The anti-programmed-death-receptor-1 (PD-1) antibody, pembrolizumab (MK-3475), is effective and tolerable in patients with metastatic melanoma who have previously received another metastatic melanoma therapy.
The overall response rate was 26% among 173 patients who received one of two doses of pembrolizumab, in development for melanoma and other tumor types. The median follow-up duration was 8 months with a minimum of 6 months. At 8 months, 88% of patients who initially responded continued to respond to the therapy. The study is published in a recent issue of The Lancet.
The results are part of the phase 1b monotherapy clinical trial that was partially presented at the American Society of Clinical Oncology (ASCO) annual meeting in Chicago in June. This is the largest reported study of an anti-PD-1 immunotherapy in patients with melanoma, according to the study authors.
The overall response rate was similar in both the 2 mg/kg dose cohort (26%, 21 of 81 patients) and in the 10 mg/kg dose cohort (26%, 20 of 76 patients) (P= .96) by Response Evaluation Criteria In Solid Tumors (RECIST) criteria. Both dosage cohorts had similar tolerability and safety profiles. There were no drug-related deaths on the study.
One percent of the patients (one in each dosage cohort), had a complete response. The median time to response was 12 weeks in either cohort. At 24 weeks, 45% and 37% of the patients in the 2 mg/kg and 10 mg/kg cohorts were progression-free. Median progression-free survival was 22 weeks in the 2 mg/kg group and 14 weeks in the 10 mg/kg group.
Common drug-related adverse events in the lower and higher dose cohorts were fatigue (33% and 37%, respectively), pruritus (26% and 19%, respectively), and rash (18% in both cohorts). Grade 3 fatigue was seen in 3% of patients in the 2 mg/kg cohort-the only high-grade adverse event in more than one patient on the study.
The open-label, international study randomized patients (one to one) to intravenous pembrolizumab at 2 mg/kg every 3 weeks or 10 mg/kg every 3 weeks. The primary endpoint was overall response rate.
Currently, metastatic melanoma patients have the options of being treated with the anti-cytotoxic T-lymphocyte-associated-antigen-4 (CTLA-4) antibody, ipilimumab, or one of three targeted agents: vemurafenib, dabrafenib, or trametinib for those patients whose tumors harbor a BRAF mutation. But, for those patient's that relapse or do not respond to therapy, metastatic melanoma still remains an unmet need.
The current results are from an expansion cohort of this phase 1b clinical trial of patients previously treated and progressed on either ipilimumab, one of the three targeted therapies, or both.
Eighty-two percent of the patients enrolled in this cohort had BRAF wild-type disease and 9% of the patients had brain metastases.
An ongoing, randomized phase 2 clinical trial (NCT01704287) is currently evaluating these two doses in a larger cohort of patients who either did not respond to ipilimumab or for those with BRAF-mutated disease who progressed after treatment with a BRAF or MEK inhibitor targeted therapy.
In an editorial that accompanied the article, Shailender Bhatia, MD and John A Thompson, MD, both of the Seattle Cancer Alliance and the University of Washington in Seattle, stated that the results of the study “provide confirmation of pembrolizumab as an active agent in melanoma, and show the potential of PD-1 blockade in patients with melanoma who might not have the desired durable response to CTLA-4 blockade.”
“The encouraging results of the clinical trial add to the burgeoning literature on the potential of PD-1 blockade to improve outcomes in patients with metastatic melanoma,” the editorial authors conclude.