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Lecomte T, Giraudeau B, Phelip JM, Tournigand C, Ducreux M, Tougeron D, Lepage C, Mineur L, Laplaige P, Desgrippes R, Artru P, Borg C, Jary M, Bouché O, Metges JP, Guimbaud R, Aparicio T, Foubert F, Hautefeuille V, Muller M, Bouhier-Leporrier K, Darrius R, Lobet S, Monmousseau F, Bejan-Angoulvant T, Paintaud G, Ternant D. Bevacizumab-based chemotherapy adaptive to pharmacokinetic of bevacizumab in first-line treatment of patients with unresectable metastatic colorectal cancer: A double-blind, multicenter, randomized phase III trial study (PHARBEVACOL trial). Dig Liver Dis 2025; 57:624-630. [PMID: 40044552 DOI: 10.1016/j.dld.2025.02.002] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/09/2025] [Accepted: 02/13/2025] [Indexed: 04/27/2025]
Abstract
Bevacizumab shows inter-individual pharmacokinetic variability, with an exposure-response relationship in metastatic colorectal cancer (mCRC) patients. This study explores whether a double dose of bevacizumab, compared to a standard dose, increases efficacy in mCRC patients treated with bevacizumab-based chemotherapy as first-line therapy and who have a low initial trough concentration of bevacizumab. PHARBEVACOL is a multicenter, randomized, double-blind, two-parallel group trial. All patients will receive first-line bi-weekly 5 mg/kg bevacizumab-based chemotherapy and those with low initial bevacizumab concentrations (≤15.5 mg/L) will be randomized to either continue the standard dose (5 mg/kg every 14 days) or receive a double dose (10 mg/kg every 14 days). The primary objective is to evaluate the effect of doubling dose on progression-free survival (PFS). During a screening phase, the first serum trough concentration will be measured on day 14, before the second infusion of bevacizumab. We hypothesize a 40 % PFS in the control group at 9 months versus 60 % in the study group, corresponding to a hazard ratio of 0.56. With 80 % power, a 5 % two-sided type I error, and a minimum 12-month follow-up, 116 patients need to be included. Since only 50 % of screened patients will be eligible for randomization, approximately 244 patients will be screened. Recruitment is scheduled to begin in February 2025.
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Affiliation(s)
- Thierry Lecomte
- Service d'Hépato-gastroentérologie et de cancérologie digestive, CHU de Tours, Tours, France; INSERM UMR 1069, N2COx "Niche, Nutrition, Cancer and Oxidative Metabolism", Université de Tours, Tours, France.
| | | | - Jean-Marc Phelip
- Service d'Hépato-gastroentérologie et de cancérologie digestive, CHU Saint Etienne, Saint Etienne, France
| | | | - Michel Ducreux
- Service d'Oncologie digestive, Institut Gustave Roussy, Villejuif, France
| | - David Tougeron
- Service d'Hépato-gastroentérologie, CHU de Poitiers, Poitiers, France
| | - Côme Lepage
- Service d'Hépato-gastroentérologie et de cancérologie digestive, CHU de Dijon, Dijon, France
| | | | | | - Romain Desgrippes
- Service d'Hépato-gastroentérologie et de cancérologie digestive, CH de Saint-Malo, Saint-Malo, France
| | | | - Christophe Borg
- Service d'Oncologie Médicale, CHU de Besançon, Besançon, France
| | - Marine Jary
- Service de chirurgie digestive, CHU Estaing, Clermont-Ferrand, France
| | - Olivier Bouché
- Service d'Hépato-gastroentérologie et de cancérologie digestive, CHU de Reims, Reims, France
| | | | - Rosine Guimbaud
- Service d'oncologie médicale, CHU de Toulouse, Toulouse, France
| | - Thomas Aparicio
- Service d'Hépato-gastroentérologie et de cancérologie digestive, Hôpital Saint-Louis, AP-HP, Paris, France
| | - Fanny Foubert
- Service d'Hépato-gastroentérologie et de cancérologie digestive, CHU de Nantes, Nantes, France
| | - Vincent Hautefeuille
- Service d'Hépato-gastroentérologie et de cancérologie digestive, CHU d'Amiens, Amiens, France
| | - Marie Muller
- Service d'Hépato-gastroentérologie et de cancérologie digestive, CHU de Nancy, Nancy, France
| | | | - Rémi Darrius
