Nick Mulcahy

April 19, 2015

PHILADELPHIA — What has been believed in the treatment of advanced melanoma has now been definitively proven: pembrolizumab (Keytruda, Merck) is a better initial therapy than the current standard, ipilimumab (Yervoy, Bristol-Myers Squibb).

In the first head-to-head trial of two types of immune checkpoint inhibitors, pembrolizumab significantly prolonged progression-free survival and overall survival and had less high-grade toxicity.

The phase 3 trial was stopped early last month as primary endpoints were met.

Now, the full results were presented here today at the American Association for Cancer Research (AACR) 2015 Annual Meeting.

The study, known as KEYNOTE-006, was also simultaneously published in the New England Journal of Medicine. The new results change the treatment of melanoma, said experts.

"We think this data should change the paradigm of treatment of these patients," said lead author Antoni Ribas, MD, PhD, from the University of California, Los Angeles, Jonsson Comprehensive Cancer Center, at a meeting press briefing.

"This [study] is now expected to change the treatment landscape for melanoma — this is a very high-impact trial," said Suzanne Topolian, MD, from the Kimmel Comprehensive Cancer Center at Johns Hopkins University in Baltimore, Maryland, who moderated the press briefing.

The study results are not completely surprising, as earlier studies had suggested that programmed cell death-1 (PD-1) inhibitors including pembrolizumab and nivolumab (Opdivo, Bristol-Myers Squibb) are more effective than ipilimumab, a cytotoxic T-lymphocyte antigen 4 (CTLA-4) inhibitor.

This study clearly demonstrates the superiority of the PD-1 inhibitor. Dr Anthony Olszankski

"This study clearly demonstrates the superiority of the PD-1 inhibitor compared to the CTLA-4 inhibitor," said Anthony Olszankski, MD, RPh, from Fox Chase Cancer Center in Philadelphia, Pennsylvania, who was not involved in the study, in comments to Medscape Medical News. "It was an absolutely necessary trial."

At this time, in the initial treatment of advanced melanoma (that does not have a BRAF mutation), ipilimumab is the standard of care and has been the lone approved drug in this first-line setting in the United States since 2011.

Pembrolizumab is currently only approved for use in patients who are no longer responding to other drugs, including ipilimumab and BRAF inhibitors. This indication received accelerated approval from the US Food and Drug Administration in 2014 on the basis of tumor response rate and durability of response. Merck intends to submit a supplemental New Drug Application for pembrolizumab as first-line therapy for advanced melanoma in mid-2015, the company said in a press release.

Nevertheless, in the United States, the Centers for Medicare and Medicaid pay for pembrolizumab use in the first-line.

Still, pembrolizumab is ready for a full change of status in regulatory bodies, said Dr Ribas

"I hope the drug regulatory agencies around the world act fast on approving pembrolizumab for front-line therapy for metastatic melanoma," he declared in a meeting press statement.

I hope the drug regulatory agencies around the world act fast. Dr Antoni Ribas

Even more change in the first-line setting is eventually anticipated, as investigators will report results here tomorrow of another phase 3 trial that features a different PD-1 inhibitor: nivolumab and ipilimumab.

In the current trial, 834 patients with advanced melanoma (two thirds of whom were treatment-naive) were randomly assigned to receive pembrolizumab either every 2 weeks or every 3 weeks (both given indefinitely at 10 mg/kg body weight) or to a total of four doses of ipilimumab (at 3 mg/kg body weight).

The estimated 6-month progression-free survival rates for the newer drug were nearly twice as good as those for the older drug: 47.3% for pembrolizumab every 2 weeks, 46.4% for pembrolizumab every 3 weeks, and 26.5% for ipilimumab (hazard ratio [HR] for disease progression, 0.58; P < .001 for both pembrolizumab regimens vs ipilimumab).

The estimated 12-month survival rates were 74.1%, 68.4%, and 58.2%, respectively (HR for death for pembrolizumab every 2 weeks, 0.63; P = .0005; HR for pembrolizumab every 3 weeks, 0.69; P = .0036).

"Most importantly, overall survival was impacted," said Dr Olszankski about the various results.

The response rates were nearly three times greater for pembrolizumab: 33.7% for the every-2-week schedule and 32.9% for every 3 weeks compared with 11.9% for ipilimumab (P < .001 for both comparisons).

Responses were ongoing in 89.4%, 96.7%, and 87.9% of responding patients, respectively, after a median follow-up of 7.9 months.

That is really amazing. Dr Anthony Olszankski

"What's encouraging here is that patients who get a response are likely to have an ongoing response," said Dr Olszankski.

"Prior to immunotherapy, we didn't use the term durable response," he said

The fact that the average response is 8 months at this point is a good sign, he said, but durability can mean much more. "Many responders live for a long time, and that is really amazing," commented Dr Olszankski.

Adverse Events and a Note About PD-L1 Expression

The safety profile of pembrolizumab was similar to that in previous studies, write the authors in their new paper, "with no unexpected safety concerns and few grade 3 to 5 treatment-related adverse events reported to date."

Pembrolizumab was administered indefinitely (until disease progression or unacceptable adverse effects), but ipilimumab was given in four doses, as indicated.

The treatment schedules resulted in patients receiving pembrolizumab for much longer periods. In fact, exposure to treatment was approximately three times as long with pembrolizumab as with ipilimumab, "which may account for an increase in the cumulative number of adverse events [with pembrolizumab]," write the study authors.

However, Dr Olszankski said other adverse event data were more important.

"Patients treated with ipilimumab were nearly twice as likely to have a serious side effect and to discontinue therapy due to side effects, compared to pembrolizumab. Additionally, the rate of autoimmune side effects favored pembrolizumab as well," he summarized.

Grade 3 to 5 adverse events attributed to a study drug by investigators occurred in 13.3%, 10.1%, and 19.9% of patients in the pembrolizumab groups (every 2 weeks and 3 weeks) and the ipilimumab group, respectively.

There was one treatment-related death in the ipilimumab group.

The rate of discontinuation resulting from treatment-related adverse events was lower in each pembrolizumab group than in the ipilimumab group (4.0%, 6.9%, and 9.4%, respectively).

The autoimmune or immune-related adverse events most frequently observed with pembrolizumab were hypothyroidism (10.1% in the 2-week group and 8.7% in the 3-week group) and hyperthyroidism (6.5% and 3.2%, respectively).

Grade 3 to 4 events that were reported in more than 1% of pembrolizumab-treated patients were colitis (1.4% and 2.5%, respectively) and hepatitis (1.1% and 1.8%, respectively).

In the ipilimumab group, the most common autoimmune or immune-related adverse event was colitis, which occurred in 8.2% of patients. Grade 3 to 4 events occurring in more than 1% of ipilimumab-treated patients were colitis (7.0%) and inflammation of the pituitary gland (1.6%).

The study design included an analysis of treatment response by PD-1 ligand (PD-L1) expression, the presence of which helps inactivate the immune system's T-cells that seek to combat cancer.

However, the authors report that, for PD-L1 expression, the sample size "was too small (less than 20% of patients) to draw a definite conclusion on relative efficacy."

The study was funded by Merck. One coauthor reports financial ties to MSD, Bristol-Myers Squibb, Roche, Novartis, GlaxoSmithKline, and Amgen. Dr Ribas reports financial ties to Merck. Dr Olszankski has disclosed no relevant financial relationships.

American Association for Cancer Research (AACR) 2015 Annual Meeting: Abstract 101. Presented April 19, 2014.

N Engl J Med. Published online April 19, 2015. Full text


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