Phase I Study of Pembrolizumab (MK-3475; Anti–PD-1 Monoclonal Antibody) in Patients with Advanced Solid Tumors
By A. Patnaik, S. Kang, D. Rasco, K. Papadopoulos, J. Elassaiss-Schaap, M. Beeram, R. Drengler, Cong Chen, Lon S. Smith, G. Espino and 12 more. Clinical Cancer Research, 2015
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Purpose: This phase I study evaluated the safety, maximum tolerated dose, antitumor activity, and pharmacokinetics and pharmacodynamics of pembrolizumab in patients with advanced solid tumors. Experimental Design: In a 3 + 3 dose escalation study, 10 patients received pembrolizumab 1, 3, or 10 mg/kg intravenously every 2 weeks until progression or intolerable toxicity. Seven additional patients received 10 mg/kg every 2 weeks. Thirteen patients participated in a 3-week intrapatient dose escalation (dose range, 0.005–10 mg/kg) followed by 2 or 10 mg/kg every 3 weeks. Tumor response was assessed by Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1. Results: No dose-limiting toxicities were observed. Maximum administered dose was 10 mg/kg every 2 weeks. One patient with melanoma and one with Merkel cell carcinoma experienced complete responses of 57 and 56+ weeks' duration, respectively. Three patients with melanoma experienced partial responses. Fifteen patients with various malignancies experienced stable disease. One patient died of cryptococcal infection 92 days after pembrolizumab discontinuation, following prolonged corticosteroid use for grade 2 gastritis considered drug related. Pembrolizumab exhibited pharmacokinetic characteristics typical of humanized monoclonal antibodies. Maximum serum target engagement was reached with trough levels of doses greater than or equal to 1 mg/kg every 3 weeks. Mechanism-based translational models with a focus on intratumor exposure prediction suggested robust clinical activity would be observed at doses ≥2 mg/kg every 3 weeks. Conclusions: Pembrolizumab was well tolerated and associated with durable antitumor activity in multiple solid tumors. The lowest dose with full potential for antitumor activity was 2 mg/kg every 3 weeks. Clin Cancer Res; 21(19); 4286–93. ©2015 AACR. See related commentary by van Elsas et al., p. 4251
Subfields: Immunology, Oncology
View Paper: https://www.semanticscholar.org/paper/30a1a006b9478cc558c15d10d0aca9d87dab3416
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Citations in the corpus
- Incidence of Endocrine Dysfunction Following the Use of Different Immune Checkpoint Inhibitor Regimens: A Systematic Review and Meta-analysis (2017, neutral): “1(12) (R Project) and the metafor package.(13)”
- Targeting FTO suppresses cancer stem cell maintenance and immune evasion (2020, positive): “Monoclonal antibodies targeting the PD-1/PD-L1/PD-L2 axis have achieved encouraging effects in clinical practice in treating multiple types of solid tumors (Gopalakrishnan et al., 2018; Patnaik et al., 2015; Topalian et al., 2012), but demonstrated only limited effects in AML (Berger et al.”
- Regulatory mechanisms of PD-1/PD-L1 in cancers (2024, background): “Pembrolizumab (trade name Keytruda) is a high-affinity humanized IgG4 anti-PD-1 antibody, it was the first treatment globally approved by the FDA for patients with metastatic melanoma [320] and the first therapy approved to treat all high-mutated solid tumors [321].”