Phase I Study of Pembrolizumab (MK-3475; Anti-PD-1 Monoclonal Antibody) in Patients with Advanced Solid Tumors.

Abstract

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.

• Authors: Amita Patnaik, S Peter Kang, Drew Rasco, Kyriakos P Papadopoulos, Jeroen Elassaiss-Schaap, Muralidhar Beeram, Ronald Drengler, Cong Chen, Lon Smith, Guillermo Espino, Kevin Gergich, Liliana Delgado, Adil Daud, Jill A Lindia, Xiaoyun Nicole Li, Robert H Pierce, Jennifer H Yearley, Dianna Wu, Omar Laterza, Manfred Lehnert, Robert Iannone, Anthony W Tolcher
• Journal: Clinical cancer research : an official journal of the American Association for Cancer Research (Clin Cancer Res) Vol. 21 Issue 19 Pg. 4286-93 (Oct 01 2015) ISSN: 1557-3265 [Electronic] United States
• PMID: 25977344 (Publication Type: Clinical Trial, Phase I, Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: ©2015 American Association for Cancer Research.

Chemical References

• Antibodies, Monoclonal, Humanized
• Antineoplastic Agents
• Programmed Cell Death 1 Receptor
• pembrolizumab

Topics

• Adult
• Aged
• Aged, 80 and over
• Antibodies, Monoclonal, Humanized (pharmacology, therapeutic use)
• Antineoplastic Agents (pharmacology, therapeutic use)
• Drug Monitoring
• Female
• Humans
• Male
• Middle Aged
• Molecular Targeted Therapy
• Neoplasm Staging
• Neoplasms (drug therapy, immunology, metabolism, pathology)
• Programmed Cell Death 1 Receptor (antagonists & inhibitors)
• Treatment Outcome