KEYNOTE-001 findings add support to pembrolizumab for advanced melanoma

By Lynda Williams

A third of patients with advanced or metastatic melanoma will achieve an objective response to treatment with the programmed cell death protein (PD-1) inhibitor pembrolizumab, suggest KEYNOTE-001 findings, regardless of whether they have previously been treated with ipilimumab.

Describing the study's objective response rate as "clinically meaningful", Antoni Ribas, from University of California-Los Angeles in the USA, and co-investigators write in JAMA: "Results of the progression-free survival analysis also support the durability of the clinical benefit associated with pembrolizumab.

"Collectively, these data suggest that the majority of patients with melanoma treated with pembrolizumab will experience lasting objective responses."

The open-label phase Ib trial includes 665 patients enrolled in randomised or nonrandomised study groups and treated with pembrolizumab 10 mg/kg every 2 weeks, 10 mg/kg every 3 weeks or 2 mg/kg every 3 weeks until disease progression, intolerable toxicity or investigator decision.

A RECIST v1.1 objective response was achieved by 33% of 581 patients who had measurable disease at baseline, with a complete response reported in 8% and a disease control rate of 51%.

The researchers note that responses were ongoing in 74% of 205 patients at the time of data cutoff, after a median of 21 months, with 79% achieving a response for at least 6 months and 44% for a least a year.

Subgroup analysis gave an objective response rate of 29% for 304 patients who had previously been treated with the cytotoxic T lymphocyte-associated protein-4 (CTLA-4) inhibitor ipilimumab and 39% for 107 ipilimumab-naïve patients. And for 133 patients with no prior treatment for advanced disease, a RECIST objective response was achieved by 45%, a complete response by 14% and disease control in 61%.

Twelve-month progression-free survival (PFS) was achieved by 35% of patients, rising to 52% for treatment-naïve patients. And median overall survival was 23 months with 66% achieving 12 months and 49% 2 years. In the treatment-naïve patients, these values were 31 months, 73% and 60%, respectively.

The researchers note that 14% of the 665 patients had at least one grade 3 or 4 adverse event and 4% discontinued treatment because of side effects. There were serious treatment-related adverse events in 9% of patients.

In an accompanying editorial, Shailender Bhatia and John Thompson, from Fred Hutchinson Cancer Research Center in Seattle, Washington, USA, write: "Approximately 50% of all patients were alive at the 24-month time point, which is noteworthy considering that the median overall survival in most previous clinical trials involving patients with metastatic melanoma was consistently less than 12 months."

However, the editorialists caution that the 12-month PFS rate of 35% "suggests failure of the host immune system to adequately control melanoma tumours in two-thirds of all patients within the first year."

Nevertheless, they conclude: "Although most patients may not experience the ideal outcome of durable complete remission with current regimens, these immune checkpoint-blocking agents provide hope for patients and represent a solid foundation for future research."

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