Pembrolizumab Shows Benefit in Mucosal Melanoma

Patients with mucosal melanoma—–a rare subtype of melanoma––may benefit from the immunotherapy pembrolizumab, and should be offered immunotherapy as a standard of care, according to the results from a series of clinical trials.

The findings were presented in 2 presentations at the European Cancer Congress 2017.

Mucosal melanoma differs from melanoma, in that it occurs in the moist surfaces lining the body’s cavities, such as the airways, digestive tract, and genitourinary tracts, rather than the skin. Furthermore, it is not caused by UV radiation.

Although mucosal melanoma only accounts for 1% of all melanomas, it has a poor prognosis because it is usually diagnosed in later stages. Most patients with metastatic disease who receive conventional treatment have an average survival of less than 1 year.

In the 3 clinical trials, KEYNOTE-001, KEYNOTE-002, and KEYNOTE-006, investigators examined pembrolizumab in patients with advanced melanoma. In all 3 studies, 84 of 1567 patients had advanced mucosal melanoma.

“Sixteen of these patients (19%) responded to treatment with pembrolizumab, of whom, 12 are still alive without their disease progressing,” said investigator Dr Marcus Butler. “So far, the longest time some of these patients have continued to be successfully treated is more than 27 months.”

The results of the trials showed that of 1483 patients with other forms of advanced melanoma who received at least 1 dose of pembrolizumab, 33% responded to the treatment and 72% were still alive without disease progression. The median overall survival time was nearly 2 years, according to the investigators. The median overall survival for patients with mucosal melanoma was 11.3 months.

“Immunotherapy for melanoma has revolutionized treatment of the disease,” Dr Butler said. “There are some patients with mucosal melanoma who have had complete responses to pembrolizumab and essential return to a normal life. Some, of course, have less spectacular responses, but they still benefit from therapy.

“In earlier studies, mucosal melanoma was excluded since it is a rare subtypes. These findings suggest that mucosal melanoma patients should be offered immunotherapy as standard of care and not excluded. Response rates may be a bit lower than for other types of melanoma, so further studies to improve benefit need to be conducted.”

Pembrolizumab is designed to bind to programmed cell death protein 1 (PD-1) to block the interaction between PD-1 and its ligands—PD-L1 and PD-L2— to activate T lymphocyte cells, which may affect tumor cells and healthy cells.

In the KEYNOTE trials, 70% of patients with mucosal melanoma and PD-L1 status had PD-L1 positive tumors, according to the investigators.

“The data presented here are important because they prove that patients with mucosal melanoma can benefit from anti-PD-1 therapy and should not be excluded from this treatment,” Dr Butler said. “At this stage we don’t know why some mucosal melanoma patients responded to pembrolizumab, while others did not. This is an important question and research is ongoing.”

In the study, 90% of patients with mucosal melanoma received at least 1 prior treatment, with 39% administered ipilimumab.

“Our results show that patients benefitted from pembrolizumab regardless of whether or not they had been pretreated with ipilimumab,” Dr Butler said.

The participants received pembrolizumab intravenously at either 2-mg/kg or 10-mg/kg doses every 2 weeks, or 10-mg/kg every 2 weeks.

By combining 3 trials together, the investigators were able to show that long-lasting responses also occur in patients with mucosal melanoma treated with pembrolizumab

In the phase 3 KEYNOTE-045 trial, the findings showed that treatment with pembrolizumab resulted in longer overall survival with fewer adverse events for patients with previously treated advanced bladder cancer compared with patients treated with chemotherapy.

“KEYNOTE-045 is a landmark study,” said Dr Andrea Necchi. “It represents a real advance in the second-line treatment of advanced bladder cancer because pembrolizumab is the first therapy to show a significant survival advantage over chemotherapy for these patients.”

The KEYNOTE-45 study randomized 45 patients from 29 countries between November 2014 and November 2015 to receive either 200-mg of pembrolizumab intravenously once every 3 weeks for up to 24 months, or 1 of 3 chemotherapy options chosen by the investigators. All of the patients with advanced bladder cancer were previously treated with platinum-based chemotherapy.

The study participants administered pembrolizumab lived significantly longer compared with patients administered chemotherapy. The median overall survival was 10.3 months with pembrolizumab and 7.4 months with chemotherapy.

“In addition to helping patients live longer, more patients treated with pembrolizumab responded to treatment and for a longer duration than those treated with chemotherapy; the objective response rate—–the percentage of patients whose tumors shrank or disappeared––was almost twice as high with pembrolizumab: 21% compared to 11% on chemotherapy,” Dr Necchi said.

“The median duration of response for patients who responded to pembrolizumab has not been reached, while the median duration of response for patients who responded to chemotherapy was only 4.3 months. We estimate that almost twice as many pembrolizumab responders will respond to the therapy for at least one year: 68% versus 35%.”

Regardless of the levels of PD-L1 expression, survival and response benefits were observed.

“In addition to the overall survival benefit over chemotherapy, pembrolizumab was also associated with a much lower incidence of treatment-related [adverse events],” Dr Necchi said. “This is important because this patient population tends to be mostly elderly patients who have many other illnesses and health conditions as well. These results support the use of pembrolizumab as the new standard of care for advanced bladder cancer.”

In the trials, 61% of patients treated with pembrolizumab experienced adverse events (AEs) of any grade of severity compared with 90% of patients treated with chemotherapy. AEs that were grade 3, 4, or 5 were reported in 15% and 49% of patients, respectively.

Currently, there are no standard second-line therapy for advanced bladder cancer. Although paclitaxel, docetaxel, and vinflunine are the most commonly-used anti-cancer drugs, they have limited benefit, the study concluded.