- Service d'Hépato-gastroentérologie et de cancérologie digestive, CH de Colmar, Colmar, France
| | - Sarah Lobet
- INSERM UMR 1069, N2COx "Niche, Nutrition, Cancer and Oxidative Metabolism", Université de Tours, Tours, France
| | | | - Théodora Bejan-Angoulvant
- Service de Pharmacologie Médicale, CHU de Tours, Tours, France; UMR 1327, ISCHEMIA, Membrane signalling and inflammation in reperfusion injuries, INSERM, Université de Tours, Tours, France; Plateforme Recherche, Centre Pilote de suivi Biologique des traitements par Anticorps, CHU de Tours, Tours, France
| | - Gilles Paintaud
- Service de Pharmacologie Médicale, CHU de Tours, Tours, France; UMR 1327, ISCHEMIA, Membrane signalling and inflammation in reperfusion injuries, INSERM, Université de Tours, Tours, France; Plateforme Recherche, Centre Pilote de suivi Biologique des traitements par Anticorps, CHU de Tours, Tours, France
| | - David Ternant
- Service de Pharmacologie Médicale, CHU de Tours, Tours, France; UMR 1327, ISCHEMIA, Membrane signalling and inflammation in reperfusion injuries, INSERM, Université de Tours, Tours, France; Plateforme Recherche, Centre Pilote de suivi Biologique des traitements par Anticorps, CHU de Tours, Tours, France
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Wang M, Ma Q, Suthe SR, Hudson RE, Pan JY, Mikelis C, Zhu MJ, Wu ZG, Shi DR, Yao HP. Humanized dual-targeting antibody-drug conjugates specific to MET and RON receptors as a pharmaceutical strategy for the treatment of cancers exhibiting phenotypic heterogeneity. Acta Pharmacol Sin 2025; 46:1375-1389. [PMID: 39837982 PMCID: PMC12032285 DOI: 10.1038/s41401-024-01458-7] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/13/2024] [Accepted: 12/12/2024] [Indexed: 01/23/2025]
Abstract
Cancer heterogeneity, characterized by diverse populations of tumorigenic cells, involves the occurrence of differential phenotypes with variable expressions of receptor tyrosine kinases. Aberrant expressions of mesenchymal-epithelial transition (MET) and recepteur d'origine nantais (RON) receptors contribute to the phenotypic heterogeneity of cancer cells, which poses a major therapeutic challenge. This study aims to develop a dual-targeting antibody-drug conjugate (ADC) that can act against both MET and RON for treating cancers with high phenotypic heterogeneity. Through immunohistochemical staining, we show that MET and RON expressions are highly heterogeneous with differential combinations in more than 40% of pancreatic and triple-negative breast cancer cases. This expressional heterogeneity provides the rationale to target both receptors for cancer therapy. A humanized bispecific monoclonal antibody specific to both MET and RON (PCMbs-MR) is generated through IgG recombination using monoclonal antibody sequences specific to MET and RON, respectively. Monomethyl auristatin E is conjugated to PCMbs-MR to generate a dual-targeting ADC (PCMdt-MMAE), with a drug-to-antibody ratio of 4:1. Various cancer cell lines were used to determine PCMdt-MMAE-mediated biological activities. The efficacy of PCMdt-MMAE in vivo is evaluated using multiple xenograft tumor models. PCMdt-MMAE shows a favorable pharmacokinetic profile, with a maximum tolerated dose of ~30 mg/kg in mice. Toxicological studies using Sprague-Dawley rats reveal that PCMdt-MMAE is relatively safe with slight-to-moderate, temporary, and reversible adverse events. Functionally, PCMdt-MMAE induces a robust internalization of both MET and RON and causes a large-scale cell death in cancer cell lines exhibiting MET and RON heterogeneous co-expressions. Both in vitro and in vivo studies demonstrate that the dual-targeting approach in the form of an ADC is highly effective with a long-lasting effect against tumors exhibiting MET/RON heterogeneous phenotypes. Hence, we can suggest that a dual-targeting ADC specific to both MET and RON can be employed as a novel therapeutic strategy for tumors with expressional phenotypic heterogeneity.
