The Lynx Group

PD-1 Monoclonal Antibodies Usher in the Era of Immunotherapy in Oncology

September 2014, Vol 5, No 7

Oncologists’ excitement about the promise of immunotherapy is about to be tested in clinical practice, with the recent FDA approval of pembrolizumab (Kytruda; Merck), the first anti–programmed death receptor-1 (PD-1) monoclonal antibody

New data were presented for the monoclonal PD-1 antibodies, especially for nivolumab and pembrolizumab, at the 2014 American Society of Clinical Oncology (ASCO) meeting and in subsequent publications.

Early Pembrolizumab Data Used by FDA
Data presented at ASCO 2014 for pembrolizumab came from the phase 1b KEYNOTE-001 dose-finding study and were later used by the FDA for its accelerated approval of the first anti–PD-1 for melanoma.

A total of 411 patients with advanced melanoma received different doses, from 2 mg/kg to the higher dose of 10 mg/kg.

In the phase 1b KEYNOTE-001 trial of 411 patients, all patients had stopped responding to previous melanoma therapy, including ipilimumab. Overall, 34% of patients responded to pembrolizumab therapy. At 1 year, 88% of responders were still responding, with the longest response at the time of the meeting being 76 weeks. The median progression-free survival (PFS) was 5.5 months, and the estimated overall survival (OS) rate at 1 year was 69%. The median OS was not reached at the time of analysis.

“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, University of California, Los Angeles, at the meeting. 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%.

Ongoing confirmatory phase 2 and 3 clinical trials are under way to provide further survival information to the FDA, as confirmation of the accelerated approval and breakthrough therapy designation for pembrolizumab.

Nivolumab Shows Durable Results
The long-term follow-up of the pivotal phase 1 trial of nivolumab showed ongoing responses in 56% of 107 patients with melanoma. At a median follow-up of 22 months, the median 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 PFS was 9.7 months and the median OS was 20.3 months, reported Stephen Hodi, MD, of Dana-Farber Cancer Institute, Boston.

Mario Sznol, MD, of Yale School of Medicine, New Haven, CT, discussed the concurrent treatment of nivolumab and the anti–cytotoxic T-lymphocyte antigen 1 antibody ipilimumab, which led to a 2-year OS rate of 79%, and 88% of responders had ongoing responses at the time of analysis. The 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 phase 1 CA209-004 trial and for the phase 2/3 trials. All 94 patients had stage III or IV melanoma. In the phase 1 cohort of 53 patients, 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.

“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,” said Jeffrey S. Weber, MD, PhD, of H. Lee Moffitt Cancer Center and Research Institute in Tampa, FL, when discussing the results.

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.

Anti–PD-1 Antibodies in NSCLC and Renal Carcinoma
The phase 1 multicohort CA209-012 trial of patients with non–small-cell lung cancer (NSCLC) evaluated nivolumab as a single agent and in combination with ipilimumab, chemotherapy, and erlotinib. Nivolumab monotherapy in the first-line setting produced responses in 30% of patients, but the median duration of response was not reached. “Responses are ongoing in 4 of 6 (67%) responders,” said Scott N. Gettinger, MD, of Yale.

The PFS at 24 weeks was 60%, and the median PFS was 47.2 weeks in patients with nonsquamous histology and 15.1 weeks in patients with squamous tumors; the 1-year OS rate was 75%. The median OS was not reached at the time of analysis.

All of the responders expressed the PD-L1 ligand, which may possibly serve as a biomarker of activity. In this subgroup, the results were most impressive, with a 1-year OS rate of 80%.

In the phase 2 CheckMate-010 trial in advanced renal carcinoma, single-agent nivolumab produced responses in 20% to 22% of patients and yielded 1-year survival rates of 63% to 72% in patients with previous antiangiogenic treatment. In previously treated patients, the median OS was 25 months with 2-mg/kg dosing.

In a phase 1b trial of previously treated as well as treatment-naïve patients, nivolumab combined with ipilimumab showed responses in 43% to 48% of patients and a 24-week PFS rate of 65%.

“These data are encouraging as we seek to identify new treatments for patients, particularly those who pro­gress following treatment with anti­angiogenic therapy, as they have limited options,” said Robert Motzer, MD, of Memorial Sloan Kettering Cancer Center, NY.

Safety and Tolerability
The toxicities associated with anti–PD-1 agents are primarily immune-related and transient, although some can be concerning.

Nivolumab was associated with adverse events (AEs) in 85% of patients, but only 20% were grade 3/4. The combination of nivolumab and ipilim­umab resulted in grade 3/4 AEs in 49% of patients across the arms; 6% of patients had grade 3/4 pneumonitis, which was reversible. Approximately 33% of patients discontinued treatment because of AEs, and 3 patients died.

With pembrolizumab, almost 66% of patients had at least 1 drug-related AE of any grade, and 10% of patients had grade 3/4 toxicity. Grade 3/4 pneumonitis was reported in 4 patients.

It is safe to assume that oncologists will learn to manage the immune-related toxicities associated with anti–PD-1 agents.

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