CHICAGO—The PD-1 targeting antibody pembrolizumab (MK3475) has high and long-lasting activity against metastatic melanoma, according to the results of a large Phase I trial that found high survival rates, including in patients with advanced melanoma who were previously treated with ipilimumab.
“This is probably the biggest Phase I trial ever conducted in oncology. We were excited to see that MK-3475 was effective in previously untreated patients as well as in those who had multiple prior therapies, including ipilimumab,” said the study's lead author, Antoni Ribas, MD, PhD, Professor of Medicine at the David Geffen School of Medicine at UCLA, reporting the results at the American Society of Clinical Oncology Annual Meeting here (Abstract LBA9000).
“These are early data, but they tell us we are on to something really important.”
The moderator of an ASCO news briefing devoted to progress in immunotherapy, Steven O'Day, MD, Clinical Associate Professor of Medicine at the University of Southern California, Keck School of Medicine, commented: “This large Phase I clinical trial demonstrates continued excitement for anti-PD-1 therapy. We're seeing that MK-3475 results in long-lasting clinical responses in the majority of patients, and impressive overall survival with low toxicity.
“Importantly, it is effective regardless of prior ipilimumab treatment. Anti-PD-1 as a single agent is a major breakthrough and improves on the initial success of ipilimumab in metastatic melanoma.”
Release Break on Antitumor T Cells
PD-1 blocking antibodies unleash an immune response against cancer by releasing a break on antitumor T cells, Ribas explained. At last year's ASCO Annual Meeting, early results from this trial on the first 135 patients with metastatic melanoma treated with pembrolizumab, showed that the drug, which is made by Merck, led to a 41 percent response. The report for this year's meeting was an update based on 411 patients.
The study enrolled 221 patients with prior ipilimumab treatment and 190 patients who had not previously received ipilimumab. The ipilimumab-treated group was required to have at least two doses of the drug. He noted that these patients had a higher baseline tumor load, and there were more BRAF mutations in the ipilimumab-naïve group.
All patients had advanced melanoma that had spread to the skin, lungs, or other major organs. Three different dose schedules of pembrolizumab as a single agent were tested. The schedule included 162 patients who received 2 mg/kg every three weeks, 192 patients who received 10 mg/kg every three weeks, and 57 patients who received 10 mg/kg every two weeks.
Responses were evaluated every three months, and the study included seven different cohorts with different eligibility and dosing regimens.
Overall, 34 percent of patients experienced tumor response, as assessed by independent review, including 40 percent of patients not previously treated with ipilimumab and 28 percent whose disease progressed on prior ipilimumab.
“This is a remarkably high response rate in patients with high-risk factors for an antibody that hits the immune system, not the tumor directly,” Ribas said at the news briefing. Responses were durable, with 88 percent ongoing at the time of analysis after a median follow-up of 12 months. The majority of patients responded by three months, he said.
Complete response was achieved by five percent of patients overall—eight percent in the group who had not received ipilimumab and two percent in the pretreated group.
Activity was observed across all dose levels and patient subgroups, irrespective of prior ipilimumab therapy, performance status, LDH levels, BRAF mutation status, tumor stage, and number and type of prior therapies. Currently, there are no effective treatment options for patients whose disease progresses following ipilimumab therapy, Ribas noted.
The one-year overall survival rate was 69 percent across all patient subgroups, including 74 percent in patients who had not received ipilimumab and 65 percent in those who did. The median overall survival was not reached.
Median progression-free survival (PFS) was 5.5 months. “These patients used to survive six to nine months. Now we have one-year overall survival at 69 percent and 18-month survival of 62 percent,” he said, noting, though, that patients do have to be followed longer.
‘Manageable Safety Profile’
Pembrolizumab demonstrated a manageable safety profile across all doses, schedules, and ipilimumab-status subgroups, he said. “This is one of the most benign therapies I have used in my clinic.”
