Immunogenicity of pembrolizumab (pembro) in patients (pts) with advanced melanoma (MEL) and non-small cell lung cancer (NSCLC): Pooled results from KEYNOTE-001, 002, 006, and 010.

Vugt, Marianne van; Greef, Rik de; Freshwater, Tomoko; Mangin, Eric; Aarle, Frank van; Kondic, Anna G.

doi:10.1200/jco.2016.34.15_suppl.3063

Cited by 11 publications

(6 citation statements)

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“…The immunogenicity assessment for pembrolizumab monotherapy in the nonadjuvant (advanced or metastatic) setting is based on a sufficiently large data set of patients across several indications, with very low observed rates of total TE ADAs (~ 2%) and of NAbs (~ 0.6%) and no demonstrated impact on efficacy or safety, as currently summarized in the United States prescribing information and European Medicines Agency summary of product characteristics for pembrolizumab [6, 7]. The evaluation confirmed the assessment that pembrolizumab has limited potential to elicit the formation of ADAs in the adjuvant monotherapy setting, which is consistent with the results of prior immunogenicity evaluations of pembrolizumab in the nonadjuvant monotherapy setting [6, 21].…”

Section: Discussionsupporting

confidence: 74%

Immunogenicity of pembrolizumab in patients with advanced tumors

Vugt¹,

Stone²,

Greef³

et al. 2019

j. immunotherapy cancer

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Background Pembrolizumab is a potent, humanized, monoclonal anti–programmed death 1 antibody that has demonstrated effective antitumor activity and acceptable safety in multiple tumor types. Therapeutic biologics can result in the development of antidrug antibodies (ADAs), which may alter drug clearance and neutralize target binding, potentially reducing drug efficacy; such immunogenicity may also result in infusion reactions, anaphylaxis, and immune complex disorders. Pembrolizumab immunogenicity and its impact on exposure, safety, and efficacy was assessed in this study. Patients and methods Pembrolizumab immunogenicity was assessed in 3655 patients with advanced or metastatic cancer treated in 12 clinical studies. Patients with melanoma, non–small cell lung cancer, head and neck squamous cell carcinoma, colorectal cancer, urothelial cancer, and Hodgkin lymphoma were treated with pembrolizumab at 2 mg/kg every 3 weeks, 10 mg/kg every 2 weeks, 10 mg/kg every 3 weeks, or 200 mg every 3 weeks. An additional study involving 496 patients with stage III melanoma treated with 200 mg adjuvant pembrolizumab every 3 weeks after complete resection was analyzed separately. Results Of 3655 patients, 2000 were evaluable for immunogenicity analysis, 36 (1.8%) were treatment-emergent (TE) ADA-positive; 9 (0.5%) of these TE-positive patients had antibodies with neutralizing capacity. The presence of pembrolizumab-specific ADAs did not impact pembrolizumab exposure, nor did pembrolizumab immunogenicity affect the incidence of drug-related adverse events (AEs) or infusion-related reactions. There was no clear relationship between the presence of pembrolizumab-specific ADAs and changes in tumor size across treatment regimens. Of the 496 patients treated with pembrolizumab as adjuvant therapy, 495 were evaluable, 17 (3.4%) were TE ADA–positive; none had neutralizing antibodies. Conclusions The incidence of TE (neutralizing positive) ADAs against pembrolizumab was low in patients with advanced tumors. Furthermore, immunogenicity did not appear to have any clinically relevant effects on the exposure, safety, or efficacy of pembrolizumab. Trial registration ClinicalTrials.gov, NCT01295827 (February 15, 2011), NCT01704287 (October 11, 2012), NCT01866319 (May 31, 2013), NCT01905657 (July 23, 2013), NCT02142738 (May 20, 2014), NCT01848834 (May 8, 2013), NCT02255097 (October 2, 2014), NCT02460198 (June 2, 2015), NCT01953692 (October 1, 2013), NCT02453594 (May 25, 2015), NCT02256436 (October 3, 2014), NCT02335424 (January 9, 2015), NCT02362594 (February 13, 2015). ...

