Skip to main page content
U.S. flag

An official website of the United States government

Dot gov

The .gov means it’s official.
Federal government websites often end in .gov or .mil. Before sharing sensitive information, make sure you’re on a federal government site.

Https

The site is secure.
The https:// ensures that you are connecting to the official website and that any information you provide is encrypted and transmitted securely.

Access keys NCBI Homepage MyNCBI Homepage Main Content Main Navigation
Clinical Trial
. 2024 Nov 12;19(11):e0309778.
doi: 10.1371/journal.pone.0309778. eCollection 2024.

Pembrolizumab 400 mg every 6 weeks as first-line therapy for advanced melanoma (KEYNOTE-555): Results from cohort B of an open-label, phase 1 study

Graham Cohen  1 , Bernardo Rapoport  2   3 , Sze W Chan  4 , Paul Ruff  5 , Ana Arance  6 , Karmele Mujika Eizmendi  7 , Baerin Houghton  8 , Michael P Brown  9 , Robert M Zielinski  10   11 , Eva Muñoz Couselo  12 , Megan Lyle  13 , James R Anderson  14 , Lokesh Jain  14 , Dinesh de Alwis  14 , Mallika Lala  14 , Omobolaji Akala  14 , Elliot Chartash  14 , Conrad Jacobs  15
Affiliations
Clinical Trial

Pembrolizumab 400 mg every 6 weeks as first-line therapy for advanced melanoma (KEYNOTE-555): Results from cohort B of an open-label, phase 1 study

Graham Cohen et al. PLoS One. .

Abstract

Intravenous pembrolizumab 400 mg every 6 weeks was approved across tumor types based on pharmacokinetic modeling, which showed exposures consistent with previous standard dosing of 200 mg or 2 mg/kg every 3 weeks, and early results of cohort B of the phase 1 KEYNOTE-555 study. Results after ≥1 year of potential follow-up for all patients in cohort B of KEYNOTE-555 are presented. Patients aged ≥18 years with previously untreated stage III/IV melanoma received pembrolizumab 400 mg every 6 weeks for ≤18 cycles. The primary endpoint was objective response rate per RECIST v1.1 by blinded independent central review. Secondary endpoints included duration of response, progression-free survival, pharmacokinetics, and safety. Overall, 101 patients received pembrolizumab. Median projected follow-up was 21.9 months (range, 17.0-25.7). The objective response rate was 50.5% (95% CI: 40.4-60.6; 19 complete responses, 32 partial responses). Median duration of response was not reached (NR; range, 2.4+ to 21.0+ months). Median progression-free survival was 13.8 months (95% CI: 4.1-NR). Observed pharmacokinetic exposures were consistent with model predictions for pembrolizumab 400 mg every 6 weeks and other approved and tested schedules (2 mg/kg or 200 mg every 3 weeks). Grade 3-4 treatment-related adverse events occurred in 13 patients (12.9%). No deaths were considered treatment related. These results support the pharmacokinetic modeling and demonstrate that the benefit-risk profile of pembrolizumab 400 mg Q6W is consistent with that of 200 mg or 2 mg/kg every 3 weeks. Clinically meaningful objective response rate and durable progression-free survival within the expected range for first-line pembrolizumab were observed. Clinical trial registry: ClinicalTrials.gov, NCT03665597.

