PMID- 31395089 OWN - NLM STAT- MEDLINE DCOM- 20200828 LR - 20200828 IS - 2051-1426 (Electronic) IS - 2051-1426 (Linking) VI - 7 IP - 1 DP - 2019 Aug 8 TI - Immunogenicity of pembrolizumab in patients with advanced tumors. PG - 212 LID - 10.1186/s40425-019-0663-4 [doi] LID - 212 AB - 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). FAU - van Vugt, Marianne J H AU - van Vugt MJH AD - Integrated Drug Development, Certara, Oss, Netherlands. FAU - Stone, Julie A AU - Stone JA AD - Quantitative Pharmacology, Merck & Co., Inc, Kenilworth, NJ, USA. FAU - De Greef, Rik H J M M AU - De Greef RHJMM AD - Integrated Drug Development, Certara, Oss, Netherlands. FAU - Snyder, Ellen S AU - Snyder ES AD - Quantitative Pharmacology, Merck & Co., Inc, Kenilworth, NJ, USA. FAU - Lipka, Leslie AU - Lipka L AD - Quantitative Pharmacology, Merck & Co., Inc, Kenilworth, NJ, USA. FAU - Turner, David C AU - Turner DC AD - Quantitative Pharmacology, Merck & Co., Inc, Kenilworth, NJ, USA. FAU - Chain, Anne AU - Chain A AD - Quantitative Pharmacology, Merck & Co., Inc, Kenilworth, NJ, USA. FAU - Lala, Mallika AU - Lala M AD - Quantitative Pharmacology, Merck & Co., Inc, Kenilworth, NJ, USA. FAU - Li, Mengyao AU - Li M AD - Quantitative Pharmacology, Merck & Co., Inc, Kenilworth, NJ, USA. FAU - Robey, Seth H AU - Robey SH AD - Quantitative Pharmacology, Merck & Co., Inc, Kenilworth, NJ, USA. FAU - Kondic, Anna G AU - Kondic AG AD - Decision Analytics, Certara, Princeton, NJ, USA. FAU - De Alwis, Dinesh AU - De Alwis D AD - Quantitative Pharmacology, Merck & Co., Inc, Kenilworth, NJ, USA. FAU - Mayawala, Kapil AU - Mayawala K AD - Quantitative Pharmacology, Merck & Co., Inc, Kenilworth, NJ, USA. FAU - Jain, Lokesh AU - Jain L AD - Quantitative Pharmacology, Merck & Co., Inc, Kenilworth, NJ, USA. FAU - Freshwater, Tomoko AU - Freshwater T AD - Quantitative Pharmacology, Merck & Co., Inc, Kenilworth, NJ, USA. tomoko.freshwater@merck.com. LA - eng SI - ClinicalTrials.gov/NCT02362594 SI - ClinicalTrials.gov/NCT02460198 SI - ClinicalTrials.gov/NCT01866319 SI - ClinicalTrials.gov/NCT02255097 SI - ClinicalTrials.gov/NCT01953692 SI - ClinicalTrials.gov/NCT02453594 SI - ClinicalTrials.gov/NCT02256436 SI - ClinicalTrials.gov/NCT01905657 SI - ClinicalTrials.gov/NCT01704287 SI - ClinicalTrials.gov/NCT02142738 SI - ClinicalTrials.gov/NCT01295827 SI - ClinicalTrials.gov/NCT02335424 SI - ClinicalTrials.gov/NCT01848834 PT - Journal Article PT - Research Support, Non-U.S. Gov't DEP - 20190808 PL - England TA - J Immunother Cancer JT - Journal for immunotherapy of cancer JID - 101620585 RN - 0 (Antibodies, Monoclonal, Humanized) RN - 0 (Antineoplastic Agents, Immunological) RN - DPT0O3T46P (pembrolizumab) SB - IM MH - Antibodies, Monoclonal, Humanized/pharmacology/*therapeutic use MH - Antineoplastic Agents, Immunological/pharmacology/*therapeutic use MH - Female MH - Humans MH - Male MH - Neoplasms/*drug therapy/pathology PMC - PMC6686242 OTO - NOTNLM OT - Advanced tumors OT - Efficacy OT - Immunogenicity OT - Pembrolizumab OT - Safety OT - Treatment-emergent ADA COIS- LL, DCT, AC, ML, M. Li, SHR, AGK, DDA, KM, LJ, and TF are current or former employees of Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc., Kenilworth, NJ, USA. JAS and ESS are employees of Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc., Kenilworth, NJ, USA, and hold stock in the company. MJHvV and HJMMdG have nothing to disclose. DCT was an employee of Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc., Kenilworth, NJ at the time of the analysis and is currently employed by GlaxoSmithKline, and M. Li was an employee of Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc., Kenilworth, NJ at the time of the analysis and is currently employed by Sanofi. EDAT- 2019/08/10 06:00 MHDA- 2020/08/29 06:00 PMCR- 2019/08/08 CRDT- 2019/08/10 06:00 PHST- 2019/02/13 00:00 [received] PHST- 2019/07/04 00:00 [accepted] PHST- 2019/08/10 06:00 [entrez] PHST- 2019/08/10 06:00 [pubmed] PHST- 2020/08/29 06:00 [medline] PHST- 2019/08/08 00:00 [pmc-release] AID - 10.1186/s40425-019-0663-4 [pii] AID - 663 [pii] AID - 10.1186/s40425-019-0663-4 [doi] PST - epublish SO - J Immunother Cancer. 2019 Aug 8;7(1):212. doi: 10.1186/s40425-019-0663-4.