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Affiliation(s)
- Minghai Wang
- State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, National Clinical Research Center for Infectious diseases, First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, 310003, China
- Department of Pharmaceutical Sciences, Jerry H. Hodge School of Pharmacy, Texas Tech University Health Sciences Center, Amarillo, 79106, TX, USA
- Cancer Biology Research Center, Jerry H. Hodge School of Pharmacy, Texas Tech University Health Sciences Center, Amarillo, 79106, TX, USA
| | - Qi Ma
- Comprehensive Genitourinary Cancer Center, First Affiliated Hospital of Ningbo University, Ningbo, 315000, China
- Translational Research Laboratory for Urology, The Key Laboratory of Ningbo City, Ningbo, 315000, China
| | - Sreedhar Reddy Suthe
- Department of Pharmaceutical Sciences, Jerry H. Hodge School of Pharmacy, Texas Tech University Health Sciences Center, Amarillo, 79106, TX, USA
| | - Rachel E Hudson
- Department of Pharmaceutical Sciences, Jerry H. Hodge School of Pharmacy, Texas Tech University Health Sciences Center, Amarillo, 79106, TX, USA
| | - Jing-Ying Pan
- State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, National Clinical Research Center for Infectious diseases, First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, 310003, China
| | - Constantinos Mikelis
- Department of Pharmaceutical Sciences, Jerry H. Hodge School of Pharmacy, Texas Tech University Health Sciences Center, Amarillo, 79106, TX, USA
- Cancer Biology Research Center, Jerry H. Hodge School of Pharmacy, Texas Tech University Health Sciences Center, Amarillo, 79106, TX, USA
| | - Miao-Jin Zhu
- State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, National Clinical Research Center for Infectious diseases, First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, 310003, China
| | - Zhi-Gang Wu
- State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, National Clinical Research Center for Infectious diseases, First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, 310003, China
| | - Dan-Rong Shi
- State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, National Clinical Research Center for Infectious diseases, First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, 310003, China
| | - Hang-Ping Yao
- State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, National Clinical Research Center for Infectious diseases, First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, 310003, China.
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Géraud A, Gougis P, de Nonneville A, Beaufils M, Bertucci F, Billon E, Brisou G, Gravis G, Greillier L, Guerin M, Mezni E, Mitry E, Noel R, Pignon J, Sabatier R, Seguin L, Spano JP, Vicier C, Viret F, Goncalves A, Ciccolini J. Pharmacology and pharmacokinetics of antibody-drug conjugates, where do we stand? Cancer Treat Rev 2025; 135:102922. [PMID: 40157134 DOI: 10.1016/j.ctrv.2025.102922] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/24/2025] [Revised: 03/11/2025] [Accepted: 03/12/2025] [Indexed: 04/01/2025]
Abstract
Antibody-drug conjugates (ADCs) are a rising therapeutic class in oncology and hematology, with eleven drugs approved by the US Food and Drug Administration as of January 2025. These "magic bullets" have a complex structure, including a monoclonal antibody, a linker, attachment sites, and a payload usually disrupting microtubules, targeting DNA, or inhibiting topoisomerase 1. By targeting specific tumor antigens, they are expected to be exquisitely effective in releasing "supertoxic" payloads inside tumor cells after intracellular trafficking. Additionally, they may exert a bystander effect, wherein the released payloads act on neighboring cells, amplifying their therapeutic impact regardless of target expression. ADCs have been game-changing drugs to treat tumors with once dismal prognoses or with previously considered unactionable targets, such as HER2-low or triple-negative breast cancer. To what extent there is room for personalized medicine to improve the toxicity/efficacy ratio remains unknown. However, there are inherent issues related to the complexity of the pharmacokinetics of ADCs and their assessments: efficacy or toxicity may be influenced by the clearance of the intact ADC, the circulating payload, or the payload-linker complex. Deciphering these multifaceted exposure-outcomes relationships for both efficacy and safety endpoints, is critical for advancing precision medicine and enabling personalized dosing strategies. To improve future developments and broaden their therapeutic scope, several strategies can be developed, including developing adequate combinations with other treatment classes (cytotoxic agents, immune-checkpoint inhibitors, oral molecular-targeted therapies). In this review, we will discuss the PK/PD aspects of ADCs and their dosing to improve their use in current and future indications.