PubMed Disclaimer

Conflict of interest statement

I have read the journal’s policy and the authors of this manuscript have the following competing interests: BR reports honoraria, advisory/consultancy, and speakers bureau from MSD, Roche South Africa, and AstraZeneca South Africa; research grant/funding from Roche South Africa; and travel/accommodations/expenses from MSD. PR reports honoraria, advisory/consultancy, speakers bureau, research grant/funding, and travel/accommodations/expenses from Charlotte Maxeke Johannesburg Academic Hospital to their institution. AA reports honoraria, speakers bureau, research grant/funding, and travel/accommodations/expenses from Pierre-Fabre, Novartis, MSD, Bristol Myers Squibb, Roche, Merck, and Sanofi. MPB reports honoraria and advisory/consultancy from MSD, Bristol Myers Squibb, and Novartis to their institution; research grant/funding from MSD and BMS to their institution; and travel/accommodations/expenses from MSD. RMZ reports advisory/consultancy for AstraZeneca; speakers bureau for Limbic Oncology; and researching grant/funding to their institution from Bristol Myers Squibb and Roche. EMC reports consulting fees from Bristol Myers Squibb, Merck Serono, Amgen, Pierre-Fabre, Sanofi, and Roche; honoraria from Bristol Myers Squibb, Novartis, Sanofi, Merck Serono, and Pierre-Fabre; travel/accommodations/expenses from Bristol Myers Squibb, Novartis, Merck Serono, and Sun Pharmaceuticals; and participation on data safety monitoring board or advisory board for Bristol Myers Squibb. ML reports advisory/consultancy from Bristol Myers Squibb, MSD, Novartis, and Roche; speakers bureau from BMS and MSD; and travel/accommodations/expenses from Pierre-Fabre and Merck. JRA is an employee of Merck Sharp & Dohme LLC, a subsidiary of Merck & Co., Inc., Rahway, NJ, USA and stockholder of Merck & Co., Inc., Rahway, NJ, USA. LJ and DDA are a stockholders of Merck & Co., Inc., Rahway, NJ, USA. ML, OA, and EC are employees of Merck Sharp & Dohme LLC, a subsidiary of Merck & Co., Inc., Rahway, NJ, USA, stockholders of Merck & Co., Inc., Rahway, NJ, USA, and hold patents/licensing/royalties/other intellectual property at Merck & Co., Inc., Rahway, NJ, USA. All remaining authors (GC, SWC, KME, BH, and CJ) have declared no conflicts of interest.

Figures

Fig 1
Fig 1. KEYNOTE-555 cohort B CONSORT flow diagram.
PK, pharmacokinetics. aMaximum serum concentration (Cmax) or trough serum concentration (Ctrough) or both.
Fig 2
Fig 2. Best percentage change from baseline in target lesions as per RECIST v1.1 by BICRa.
BICR, blinded independent central review; RECIST v1.1, Response Evaluation Criteria in Solid Tumors version 1.1. aIncludes patients with baseline and postbaseline target lesion assessment. *Indicates patient had progressive disease in non-target lesions.
Fig 3
Fig 3. Kaplan-Meier estimate of progression-free survival as per RECIST v1.1 by BICR.
BICR, blinded independent central review; NR, not reached; PFS, progression-free survival; RECIST v1.1, Response Evaluation Criteria in Solid Tumors version 1.1.
Fig 4
Fig 4
Observed pharmacokinetic data from patients treated with pembrolizumab 400 mg Q6W in cohort B of KEYNOTE-555 compared with (A, B) the model-predicted pharmacokinetic profile for pembrolizumab 400 mg Q6W (median and 90% prediction interval); (C, D) the model-predicted Ctrough for pembrolizumab 200 mg Q3W, 2 mg/kg Q3W, and 400 mg Q6W; (E, F) and the model predicted Cmax for pembrolizumab 2 mg/kg Q3W, 200 mg Q3W, 400 mg Q6W, and 10 mg/kg Q2W. The green dots are the observed pharmacokinetic data from patients treated with pembrolizumab 400 mg Q6W in cohort B of KEYNOTE-555. Cmax, maximum serum concentration; Ctrough, trough serum concentration; Q3W, every 3 weeks; Q6W, every 6 weeks.
See this image and copyright information in PMC

References

    1. Sehgal K, Costa DB, Rangachari D. Extended-interval dosing strategy of immune checkpoint inhibitors in lung cancer: will it outlast the COVID-19 pandemic? Front Oncol. 2020; 10. doi: 10.3389/fonc.2020.01193 - DOI - PMC - PubMed
    1. KEYTRUDA® (pembrolizumab) injection, for intravenous use [prescribing information]. Merck & Co., Inc; Rahway, NJ: 2024.
    1. Freshwater T, Kondic A, Ahamadi M, Li CH, de Greef R, de Alwis D, et al.. Evaluation of dosing strategy for pembrolizumab for oncology indications. J Immunother Cancer. 2017; 5:43. doi: 10.1186/s40425-017-0242-5 . - DOI - PMC - PubMed
    1. US Food and Drug Administration. FDA approves new dosing regimen for pembrolizumab Bethesda, MD: US Food and Drug Administration; 2022 [updated 04/28/2022; cited 2022 06/14/2022]. https://www.fda.gov/drugs/resources-information-approved-drugs/fda-appro....
    1. B.V. MSaD. KEYTRUDA 25 mg/mL concentrate for solution for infusion. (SPC). 2022. Merck Sharp and Dohme B.V.: The Netherlands; 2022. p. 116.

Publication types

MeSH terms

Substances

Associated data