Zosia Chustecka

November 28, 2014

ZURICH, Switzerland — The durability of the responses seen with immunotherapy in advanced metastatic melanoma continues to impress.

The latest data reported here at the Society for Melanoma Research (SMR) 2014 International Congress update results from several early trials and show that the some responses are maintained for years. Not long ago, the survival in these patients was measured in months.

The longest-term data are available for ipilimumab (Yervoy, Bristol Myers Squibb), the first of the new immune checkpoint inhibitors, launched in the United States in 2011. Some patients treated with this drug are still alive 10 years later, Stephen Hodi, MD, assistant professor of medicine at the Dana-Farber Cancer Institute, Boston, Massachusetts, reported last year. He described a survival curve that plateaus after around 3 years, with about 20% of patients receiving ipilimumab showing long-term responses, with the longest lasting up to 10 years.

In the preipilimumab era, patients with advanced metastatic melanoma were treated with chemotherapy and interferon, and survival was measured in months (on average, 10 to 11 months, with a range of 6 to 18 months, depending on where the disease had manifested itself, Dr Hodi commented at the time).

Now, at the SMR meeting, Dr Hodi reported long-term data for nivolumab (Bristol Myers Squibb), which also acts as an immune checkpoint inhibitor, but at a different site: on the programmed death pathway. This drug has been launched in Japan, but not elsewhere as yet, although it is expected to do so soon.

The long-term nivolumab data come from a phase 1 trial (the 003 study) that tested several doses of the drug, given for 96 weeks, in a total of 107 patients with advanced metastatic melanoma, who had been treated with two to five previous systemic therapies (65% had received prior immunotherapy). The overall response rate was 32%, but at the 3 mg/kg dose of nivolumab every 2 weeks (which was selected for commercialization), the response rate was 44% (7 of 17 patients). At this dose, the median progression-free survival was 10 months, and the median overall survival was 20 months.

For all patients, the survival rate at 1 year was 63%, at 2 years it was 48%, at 3 years it was 42%, and at 1 year it was 32%, Dr Hodi reported.

For patients receiving the 3 mg/kg dose, the rates were similar, with 41% survival at 3 years and 35% at 4 years.

"This is the longest follow-up of patients on any [programmed death]-inhibitor," he noted.

Nivolumab was generally well-tolerated, Dr Hodi said. Immune-related adverse events were seen in 58% of patients, but were severe (grade 3 or 4) only in 5%, and the most common were skin (38%), followed by gastrointestinal (19%, severe in 2%), endocrine (14%), and hepatic (7%) adverse events.

Long-term Data on Combination

Long-term data were also presented at the meeting on the combination of ipilimumab and nivolumab by Harriet Kluger, MD, associate professor of medicine (medical oncology) from the Yale Cancer Center, New Haven, Connecticut. These data also come from a phase 1 trial (Study 004), and again nivolumab was tested at several doses, but the dose of the combination chosen for further study was nivolumab 1 mg/kg and ipilimumab 3 mg/kg, which was used in an expansion cohort of 41 patients.

The overall response rate in the whole study, as well as in this expansion cohort, was 42%, Dr Kluger said. "We saw a fair number of deep responses," she commented, explaining that this is defined as more than 80% tumor burden reduction at 36 weeks.

The majority of responses are ongoing, as median duration of response has not yet been reached, and median overall survival for all cohorts also has not been reached.

The 2-year survival for all cohorts was 79%, Dr Kluger reported.

She also noted that the initial cohort receiving the 1 mg/kg nivolumab with 3 mg/k ipilimumab combination showed a 2-year survival rate of 88%, but noted that the data for the expansion cohort are not yet mature.

This survival is unprecedented, she commented, and several speakers at the meeting referred back to these survival rates, describing them as "outstanding."

However, the combination of the two immunotherapies had a higher rate of adverse events, Dr Kluger commented.

For all patients, grade 3 adverse events were reported in 63% of the patients (and 66% of patients in the expansion cohort), There was one treatment-related death in the expansion cohort, Dr Kluger noted. That patient developed colitis and then had infectious complications.

Immune-related gastrointestinal toxicity (grade 3 or 4) with the combination was seen in 9% to 20% of patients and is probably higher than is seen with ipilimumab alone (about 12%), she said. Hepatic toxicity was also more frequent (seen in 12% - 15% of patients), and sometimes required treatment with mycophenolate, but was always reversible.

Talking to Medscape Medical News, Dr Kluger said the response to the combination is better than that seen with either agent alone. Responses seen previously are about 12% with ipilimumab, and 30% with nivolumab, whereas the combination showed response rates of 40%, but it is not clear whether this is additive — are they same patients who would have responded?

The combination also appears to greatly improve survival rates. The 2-year survival with nivolumab alone was reported by Dr Hodi as 48%, whereas the 2-year survival for the combination in the expansion cohort reported by Dr Kluger was 88%.

However, Dr Kluger emphasized that these results come from different trials and said that a true comparison can be made only from the same trial. Such a trial has been conducted, she noted: The Checkmate 067 trial compared nivolumab alone with ipilimumab alone versus the combination of nivolumab and ipilimumab in patients with previously untreated metastatic melanoma. "The trial is done, we are now waiting for the results to be announced," she said.

Dr Kluger also noted that adverse events were more frequent with the combination than has been reported with the agents used alone. They are manageable, she said, but "you need experienced hands to handle these side effects," and she recommended the combination should be used only at expert centers that have such experience. Patients can feel quite ill, but then the treatment is over and done with, she said. Maybe that is a better option than having treatment every few weeks, but that is a patient choice, she said.

The studies were supported by Bristol-Myers Squibb, manufacturer of ipilimumab and nivolumab.

Society for Melanoma Research (SMR) 2014 International Congress: Oral presentations.


Comments on Medscape are moderated and should be professional in tone and on topic. You must declare any conflicts of interest related to your comments and responses. Please see our Commenting Guide for further information. We reserve the right to remove posts at our sole discretion.