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Affiliation(s)
- Arthur Géraud
- Aix-Marseille Univ, CNRS, INSERM, Institut Paoli-Calmettes, Department of Medical Oncology, CRCM, Marseille, France; COMPO Team, Centre de Recherche en Cancérologie de Marseille (CRCM), Inserm U1068, Aix Marseille University, 13009 Marseille, France.
| | - Paul Gougis
- Department of Medical Oncology, Pitié-Salpêtrière, Assistance Publique - Hôpitaux de Paris (AP-HP), 75013 Paris, France; Sorbonne Université, Institut National de la Santé et de la Recherche Médicale (INSERM), Assistance Publique - Hôpitaux de Paris (AP-HP), Clinical Investigation Center (CIC-1901), Department of Pharmacology, Pitié-Salpêtrière Hospital, Paris, France; Residual Tumor & Response to Treatment Laboratory, RT2Lab, INSERM, U932 Immunity and Cancer, Institut Curie, France
| | - Alexandre de Nonneville
- Aix-Marseille Univ, CNRS, INSERM, Institut Paoli-Calmettes, Department of Medical Oncology, CRCM, Marseille, France
| | - Mathilde Beaufils
- Aix-Marseille Univ, CNRS, INSERM, Institut Paoli-Calmettes, Department of Medical Oncology, CRCM, Marseille, France
| | - François Bertucci
- Aix-Marseille Univ, CNRS, INSERM, Institut Paoli-Calmettes, Department of Medical Oncology, CRCM, Marseille, France
| | - Emilien Billon
- Aix-Marseille Univ, CNRS, INSERM, Institut Paoli-Calmettes, Department of Medical Oncology, CRCM, Marseille, France
| | - Gabriel Brisou
- Department of Hematology, Institut Paoli-Calmettes, CRCM, Aix-Marseille University,13009 Marseille, France
| | - Gwenaelle Gravis
- Aix-Marseille Univ, CNRS, INSERM, Institut Paoli-Calmettes, Department of Medical Oncology, CRCM, Marseille, France
| | - Laurent Greillier
- COMPO Team, Centre de Recherche en Cancérologie de Marseille (CRCM), Inserm U1068, Aix Marseille University, 13009 Marseille, France; Department of Multidisciplinary Oncology and Therapeutic Innovations, Assistance Publique-Hôpitaux de Marseille (AP-HM), Aix Marseille University (AMU), 13015 Marseille, France
| | - Mathilde Guerin
- Aix-Marseille Univ, CNRS, INSERM, Institut Paoli-Calmettes, Department of Medical Oncology, CRCM, Marseille, France
| | - Essia Mezni
- Aix-Marseille Univ, CNRS, INSERM, Institut Paoli-Calmettes, Department of Medical Oncology, CRCM, Marseille, France
| | - Emmanuel Mitry
- Aix-Marseille Univ, CNRS, INSERM, Institut Paoli-Calmettes, Department of Medical Oncology, CRCM, Marseille, France
| | - Robin Noel
- Department of Hematology, Institut Paoli-Calmettes, CRCM, Aix-Marseille University,13009 Marseille, France
| | - Joséphine Pignon
- Aix-Marseille Univ, CNRS, INSERM, Institut Paoli-Calmettes, Department of Medical Oncology, CRCM, Marseille, France
| | - Renaud Sabatier
- Aix-Marseille Univ, CNRS, INSERM, Institut Paoli-Calmettes, Department of Medical Oncology, CRCM, Marseille, France
| | - Lorène Seguin
- Aix-Marseille Univ, CNRS, INSERM, Institut Paoli-Calmettes, Department of Medical Oncology, CRCM, Marseille, France
| | - Jean-Philippe Spano
- Department of Medical Oncology, Pitié-Salpêtrière, Assistance Publique - Hôpitaux de Paris (AP-HP), 75013 Paris, France
| | - Cécile Vicier
- Aix-Marseille Univ, CNRS, INSERM, Institut Paoli-Calmettes, Department of Medical Oncology, CRCM, Marseille, France
| | - Frederic Viret
- Aix-Marseille Univ, CNRS, INSERM, Institut Paoli-Calmettes, Department of Medical Oncology, CRCM, Marseille, France
| | - Anthony Goncalves
- Aix-Marseille Univ, CNRS, INSERM, Institut Paoli-Calmettes, Department of Medical Oncology, CRCM, Marseille, France
| | - Joseph Ciccolini
- COMPO Team, Centre de Recherche en Cancérologie de Marseille (CRCM), Inserm U1068, Aix Marseille University, 13009 Marseille, France; Biogenopole, La timone University Hospital of Marseille, Assistance Publique-Hôpitaux de Marseille (AP-HM), 13005 Marseille, France
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Colombo R, Tarantino P, Rich JR, LoRusso PM, de Vries EGE. The Journey of Antibody-Drug Conjugates: Lessons Learned from 40 Years of Development. Cancer Discov 2024; 14:2089-2108. [PMID: 39439290 DOI: 10.1158/2159-8290.cd-24-0708] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/17/2024] [Revised: 08/16/2024] [Accepted: 09/09/2024] [Indexed: 10/25/2024]
