Survival 81% at 1 Year With MK-3475 in Melanoma

Nick Mulcahy

November 21, 2013

There is an overall survival rate of 81% at 1 year in patients with advanced and unresectable melanoma treated with the experimental immunotherapy MK-3475 (Merck), according to a Kaplan–Meier estimate from a phase 1 trial.

MK-3475 is an immune checkpoint blockade inhibitor that is currently in clinical trials in a variety of cancers.

The median overall survival with MK-3475 has not yet been reached for any of the 3 doses being evaluated in the 135-patient melanoma study, reported Caroline Robert, MD, head of dermatology at the Institut Gustave-Roussy in Villejuif, France.

Dr. Robert presented the overall survival results, which are the first from this trial, earlier this week at the 2013 Society for Melanoma Research Congress in Philadelphia.

A Merck official said that the 1-year overall survival rate is "quite striking" in advanced melanoma. "Forty percent or less are typically alive at 1 year," explained Eric Rubin, MD, vice president of oncology at Merck, in a Bloomberg News report.

In the study, 40% of patients had received 2 or more previous regimens, and 30% were treatment naïve.

Median progression-free survival at the time of analysis was 36 weeks (95% confidence interval, 23 - 56).

"I am excited by the results seen for [MK-3475] to date as a single agent," said Dr. Robert in a press statement. She added that combination therapy with other treatments is also a prospect.

Immune Checkpoint Blockade Rivals

MK-3475 is a monoclonal antibody that neutralizes the programmed death 1 (PD-1) protein, which is an element of tumors that enables them to evade their nemesis, the immune system.

This new class of drug has repeatedly exceeded historic benchmarks in terms of response rates and survival in melanoma.

Merck has completed enrollment in a phase 2 registration trial that will compare MK-3475 (2 doses) with chemotherapy in patients with advanced melanoma who have progressed after previous therapy. A phase 3 registration trial comparing MK-3475 with ipilimumab in ipilimumab-naïve patients with advanced melanoma is ongoing.

In the phase 1B trial conducted by Dr. Robert and colleagues, 36% of patients had previously been treated with ipilimumab, 38% with chemotherapy, 10% with a BRAF inhibitor, and 27% with another immunotherapy.

Dr. Robert reported that the objective response rate — evaluated by a blinded central review committee using RECIST 1.1 (Response Evaluation Criteria in Solid Tumors) — was now 41% (including a 9% complete response rate).

That rate is a slight increase from the 38% presented earlier this year at the annual meeting of the American Society of Clinical Oncology (ASCO), and published simultaneously in the New England Journal of Medicine (2013;369:134-144).

The majority of responses to MK-3475 occurred within the first 12 weeks of treatment.

The phase 1B overall survival data on MK-3475 in melanoma compare favorably with data from an early trial of another anti-PD1 agent, nivolumab (Bristol-Myers Squibb). In a phase 1 melanoma trial of nivolumab, 61% of 50 evaluable patients survived to 1 year, according to a Kaplan–Meier estimate presented at the ASCO meeting.

Both MK-3475 and nivolumab are being investigated in a variety of the other cancers, and have recently shown promising data in lung cancer.

The first and only immune checkpoint blockade agent to be approved by the US Food and Drug Administration is ipilimumab (Yervoy, Bristol-Myers Squib), which is indicated for metastatic melanoma. Although it also acts on the programmed death pathway, it has a different target.

Ipilimumab had a response rate of about 10% in its pivotal clinical trial. In addition to having a low response rate, it has been plagued with a high rate of serious adverse events. This led to an ongoing concern about adverse events — especially those related to immune response — in this class of drug.

In the phase 1B trial, Dr. Robert reported that 13% of participants treated with MK-3475 experienced grade 3/4 treatment-related adverse events, and 9% discontinued treatment as a consequence.

Most treatment-related adverse events were successfully managed with treatment discontinuation, supportive care, and, occasionally, glucocorticoids, she said.

There were some potentially immune-related adverse events. Hypothyroidism occurred in 8% of patients, pneumonitis (grade 1/2) in 5%, transaminase elevations (grade 3/4) in 1%, renal insufficiency (grade 3) in 1%, and colitis (grade 3/4) in 1 patient (<1%). The 1 patient who died during the study after complications from bronchoscopy had suspected grade 2 pneumonitis.

In terms of overall adverse events of any grade, Dr. Robert reported the following events: fatigue (37%), pruritus (26%), rash (22%), diarrhea (21%), arthralgia (17%), vitiligo (14%), headache (13%), nausea (12%), asthenia (11%), myalgia (11%), and AST increase (10%).

The study was supported by Merck. Dr. Robert reports serving as a consultant or advisor for Amgen, Bristol-Myers Squibb, Celgene, GlaxoSmithKline, Merck, Novartis, and Roche.

2013 Society for Melanoma Research (SMR) Congress. Presented November 18, 2013.


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