Enthusiasm High for Anti­–PD-1 Agents

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Judging by the high attendance at sessions where data on the anti–PD-1 antibodies were presented, oncologists can hardly wait to have these immunotherapies in the clinic. The key ASCO data in stage III/IV melanoma are presented here.

Data on Nivolumab Maturing

The long-term follow-up of the pivotal phase 1 trial of nivolumab showed ongoing responses in 56% of 107 patients treated with the single agent. At a median follow-up of 22 months, the median overall survival (OS) was 17.3 months, and OS rates were 63% at 1 year, 48% at 2 years, and 41% at 3 years. In the subset receiving the optimal dose, 3 mg/kg, median progression-free survival (PFS) was 9.7 months, and median OS was 20.3 months, reported Stephen Hodi, MD, of the Dana-Farber Cancer Institute, Boston, MA.

Jeffrey Weber, MD, of H. Lee Moffit Cancer Center and Research Institute in Tampa, FL, who discussed the paper, commented, “For the totality of patients, many with 3 and 4 prior regimens, and some with performance status 2, these are very good data.”

Nivolumab Plus Ipilimumab

Many melanoma experts predict that the best way to use the immune checkpoint inhibitors will be in combination. In a study presented by Mario Sznol, MD, of Yale School of Medicine, New Haven, CT, this double hit paid off.

The concurrent treatment of nivolumab and the anti–CTLA-4 antibody ipilimumab led to a 2-year OS rate of 79%, and 88% of responders had ongoing responses at the time of analysis. Grade 3/4 toxicity was 62%, but the investigators felt this was manageable with the proper education of clinicians.

“While this is a small trial, those are very impressive 2-year survival data,” Sznol said. “Concurrent therapy with nivolumab and ipilimumab results in what I believe to be an unprecedented 2-year survival.”

Sznol reported updated data for the initial 53 patients treated with concurrent combination treatment regimens in the phase 1 CA209-004 trial he reported at ASCO last year, and he announced preliminary response data for a new cohort of 41 patients treated with the regimen being used in the subsequent phase 2/3 trials. All 94 patients had stage III or IV melanoma and could have received up to 3 prior systemic therapies, although 55% had no prior systemic treatments.

In the original cohort, the 1-year OS rate was 85%, and 2-year survival was 79%. The overall response rate was 42%, with confirmed complete responses increasing from 10% to 17%. To accommodate patients who had “unconventional” responses (ie, immune-related partial responses and stable disease), the researchers used an “aggregate clinical activity rate,” and this was 70%.

In the new 41-patient cohort, the objective response rate was 43%, with 10% complete responses, and the aggregate clinical activity rate was 53%. Altogether, 82% of responses were ongoing at the time of analysis.

Now with 2 cohorts evaluated, he said, “We feel very confident that the activity of this combination regimen is real.”

Combining ipilimumab with nivolumab did result in increased toxicity compared with therapy with either agent alone, including grade 3/4 side effects in 62% of the 94 patients. These events, however, “were manageable and reversible with algorithms that were established for ipilimumab,” Sznol said.

The most common grade 3/4 toxicities were increased lipase and amylase – reversible laboratory abnormalities. One drug-related death occurred in the latest cohort, a consequence of colitis.

Weber commented on the combination: “The responses were outstanding. Eight of 9 patients in cohort 2 remain in response, as do 16 of 17 in the most recent cohort,” he noted. “And for the original 53 patients, 2-year survival is 79%. In metastatic melanoma, it doesn’t get any better than that. …I cannot help but be impressed.”

Enrollment has been completed for a phase 3 trial comparing nivolumab plus ipilimumab with nivolumab or ipilimumab alone and a phase 2 trial comparing nivolumab plus ipilimumab with ipilimumab alone.

Pembrolizumab Hits the Mark

The newest agent is pembrolizumab (MK-3475), whose activity in the phase 1 KEYNOTE-001 dose-finding study was impressive enough to earn it a spot at an ASCO press briefing. In May 2014, the FDA granted pembrolizumab (called lambrolizumab at that time) a priority review designation.

“These are early data, but they tell us we are on to something really important,” said Antoni Ribas, MD, PhD, professor of medicine at the David Geffen School of Medicine at the University of California, Los Angeles.

At the press briefing, Steven O’Day, MD, clinical professor of medicine at the University of Southern California, Keck School of Medicine, Los Angeles, agreed, noting the “remarkable” finding that almost 90% of patients achieved durable responses, with a toxicity profile that is “almost unheard of in metastatic cancer.”

In the dose-finding trial with 411 patients, pembrolizumab produced responses in 34%, including 28% of patients whose disease progressed on ipilimumab. At 1 year, 88% of responders were continuing to respond, with the longest response so far being 76 weeks. Median PFS was 5.5 months, and the estimated OS rate at 1 year was 69%. Median OS was not reached at the time of analysis.

The tolerability of the drug was also noteworthy. “This is one of the most benign therapies I’ve ever used in my clinic,” Ribas noted, reporting a rate of grade 3/4 events of 10% to 12%.

The data were less impressive for another investigational anti–PD-1 antibody, pidilizumab, which produced responses in only 5% to 6% of pretreated patients, though 1-year OS was encouraging at 64.5%. A subset of patients received subsequent treatment with ipilimumab, and their survival rate rose to 80%.

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