Enthusiasm Sky High for Immunotherapy with Anti–PD-1 Agents in Cancer

August 2014 Vol 7, Special Issue ASCO 2014 Payers' Perspectives in Oncology - Emerging Therapies

Judging by the high attendance at sessions where data on the anti–programmed death (PD)-1 antibodies were presented, oncologists can hardly wait to have these immunotherapies in the clinic. The key data from ASCO 2014 regarding 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. The OS rates were 63% at 1 year, 48% at 2 years, and 41% at 3 years. In the subset of patients receiving the optimal dose of nivolumab, 3 mg/kg, the median progression-free survival (PFS) was 9.7 months and the median OS was 20.3 months, reported F. Stephen Hodi, MD, of Dana-Farber Cancer Institute, Boston.

Jeffrey S. Weber, MD, PhD, of H. Lee Moffitt Cancer Center and Research Institute in Tampa, FL, who discussed the results, 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–cytotoxic T-lymphocyte antigen (CTLA)-1 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 rate was 62%, but this was manageable with the proper education of clinicians.

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

Dr Sznol reported updated data for the initial 53 patients who received concurrent combination treatment regimens in the phase 1 CA209-004 trial that he reported at ASCO last year. He announced preliminary response data for a new cohort of 41 patients receiving 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 previous systemic therapies, although 55% of patients received no previous systemic treatments.

In the original cohort, the 1-year OS rate was 85%, and the 2-year survival rate 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,” which was 70%.

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

Now with 2 cohorts evaluated, Dr Sznol 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 either single agent, and grade 3/4 side effects occurred in 62% of the 94 patients. These events, however, “were manageable and reversible with algorithms that were established for ipilimumab,” Dr Sznol pointed out.

The most common grade 3/4 toxicities were increased lipase and amylase—reversible laboratory abnormalities. One drug-related death occurred in the latest cohort, which resulted from colitis.

Discussing the combination, Dr Weber noted that, “The responses were outstanding. Eight of 9 patients in cohort 2 remain in response, as do 16 of 17 in the most recent cohort. 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 versus nivolumab or ipilimumab alone, as well as a phase 2 trial comparing nivolumab plus ipi­limumab versus 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 a spot at the ASCO 2014 press briefing. In May 2014, the US Food and Drug Administration granted pembrolizumab (formerly lambrolizu­mab) a priority review designation.

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

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

In the dose-finding trial of 411 patients, pembrolizumab produced responses in 34% of patients, including 28% whose disease progressed with ipilimumab therapy. At 1 year, 88% of responders were continuing to respond, with the longest response so far being 76 weeks. The median PFS was 5.5 months, and the estimated OS rate at 1 year was 69%. The 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,” Dr 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, although the 1-year OS rate 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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