Overall, 12 percent of patients had grade 3/4 toxicities. The most common all-grade adverse events were fatigue (36% of patients), pruritus (24%), and rash (20%). Overall, eight percent of patients experienced serious treatment-related side effects, but only four percent discontinued treatment due to a drug-related side effect.
“Pembrolizumab, across all dose regimens tested, provided a favorable benefit-risk profile, suggesting that it is a promising treatment option for patients with advanced melanoma,” Ribas said.
O'Day noted that two-thirds of patients appear to have some clinical benefit from pembrolizumab therapy, with an objective tumor response of about 40 percent. “Prior exposure to ipiliumumab has no dramatic effect, which is important in sequencing and combining these drugs. It's remarkable that almost 90 percent of patients have a durable response, and the toxicity profile is almost unheard of in metastatic cancer,” he said.
Status with FDA
The Food and Drug Administration had previously designated pembrolizumab Breakthrough Therapy status for unresectable or metastatic melanoma. In early May of this year, the drug was granted Priority Review under the FDA's Accelerated Approval program. Ongoing randomized controlled studies are assessing the efficacy and safety of pembrolizumab in advanced melanoma patients not previously treated with ipilimumab and those whose disease progressed on or after ipilimumab. Studies in an adjuvant setting are planned.
In addition, an expanded access program for pembrolizumab is now available for eligible patients with advanced melanoma who have previously received ipilimumab and, if indicated, a BRAF inhibitor.
Asked for his opinion, Jedd Wolchok, MD, PhD, Chief of the Melanoma and Immunotherapeutics Service at Memorial Sloan Kettering Cancer Center, who was also Chair of the meeting's Scientific Committee Program, said that the results from the additional follow-up of patients look just as strong as the original data: “In the majority of patients, the disease was controlled, with an 88 percent durable response, and the safety profile was acceptable. We will learn more about this population of patients with further studies.”
Wolchok pointed to significant activity of the PD-1 targeting antibody in patients who had prior ipilimumab and those who had no prior ipilimumab therapy: “It's not clear there is a significant difference between anti-PD-1 agents. Some are more active in more patients. We don't need a head-to-head comparison. They all look to be active.”
The Merck application with the FDA to treat the ipilimumab-refractory population of advanced melanoma patients “is great news,” he said. “This expanded access will open up the drug across the U.S.”
The Discussant for the study, Jeffrey Weber, MD, PhD, Director of the Donald A. Adam Comprehensive Melanoma Research Center at Moffitt Cancer Center, noted that at the previous year's ASCO meeting, at a clinical science symposium on PD-1 blockade and the melanoma oral session, five abstracts were presented showing that the PD-1 antibodies nivolumab and MK-3475, and PDL1 antibody MPDL 3280A, had high response rates, long durations of response, and a modest, well-tolerated toxicity profile.
“Now, the results from the extended study of pembrolizumab are impressive,” he said. “This large, Phase I study is the largest PD-1 antibody experience ever presented. Pembrolizumab has an excellent toxicity profile and overall response rate of up to 40 percent in ipilimumab-naïve patients.”
The 2 mg/kg or 10 mg/kg doses every three weeks were equally effective, he noted. “Was the 10 mg/kg every two weeks more effective? It's unclear. There is almost a hint that the 10 mg/kg dose every two weeks is superior. There are higher responses than in the other regimens.”
There were fewer grade 3-4 events in ipilimumab-treated patients, he continued, but “I was surprised at the 12 percent of grade 3 or 4 immune-related adverse event rate. I thought it would be less. In other trials it is well under 10 percent.”
Weber noted that the response rates to pembrolizumab were lower in those with disease progression after prior ipilimumab therapy, in those after receiving a prior BRAF inhibitor, and in those with high LDH.
Nevertheless, he said, “the response rate is impressive, with a PFS of 5.5 months and 62 percent of patients alive at 18 months. In this early data, an overall survival rate of 69 percent at one year is outstanding. We don't have longer follow-up, but the data are very promising. A response rate of 88 percent is an impressive statistic. Pembrolizumab looks promising, but whether it is a better drug is still a question.”