Nick Mulcahy

April 20, 2015

PHILADELPHIA — The combination of two immune checkpoint inhibitors with different mechanisms of action produced a "remarkable" overall rate of response in previously untreated patients with advanced melanoma in a two-group phase 2 trial, said lead investigator F. Stephen Hodi, MD, from the Dana-Farber Cancer Institute in Boston.

The objective response rate was 61% (44 of 72 patients) in patients who received the combination of nivolumab (Opdivo, Bristol-Myers Squibb) and ipilimumab (Yervoy, Bristol-Myers Squibb), compared with 11% (4 of 37 patients) in patients who received ipilimumab alone (P < .001).

But "more important" than the overall response, said Dr Hodi, is the complete response rate of 22% (16 patients) in the combination group. The number of patients who had their tumors completely disappear is "eye-opening," he told Medscape Medical News.

There were no complete responses in the ipilimumab monotherapy group.

In addition, partial response was better with the combination of nivolumab plus ipilimumab than with ipilimumab monotherapy (39% vs 11%).

Dr Hodi discussed the ground-breaking data during a press briefing here at the American Association for Cancer Research 2015 Annual Meeting. The study was published online in the New England Journal of Medicine to coincide with the presentation.

The treatment strategy that combines a programmed cell death-1 (PD-1) inhibitor such as nivolumab with the cytotoxic T-lymphocyte antigen 4 (CTLA-4) inhibitor ipilimumab "looks like a major step forward," said Michael Atkins, MD, from the Georgetown Lombardi Comprehensive Cancer Center in Washington, DC, who was not involved with the new study and was asked to comment by Medscape Medical News.

This looks like a major step forward.

BRAF and MEK inhibitors approved by the US Food and Drug Administration also had very high overall response rates in clinical trials in advanced melanoma, Dr Atkins noted. But the activity of those agents is time-limited, he said. Patients almost invariably develop drug resistance, typically 12 months or less after the start of therapy.

In contrast, many patients who respond to immune checkpoint blockers such as nivolumab and ipilimumab have long-term responses, he pointed out. Some ipilimumab patients now have responses of 10 years or more.

There appears to be an antitumor synergy with dual immune checkpoint blockade. Single-agent PD-1 inhibitors have demonstrated response rates of around 30% in this setting in previous studies, and single-agent ipilimumab has demonstrated response rates around 10%.

However, Dr Atkins held back his full endorsement of the combination therapy in advanced melanoma. "It remains to be seen how the combination compares with nivolumab alone," he said.

He is waiting on results from studies such as ongoing phase 3 double-blind randomized CheckMate 067 study, which is comparing combined PD-1 and CTLA-4 blockade with monotherapy.

An issue that has not been addressed because the combination has only been tested in clinical trials is cost, he noted. It has been reported that nivolumab costs $143,000 annually and ipilimumab costs $120,000 annually.

Previously Untreated Patients

In their study, Dr Hodi and his colleagues evaluated 142 patients with advanced melanoma who had not received previous therapy. Of these, 109 patients had the wild-type (normal) BRAF gene in their tumors and 33 had BRAF V600 mutations.

Patients were randomly assigned (2:1 ratio) to receive ipilimumab 3 mg/kg of body weight combined with either nivolumab 1 mg/kg or placebo once every 3 weeks for four doses, followed by nivolumab 3 mg/kg or placebo every 2 weeks until disease progression or the occurrence of unacceptable toxic effects.

In the combination group, results were worse for patients with BRAF V600 mutations than for patients with wild-type BRAF. For those with BRAF V600 mutations, the overall response rate of 44%; 17% achieved a complete response and 26% achieved a partial response.

We are in the middle of a revolution.

The encouraging results with dual immune checkpoint blockade need to be understood in a larger context, said Louis Weiner, MD, from the Lombardi Cancer Center, who moderated the press briefing. "We are in the middle of a revolution," he said, adding that more treatment breakthroughs are "on the way."

"This is going to be looked back on — when the next Emperor of All Maladies get played on PBS — as an inflection point," said Dr Weiner, suggesting that research is just starting in the field of immunotherapy.

Combo Was More Toxic

The median duration of response was not reached in either the combination or the monotherapy groups.

Median progression-free survival was better with the combination than with monotherapy; it was not reached with the combination and was 4.4 months with ipilimumab monotherapy (hazard ratio for disease progression or death, 0.40; 95% confidence interval, 0.23 - 0.68; P < .001).

However, on the downside, the combination was more toxic, the researchers report.

Drug-related adverse events of grade 3 or 4 were more common in the combination group than in the monotherapy group (54% vs 24%).

The concerning adverse events with "potential immunologic causes" were consistent with those in a phase 1 study, according to the researchers, who add that "most" resolved with immune-modulating medication.

Dr Atkins said he is not overly concerned about the higher rate of adverse events associated with combination therapy. "There is a fair amount of toxicity, but it is treatable and reversible for the most part," he said. Importantly, treatment of the toxicity does not seem to interfere with the antitumor activity of the immune checkpoint blockade, he pointed out.

This study was funded by Bristol-Myers Squibb. Dr Hodi has disclosed no relevant financial relationships. Dr Atkins reports financial ties to Bristol-Myers Squibb and multiple other pharmaceutical companies.

N Engl J Med. Published online April 20, 2015. Abstract

American Association for Cancer Research (AACR) 2015 Annual Meeting: Abstract 2860. Presented April 20, 2015.


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