Abstract
Antibody-drug conjugates (ADC) represent one of the most rapidly expanding treatment modalities in oncology, with 11 ADCs approved by the FDA and more than 210 currently being tested in clinical trials. Spanning over 40 years, ADC clinical development has enhanced our understanding of the multifaceted mechanisms of action for this class of therapeutics. In this article, we discuss key insights into the toxicity, efficacy, stability, distribution, and fate of ADCs. Furthermore, we highlight ongoing challenges related to their clinical optimization, the development of rational sequencing strategies, and the identification of predictive biomarkers. Significance: The development and utilization of ADCs have allowed for relevant improvements in the prognosis of multiple cancer types. Concomitantly, the rise of ADCs in oncology has produced several challenges, including the prediction of their activity, their utilization in sequence, and minimization of their side effects, that still too often resemble those of the cytotoxic molecule that they carry. In this review, we retrace 40 years of development in the field of ADCs and delve deep into the mechanisms of action of these complex therapeutics and reasons behind the many achievements and failures observed in the field to date.
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Affiliation(s)
| | - Paolo Tarantino
- Dana-Farber Cancer Institute, Boston, Massachusetts
- Harvard Medical School, Boston, Massachusetts
- Department of Oncology and Hemato-Oncology, University of Milan, Milan, Italy
| | - Jamie R Rich
- ADC Therapeutic Development, Zymeworks Inc., Vancouver, Canada
| | - Patricia M LoRusso
- Department of Internal Medicine (Medical Oncology), Yale University School of Medicine, New Haven, Connecticut
| | - Elisabeth G E de Vries
- Department of Medical Oncology, University Medical Center Groningen, University of Groningen, Groningen, the Netherlands
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Rached L, Geraud A, Frelaut M, Ap Thomas Z, Goldschmidt V, Beraud-Chaulet G, Nagera-Lazarovici C, Danlos FX, Henon C, Parisi C, Gazzah A, Bahleda R, Postel Vinay S, Smolenschi C, Hollebecque A, Michot JM, Ribrag V, Loriot Y, Champiat S, Ouali K, Massard C, Ponce Aix S, Bringuier M, Baldini C. Antibody drug conjugates in older patients: State of the art. Crit Rev Oncol Hematol 2024; 193:104212. [PMID: 38007063 DOI: 10.1016/j.critrevonc.2023.104212] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/29/2023] [Accepted: 11/16/2023] [Indexed: 11/27/2023] Open
Abstract
More than half of cancer cases occur in patients aged 65 years or older. The efficacy and safety of antibody drug conjugates (ADCs) in older patients remains an unclear subject as available evidence is limited. Geriatric population is underrepresented in clinical trials. Consequently, most of our knowledge regarding innovative therapeutics was studied on a younger population. In this review of published literature, we report the available information on efficacy, safety and pharmacokinetics of FDA approved ADCs for hematologic malignancies and solid tumors in the geriatric population. We explore the results of clinical trials dedicated for older individuals as well as subgroup analyses of the geriatric population in major trials evaluating these drugs. Available data suggest a similar efficacy in older adults as compared to general population. However, older patients might be prone to a higher rate of adverse events in incidence with a potential impact on quality of life. We lack data to support primary dose reductions or schedule modifications in this category of patients. No pharmacokinetic differences were reported between age groups. It is crucial to encourage the development of clinical trials dedicated to older patients with geriatric parameters (G8 score, G-CODE…) so that results can be more representative of this population outside of clinical trials.