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Section: Discussionsupporting

confidence: 74%

Immunogenicity of pembrolizumab in patients with advanced tumors

Vugt¹,

Stone²,

Greef³

et al. 2019

j. immunotherapy cancer

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“…Factors that influence clearance are albumin and bilirubin concentration, cancer type, eGFR, ECOG-PS and sex, which together account for 32% of the variation [ 41 ]. The development of post-baseline ADAs was between 0.7 and 2.5% among various trials [ 42 ]; however, the effect of ADAs on clearance was not evaluated [ 39 – 41 ]. The average half-life of pembrolizumab is in the range of 14–27.3 days, with steady state reached after approximately 18 weeks [ 39 – 41 ].…”

Section: Immune Checkpoint Inhibitors (Icis)mentioning

confidence: 99%

Clinical Pharmacokinetics and Pharmacodynamics of Immune Checkpoint Inhibitors

et al. 2019

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Immune checkpoint inhibitors (ICIs) have demonstrated significant clinical impact in improving overall survival of several malignancies associated with poor outcomes; however, only 20-40% of patients will show long-lasting survival. Further clarification of factors related to treatment response can support improvements in clinical outcome and guide the development of novel immune checkpoint therapies. In this article, we have provided an overview of the pharmacokinetic (PK) aspects related to current ICIs, which include target-mediated drug disposition and time-varying drug clearance. In response to the variation in treatment exposure of ICIs and the significant healthcare costs associated with these agents, arguments for both dose individualization and generalization are provided. We address important issues related to the efficacy and safety, the pharmacodynamics (PD), of ICIs, including exposure-response relationships related to clinical outcome. The unique PK and PD aspects of ICIs give rise to issues of confounding and suboptimal surrogate endpoints that complicate interpretation of exposure-response analysis. Biomarkers to identify patients benefiting from treatment with ICIs have been brought forward. However, validated biomarkers to monitor treatment response are currently lacking.

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“…18 Among 2910 MK-3475 treated patients, 1.7% had a treatment-emergent-positive ADA. 19 To date, no head-to-head comparison of physicochemical and biological properties and efficacy of anti-PD-1 antibodies has been reported. Herein, we characterized the affinity, receptor occupancy, and anti-tumor activity of sintilimab in humanized NOD/Shi-scid-IL2rgamma (null) (NOG) mice versus MDX-1106 and MK-3475.…”

Section: Introductionmentioning

confidence: 99%

Durable blockade of PD-1 signaling links preclinical efficacy of sintilimab to its clinical benefit

Wang¹,

Fei²,

Hua³

et al. 2019

mAbs

111

101

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Blockade of immune checkpoint pathways by programmed cell death protein 1 (PD-1) antibodies has demonstrated broad clinical efficacy against a variety of malignancies. Sintilimab, a highly selective, fully human monoclonal antibody (mAb), blocks the interaction of PD-1 and its ligands and has demonstrated clinical benefit in various clinical studies. Here, we evaluated the affinity of sintilimab to human PD-1 by surface plasmon resonance and mesoscale discovery and evaluated PD-1 receptor occupancy and anti-tumor efficacy of sintilimab in a humanized NOD/Shi-scid-IL2rgamma (null) (NOG) mouse model. We also assessed the receptor occupancy and immunogenicity of sintilimab from clinical studies in humans (9 patients with advanced solid tumor and 381 patients from 4 clinical studies, respectively). Sintilimab bound to human PD-1 with greater affinity than nivolumab (Opdivo®, MDX-1106) and pembrolizumab (Keytruda®, MK-3475). The high affinity of sintilimab is explained by its distinct structural binding mode to PD-1. The pharmacokinetic behavior of sintilimab did not show any significant differences compared to the other two anti-PD-1 mAbs. In the humanized NOG mouse model, sintilimab showed superior PD-1 occupancy on circulating T cells and a stronger anti-tumor effect against NCI-H292 tumors. The strong anti-tumor response correlated with increased interferon-γ-secreting, tumor-specific CD8+ T cells, but not with CD4+ Tregs in tumor tissue. Pharmacodynamics testing indicated a sustained mean occupancy of ≥95% of PD-1 molecules on circulating T cells in patients following sintilimab infusion, regardless of infusion dose. Sintilimab infusion was associated with 0.52% (2/381 patients) of anti-drug antibodies and 0.26% (1/381 patients) neutralizing antibodies. These data validate sintilimab as a novel, safe, and efficacious anti-PD-1 mAb for cancer immunotherapy.

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Immunogenicity of pembrolizumab (pembro) in patients (pts) with advanced melanoma (MEL) and non-small cell lung cancer (NSCLC): Pooled results from KEYNOTE-001, 002, 006, and 010.

Cited by 11 publications

References 0 publications

Immunogenicity of pembrolizumab in patients with advanced tumors

Immunogenicity of pembrolizumab in patients with advanced tumors

Clinical Pharmacokinetics and Pharmacodynamics of Immune Checkpoint Inhibitors

Durable blockade of PD-1 signaling links preclinical efficacy of sintilimab to its clinical benefit

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