The first clinical trial of the monoclonal antibody lambrolizumab (formerly known as MK-3475) for persons with advanced melanoma demonstrated that even the lowest dose resulted in a high rate of sustained tumor regression, with only mild side effects for the patient.
“This study is showing the highest rate of durable melanoma responses of any drug we have tested thus far for melanoma, and it is doing it without serious side effects in the great majority of patients,” stated research leader Antoni Ribas, MD, PhD, of the hematology-oncology division of the University of California–Los Angeles (UCLA), in a UCLA statement.
Immune responses against cancer are limited by the actions of the programmed death 1 (PD-1) receptor, explained Ribas and colleagues in their report for The New England Journal of Medicine. (Ribas also presented the findings at the American Society of Clinical Oncology annual meeting held May 31 through June 4, 2013, in Chicago, Illinois.)
The investigators tested intravenous lambrolizumab, a highly selective, anti-PD-1 humanized monoclonal antibody, in 135 persons with advanced melanoma, assessing tumor response every 12 weeks. Treatment continued until disease progression was confirmed, unacceptable toxic effects developed, or patient consent was withdrawn.
The trial was funded by Merck Sharp and Dohme, which discovered and developed lambrolizumab.
The confirmed response rate across all dose cohorts was 38%. During the course of the study 77% of patients had a reduction in the tumor burden, including eight people who were confirmed as having stable disease for longer than 24 weeks.
The highest confirmed response rate, 52%, was observed in the cohort that received 10 mg per kilogram of body weight every 2 weeks—the highest dose. One-fourth (25%) of those taking the lowest dose (2 mg per kilogram every 3 weeks) had a confirmed response rate.
Although some participants had undergone prior treatment with the immune checkpoint inhibitor ipilimumab, the lambrolizumab response rate in that group was similar to that in the non-ipilimumab group, at 38% and 37%, respectively.
The median follow-up was 11 months among persons who had a response, and responses were durable in the majority of patients. Among those who had a response, 81% were still receiving treatment in March 2013, when Ribas’s team analyzed the data. (Patients were included in the analysis if they received a first dose of lambrolizumab by early September 2012). Overall median progression-free survival among the total group of 135 patients was longer than 7 months.
Toxic effects were mainly grade 1 or grade 2. Common adverse events attributed to treatment were fatigue, rash, pruritus, and diarrhea; most of these were low-grade. However, 13% of patients had more severe side effects, including inflammation of the lung or kidney as well as thyroid problems.