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Affiliation(s)
- Layal Rached
- Gustave Roussy, Department of Therapeutic Innovation and Early Phase Trials, 94805 Villejuif, France.
| | - Arthur Geraud
- Gustave Roussy, Department of Medical Oncology , 94805 Villejuif, France.
| | - Maxime Frelaut
- Gustave Roussy, Department of Medical Oncology , 94805 Villejuif, France.
| | - Zoe Ap Thomas
- Gustave Roussy, Department of Medical Oncology , 94805 Villejuif, France.
| | - Vincent Goldschmidt
- Gustave Roussy, Department of Therapeutic Innovation and Early Phase Trials, 94805 Villejuif, France.
| | | | | | - Francois-Xavier Danlos
- Gustave Roussy, Department of Therapeutic Innovation and Early Phase Trials, 94805 Villejuif, France.
| | - Clemence Henon
- Gustave Roussy, Department of Therapeutic Innovation and Early Phase Trials, 94805 Villejuif, France.
| | - Claudia Parisi
- Gustave Roussy, Department of Therapeutic Innovation and Early Phase Trials, 94805 Villejuif, France.
| | - Anas Gazzah
- Gustave Roussy, Department of Therapeutic Innovation and Early Phase Trials, 94805 Villejuif, France.
| | - Rastilav Bahleda
- Gustave Roussy, Department of Therapeutic Innovation and Early Phase Trials, 94805 Villejuif, France.
| | - Sophie Postel Vinay
- Gustave Roussy, Department of Therapeutic Innovation and Early Phase Trials, 94805 Villejuif, France.
| | - Cristina Smolenschi
- Gustave Roussy, Department of Therapeutic Innovation and Early Phase Trials, 94805 Villejuif, France.
| | - Antoine Hollebecque
- Gustave Roussy, Department of Therapeutic Innovation and Early Phase Trials, 94805 Villejuif, France.
| | - Jean-Marie Michot
- Gustave Roussy, Department of Therapeutic Innovation and Early Phase Trials, 94805 Villejuif, France.
| | - Vincent Ribrag
- Gustave Roussy, Department of Therapeutic Innovation and Early Phase Trials, 94805 Villejuif, France.
| | - Yohann Loriot
- Gustave Roussy, Department of Therapeutic Innovation and Early Phase Trials, 94805 Villejuif, France.
| | - Stephane Champiat
- Gustave Roussy, Department of Therapeutic Innovation and Early Phase Trials, 94805 Villejuif, France.
| | - Kaissa Ouali
- Gustave Roussy, Department of Therapeutic Innovation and Early Phase Trials, 94805 Villejuif, France.
| | - Christophe Massard
- Centre Eugène Marquis, Department of Medical Oncology, 35000 Rennes, France.
| | - Santiago Ponce Aix
- Gustave Roussy, Department of Therapeutic Innovation and Early Phase Trials, 94805 Villejuif, France.
| | - Michael Bringuier
- Institut Curie, PSL Research University, Department of Medical Oncology and Department of Supportive Care, UCOG Paris Ouest, F-92210 Saint-Cloud, France.
| | - Capucine Baldini
- Gustave Roussy, Department of Therapeutic Innovation and Early Phase Trials, 94805 Villejuif, France.
