A less-frequent, more-convenient dosing schedule for pembrolizumab (400 mg every 6 weeks) was deemed safe and effective in patients with unresectable or metastatic melanoma, according to interim data from cohort B enrolled in the KEYNOTE-555 trial. These findings were presented at the 2020 Virtual Meeting of the American Association for Cancer Research (AACR).1
A few hours after this presentation, the U.S. Food and Drug Administration (FDA) approved the less-frequent dosing schedule across all current adult indications for pembrolizumab. Now, clinicians will have the choice of the longer-interval, higher-dose schedule or the lower-dose schedule of 200 mg every 3 weeks.
Mallika Lala, PhD
“Data from KEYNOTE-555 cohort B support that pembrolizumab administered at 400 mg every 6 weeks is a safe and efficacious dosing regimen,” said lead author Mallika Lala, PhD, Principal Scientist at Merck & Co.
The FDA’s news release stated: “This new dosing regimen is approved under accelerated approval based on pharmacokinetic data, the relationship of exposure to efficacy, and the relationship of exposure to safety. Continued approval for this indication may be contingent upon verification and description of clinical benefit in a confirmatory trial(s).”
“This study is important,” said Antoni Ribas, MD, PhD, AACR 2020 Program Chair and newly inaugurated President of AACR. In a separate interview, Dr. Ribas explained its particular relevance for patients with cancer receiving treatment during the COVID-19 pandemic. “We can give the infusion every 6 weeks; this will save on infusion costs and reduce exposure, which will benefit both patients and the health-care system.”
“We can give the infusion every 6 weeks; this will save on infusion costs and reduce exposure, which will benefit both patients and the health-care system.”— Antoni Ribas, MD, PhD
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The interim analysis of KEYNOTE-555 cohort B was based on data from 44 treatment-naive patients with stage III or IV melanoma enrolled in the international, open-label trial. The median age of patients was 64 years, about 60% were male, and 91% had metastatic disease. At the time Dr. Lala presented the data, 101 patients were enrolled.
The comparator group comprised 313 patients with impilimumab-naive melanoma from KEYNOTE-001, 556 patients from KEYNOTE-006, and 352 patients from KEYNOTE-252—all historical studies testing multiple 3-week and 2-week dosing regimens and the approved regimen of 200 mg every 3 weeks.
The overall response rate was 38.6%, compared with 35.1% in historical controls treated with other dosing regimens. At a median follow-up of 6.7 months, 9.1% had a complete response, 29.5% had a partial response, and 22.7% had stable disease. It is still too early to assess progression-free survival, noted Dr. Lala.
Modeling data predicted that trough and peak concentrations of pembrolizumab on the 6-week schedule would be within previous clinical experience at the approved 200-mg every-3-week schedule, as well as weight-based dosing schedules investigated in early trials. At 6 weeks, the geometric mean of observed trough concentrations in patients treated at the 400-mg dose was lower than with the 200-mg dose but higher than the 2-mg/kg weight-based schedule.
Directly following an infusion of the drug, the average peak concentration with the 400-mg dose was 136 μg/mL, which is higher than the 200-mg dose but lower than the highest clinically tested weight-based dose of 10 mg/kg every 2 weeks (220 μg/mL).
Additionally, pharmacokinetic data from previous trials have shown similar clearance of pembrolizumab across patients with 10 different tumor types.
Adverse events of any grade were reported in 97.7% of patients. Grade 3 and 4 events occurred in almost one-quarter of study patients, but just 2.3% of them were deemed to be related to treatment. Treatment-related adverse events were reported in two-thirds of patients.
Alexander M.M. Eggermont, MD, PhD
Session chair Alexander M.M. Eggermont, MD, PhD, Chief Scientific Officer of Princess Maxima Center for Pediatric Oncology, Utrecht, the Netherlands, stated: “It is very good to see this higher dose can decrease the number of visits patients have to make to outpatient facilities and further open the possibility of home care for these patients. The pharmacokinetics are consistent across the different tumor types, which is encouraging.”
Dr. Eggermont continued: “This also means that, in the adjuvant setting, the frequency of hospital visits will decrease in the near future, and this is a great service to our patients. We now await the next step in ease of administration and potential self-administration with subcutaneous development of pembrolizumab. It is wonderful to see that study data from KEYNOTE-555 are consistent with all data sets published thus far.”
DISCLOSURE: Dr. Lala is employed by and holds stock in Merck & Co. Dr. Ribas holds stock or other ownership interests in Advaxis, Arcus Biosciences, Compugen, CytomX, Five Prime Therapeutics, FLX Bio, ImaginAb, Lutris Pharma, Merus, Pact Pharma, Rgenix, and Tango Therapeutics; has received honoraria from Amgen, Chugai/Roche, Genentech/Roche, Merck Sharp & Dohme, Novartis, and Sanofi; has served as a consultant or advisor to Amgen, Chugai Pharma, Novartis, Merck, and Sanofi; and has received institutional research funding from Agilent and Bristol-Myers Squibb. Dr. Eggermont holds stock or other ownership interests in RiverD, Skyline Diagnostics, and Theranovir; has received honoraria from Biocad, Bioinvent, Bristol-Myers Squibb, CatalYm, Ellipses Pharma, GlaxoSmithKline, IO Biotech, ISA Pharmaceuticals, MSD, Nektar, Novartis, Pfizer, Sanofi, Sellas Life Sciences, Skyline Diagnostics; has served as a consultant or advisor to Bioinvent, Bristol-Myers Squibb, CatalYm, Ellipses Pharma, GlaxoSmithKline, Incyte, IO Biotech, ISA Pharmaceuticals, MSD, Nektar, Novartis, Pfizer, Sanofi, Sellas Life Sciences, and Skyline Diagnostics; has participated in a speakers bureau for MSD; has provided expert testimony on behalf of Novartis; and has been reimbursed for travel, accommodations, or other expenses by Bristol-Myers Squibb.
1. Lala M, Akala O, Chartash E, et al: Pembrolizumab 400 mg Q6W dosing: First clinical outcomes data from KEYNOTE-555 cohort B in metastatic melanoma patients. 2020 AACR Virtual Meeting. Abstract CT042. Presented April 28, 2020.
Formal discussant of KEYNOTE-555, Siwen Hu-Lieskovan, MD, PhD, of Huntsman Cancer Institute, Salt Lake City, commented on the advantages of the new schedule. “Along with the promise of prolonged survival associated with checkpoint inhibitors, convenience, quality of life, and reducing health-care...