TY - JOUR
T1 - First-in-human, open-label, phase 1/2 study of the monoclonal antibody programmed cell death protein-1 (PD-1) inhibitor cetrelimab (JNJ-63723283) in patients with advanced cancers
AU - Felip, Enriqueta
AU - Moreno, Victor
AU - Morgensztern, Daniel
AU - Curigliano, Giuseppe
AU - Rutkowski, Piotr
AU - Trigo, José Manuel
AU - Calvo, Aitana
AU - Kowalski, Dariusz
AU - Cortinovis, Diego
AU - Plummer, Ruth
AU - Maio, Michele
AU - Ascierto, Paolo A.
AU - Vladimirov, Vladimir I.
AU - Cervantes, Andres
AU - Zudaire, Enrique
AU - Hazra, Anasuya
AU - T’jollyn, Huybrecht
AU - Bandyopadhyay, Nibedita
AU - Greger, James G.
AU - Attiyeh, Edward
AU - Xie, Hong
AU - Calvo, Emiliano
N1 - Publisher Copyright:
© 2022, The Author(s).
PY - 2022/4
Y1 - 2022/4
N2 - Purpose: To assess the safety, pharmacokinetics, pharmacodynamics, and preliminary efficacy of cetrelimab (JNJ-63723283), a monoclonal antibody programmed cell death protein-1 (PD-1) inhibitor, in patients with advanced/refractory solid tumors in the phase 1/2 LUC1001 study. Methods: In phase 1, patients with advanced solid tumors received intravenous cetrelimab 80, 240, 460, or 800 mg every 2 weeks (Q2W) or 480 mg Q4W. In phase 2, patients with melanoma, non-small-cell lung cancer (NSCLC), and microsatellite instability–high (MSI-H)/DNA mismatch repair-deficient colorectal cancer (CRC) received cetrelimab 240 mg Q2W. Response was assessed Q8W until Week 24 and Q12W thereafter. Results: In phase 1, 58 patients received cetrelimab. Two dose-limiting toxicities were reported and two recommended phase 2 doses (RP2D) were defined (240 mg Q2W or 480 mg Q4W). After a first dose, mean maximum serum concentrations (Cmax) ranged from 24.7 to 227.0 µg/mL; median time to Cmax ranged from 2.0 to 3.2 h. Pharmacodynamic effect was maintained throughout the dosing period across doses. In phase 2, 146 patients received cetrelimab 240 mg Q2W. Grade ≥ 3 adverse events (AEs) occurred in 53.9% of patients. Immune-related AEs (any grade) occurred in 35.3% of patients (grade ≥ 3 in 6.9%). Overall response rate was 18.6% across tumor types, 34.3% in NSCLC, 52.6% in programmed death ligand 1–high (≥ 50% by immunohistochemistry) NSCLC, 28.0% in melanoma, and 23.8% in centrally confirmed MSI-H CRC. Conclusions: The RP2D for cetrelimab was established. Pharmacokinetic/pharmacodynamic characteristics, safety profile, and clinical activity of cetrelimab in immune-sensitive advanced cancers were consistent with known PD-1 inhibitors. Trial registrations: NCT02908906 at ClinicalTrials.gov, September 21, 2016; EudraCT 2016–002,017-22 at clinicaltrialsregister.eu, Jan 11, 2017.
AB - Purpose: To assess the safety, pharmacokinetics, pharmacodynamics, and preliminary efficacy of cetrelimab (JNJ-63723283), a monoclonal antibody programmed cell death protein-1 (PD-1) inhibitor, in patients with advanced/refractory solid tumors in the phase 1/2 LUC1001 study. Methods: In phase 1, patients with advanced solid tumors received intravenous cetrelimab 80, 240, 460, or 800 mg every 2 weeks (Q2W) or 480 mg Q4W. In phase 2, patients with melanoma, non-small-cell lung cancer (NSCLC), and microsatellite instability–high (MSI-H)/DNA mismatch repair-deficient colorectal cancer (CRC) received cetrelimab 240 mg Q2W. Response was assessed Q8W until Week 24 and Q12W thereafter. Results: In phase 1, 58 patients received cetrelimab. Two dose-limiting toxicities were reported and two recommended phase 2 doses (RP2D) were defined (240 mg Q2W or 480 mg Q4W). After a first dose, mean maximum serum concentrations (Cmax) ranged from 24.7 to 227.0 µg/mL; median time to Cmax ranged from 2.0 to 3.2 h. Pharmacodynamic effect was maintained throughout the dosing period across doses. In phase 2, 146 patients received cetrelimab 240 mg Q2W. Grade ≥ 3 adverse events (AEs) occurred in 53.9% of patients. Immune-related AEs (any grade) occurred in 35.3% of patients (grade ≥ 3 in 6.9%). Overall response rate was 18.6% across tumor types, 34.3% in NSCLC, 52.6% in programmed death ligand 1–high (≥ 50% by immunohistochemistry) NSCLC, 28.0% in melanoma, and 23.8% in centrally confirmed MSI-H CRC. Conclusions: The RP2D for cetrelimab was established. Pharmacokinetic/pharmacodynamic characteristics, safety profile, and clinical activity of cetrelimab in immune-sensitive advanced cancers were consistent with known PD-1 inhibitors. Trial registrations: NCT02908906 at ClinicalTrials.gov, September 21, 2016; EudraCT 2016–002,017-22 at clinicaltrialsregister.eu, Jan 11, 2017.
KW - Colorectal cancer
KW - Melanoma
KW - Microsatellite instability–high
KW - Monoclonal antibody PD-1 inhibitor efficacy
KW - Non-small-cell lung cancer
KW - Pharmacokinetics/pharmacodynamics
UR - http://www.scopus.com/inward/record.url?scp=85126487408&partnerID=8YFLogxK
U2 - 10.1007/s00280-022-04414-6
DO - 10.1007/s00280-022-04414-6
M3 - Article
C2 - 35298698
AN - SCOPUS:85126487408
SN - 0344-5704
VL - 89
SP - 499
EP - 514
JO - Cancer Chemotherapy and Pharmacology
JF - Cancer Chemotherapy and Pharmacology
IS - 4
ER -