In 2015, pembrolizumab was approved as the first anti-PD-1 (programmed death receptor-1) therapy approved in the United States for the treatment of advanced melanoma, specifically for the treatment of patients with unresectable or metastatic melanoma. 

Mollie Reed, MSN, ACNP-BC, from Tennessee Oncology, Nashville, TN, provided an overview of the lifetime risks and increasing mortality rates for invasive melanoma in the United States. Estimates suggest that 76,380 new cases of melanoma will be diagnosed in 2016 with 10,130 deaths. And although melanoma accounts for only 1% of all skin cancer cases, it accounts for the majority of skin cancer deaths. 

“Metastatic melanoma is a devastating disease,” Reed said. “The incidence of melanoma has changed over time, reflecting differences in occupational and recreational sun exposure. Overall, the incidence of cutaneous melanoma has risen rapidly over the past 30 years.”

Many factors contribute to the likelihood that a person will develop melanoma, including personal or family history, presence of atypical, large, or numerous (> 50) moles, exposure to UV radiation from sunlight or use of indoor tanning. A risk factor not often discussed, said Reed, is immunosuppression—patients, for example, who have asthma and have been on long-term steroids.

The key emphasis of the presentation was the role of the immune system in advanced melanoma. The body’s fully functioning immune system is designed to fight foreign pathogens like bacteria, viruses, and cancer cells. Tumor cells express multiple antigens that normal tissues don’t express. The immune system’s antigen-presenting cells—or dendritic cells—recognize foreign antigens and present them to naïve cytotoxic T cells, also known as “killer” T cells; this presentation usually occurs in lymph nodes. The naïve cytotoxic cells, in turn, become activated to specifically attack the tumor cells. To prevent the immune response from continuing indefinitely, the body has natural checkpoints that regulate the intensity, duration, and quality of the immune response, which helps prevent autoimmune diseases. PD-1 is an inhibitory checkpoint that plays a role in decreasing the body’s T-cell-mediated immune response when necessary. However, tumor cells can evade the immune system’s checkpoint, specifically through the PD-L1 and PD-L2 ligand, found on the tumor cell. These ligands are problematic because they engage the PD-1 checkpoint and can “turn off” the body’s immune response.

To keep the body’s immune system engaged, pembrolizumab, a humanized monoclonal antibody, blocks this interaction between the PD-1 and its ligands, PDL1 and PD-L2 by engaging the PD-1 receptors instead of the ligands. This allows the T-cells to remain activated to fight the tumor cells.

Reed explained the KEYNOTE-006 study, which studied the effectiveness of pembrolizumab for treating advanced melanoma by comparing it to ipilimumab. The study included and randomized patients with unresectable or metastatic melanoma whowere naïve to ipilimumab and or who had received only one dosage prior to therapy. There were three treatment arms: patients—primarily Caucasian (98%) males (60%) were randomized to receive either pembrolizumab IV dosed at 10 mg/kg every two weeks (n = 279), pembrolizumab IV dosed at 10 mg/kg every three weeks (n = 278), or ipilimumab IV dosed 3 mg/kg every three weeks for four doses (n = 278). Pembrolizumab treatment continued until disease progression or unacceptable toxicity occurred; patients were treated with ipilimumab for four doses unless discontinued earlier for disease progression or unacceptable toxicity. Reed noted that 66% of participants had no prior systemic therapy for metastatic disease.

The primary endpoints of the study were overall survival and progression-free survival using RECIST v 1.1, or the Response Evaluation Criteria in Solid Tumors Version 1.1. The secondary endpoints were overall response rate and duration of the response. Overall, the study supported the effectiveness of pembrolizumab for the treatment of advanced melanoma.

In terms of overall survival, there was a

  • 31% reduction in the risk of death with pembrolizumab 10 mg/kg every three weeks versus ipilimumab;
  • 37% reduction in the risk of death with pembrolizumab 10 mg/kg every two weeks versus ipilimumab; and 
  • Lower number of deaths observed in each arm: 92/277 with pembrolizumab every three weeks, 85/279 with pembrolizumab every two weeks, and 112/278 with ipilimumab.

The study showed, for progression-free survival,

  • A 42% reduction in the risk of disease progression or death with pembrolizumab 10 mg/kg every three weeks versus ipilimumab and pembrolizumab 10 mg/kg every two weeks versus ipilimumab 
  • Median progression-free survival (PFS) was, respectively, 4.1 months and 5.5 months for pembrolizumab 10 mg/kg every three weeks and pembrolizumab 10 mg/kg every two weeks.

The overall response rates and response durations were also positive. Patients treated with pembrolizumab 10 mg/kg every three weeks had an overall response rate (ORR) of 33%; those treated with pembrolizumab 10 mg/kg every two weeks had an ORR of 34%; and those treated with ipilimumab had an ORR of 12%. Response rates for both pembrolizumab treatment arms ranged from roughly one month to a little more than eight months.

The current U.S. Food and Drug Administration approved dosing for patients is 2 mg/kg administered an IV infusion over 30 minutes every three weeks. Reed stressed that patient lab reports should be monitored from start of treatment and periodically throughout the treatment and as indicated based on clinical evaluation. If laboratory results are unusual, further examination to confirm the etiology or exclude other causes should be done. There may be some immune-mediated adverse reactions, graded 1–4, for patients, including pneumonitis, colitis, hepatitis, hyperthyroidism, hypothyroidism, and others. Severe and life-threatening infusion-relation reactions have been reported in 0.1% of patients with melanoma or another tumor type treated with pembrolizumab. These potential immune-mediated adverse reactions should be managed with FDA-approved dose modifications and recommendations outlined in the prescribing information.

Reed stated that the most common adverse reactions observed in the KEYNOTE-006 study were grade 1 or 2, and included fatigue, diarrhea, rash, and nausea. Of the 555 patients who received pembrolizumab, 9% stopped treatment because of adverse reactions, namely colitis, autoimmune hepatitis, allergic reaction, polyneuropathy, and cardiac failure. And although pembrolizumab showed positive results for the study endpoints, the treatment may cause fetal harm, so women should use contraception during treatment and four months after the last treatment. It isn’t yet known if the treatment is excreted into human milk and the safety and effectiveness of pembrolizumab hasn’t been established in pediatric patients.

When administering, Reed said, the vial contents should be visually inspected for particulate matter or discoloration; vials should be discarded if particulates are seen. Pembrolizumab solution should be diluted before IV administration, and any unused portions should be left in the vial. Reed stressed that the drug doesn’t contain a preservative, so the diluted solution should be stored at room temperature for no more than six hours or refrigerated for no more than 24 hours; the drug should not be frozen.

Overall, “Pembrolizumab demonstrated superior overall survival, PFS, and ORR versus ipilimumab in ipilimumab-naïve patients with unresectable or metastatic melanoma,” said Reed. Because of this, pembrolizumab is recommended by the National Comprehensive Cancer Network as a category 2A option for the treatment of naïve and refractory advanced metastatic or unresectable melanoma.