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Sun Y, Li C, Wang X, Zheng Y, Wu Z, Hui AM, Diao L. Model-informed dose selection for an investigational human epidermal growth factor receptor 2 antibody-drug conjugate FS-1502 in patients with human epidermal growth factor receptor 2-expressing advanced malignant solid tumours. Br J Clin Pharmacol 2023. [PMID: 37926561 DOI: 10.1111/bcp.15955] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/08/2022] [Revised: 10/18/2023] [Accepted: 10/26/2023] [Indexed: 11/07/2023] Open
Abstract
AIMS The dose-escalation phase (phase Ia study) of a novel human epidermal growth factor receptor 2 (HER2) antibody-drug conjugate (ADC) FS-1502 included a dose range from 0.1 to 3.5 mg/kg in HER2-expressing advanced malignant solid tumours. However, the defined maximum tolerated dose was not reached. This model-informed approach integrated population pharmacokinetic (PopPK) modelling and exposure-response (E-R) analysis to facilitate dose selection for phase II. METHODS The PopPK model was constructed using PK data from 109 Chinese patients who received doses of 0.1-3.5 mg/kg FS-1502 every 3 (Q3W) or 4 weeks during a phase I dose-escalation and dose expansion trial. The structural model consisted of compartment models for FS-1502 and unconjugated monomethyl auristatin F. E-R was explored for the percentage change in tumour size, overall response rate and treatment-related adverse events. RESULTS A semi-mechanistic 2-analyte PopPK model was developed. The FS-1502 PK data were best described by a 2-compartment PK model with parallel linear and nonlinear Michaelis-Menten eliminations. The PK of unconjugated monomethyl auristatin F was described by a 2-compartment model with first-order elimination. E-R analysis supported the clinically meaningful efficacy of FS-1502 at 2.3 mg/kg and above. However, 2.3 mg/kg Q3W was considered to have a better benefit-risk balance due to a lower incidence of safety events without a significant reduction in efficacy compared to 3.0 mg/kg Q3W. CONCLUSION This PopPK and E-R analysis guided the recommended phase II dose selection of 2.3 mg/kg Q3W and supported body weight-based dosing for an investigational HER2 ADC FS-1502.
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Affiliation(s)
- Yi Sun
- Shanghai Fosun Pharmaceutical Development Co., Ltd., Shanghai, China
| | - Chao Li
- Anheart Therapeutics, New York, New York, USA
| | - Xingli Wang
- Shanghai Fosun Pharmaceutical Development Co., Ltd., Shanghai, China
| | - Yi Zheng
- Shanghai Fosun Pharmaceutical Development Co., Ltd., Shanghai, China
| | - Zhuli Wu
- Shanghai Fosun Pharmaceutical Development Co., Ltd., Shanghai, China
| | | | - Lei Diao
- Shanghai Fosun Pharmaceutical Development Co., Ltd., Shanghai, China
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Berwanger JD, Lake MA, Ganguly S, Yang J, Welch CJ, Linnes JC, Bruening M. Microporous affinity membranes and their incorporation into microfluidic devices for monitoring of therapeutic antibodies. Talanta 2023; 252:123842. [DOI: 10.1016/j.talanta.2022.123842] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/14/2022] [Revised: 08/08/2022] [Accepted: 08/11/2022] [Indexed: 10/15/2022]
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Liu G, Lu J, Lim HS, Jin JY, Lu D. Applying interpretable machine learning workflow to evaluate exposure-response relationships for large-molecule oncology drugs. CPT Pharmacometrics Syst Pharmacol 2022; 11:1614-1627. [PMID: 36193885 PMCID: PMC9755920 DOI: 10.1002/psp4.12871] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/18/2022] [Revised: 09/15/2022] [Accepted: 09/18/2022] [Indexed: 11/05/2022] Open
Abstract
The application of logistic regression (LR) and Cox Proportional Hazard (CoxPH) models are well-established for evaluating exposure-response (E-R) relationship in large molecule oncology drugs. However, applying machine learning (ML) models on evaluating E-R relationships has not been widely explored. We developed a workflow to train regularized LR/CoxPH and tree-based XGboost (XGB) models, and derive the odds ratios for best overall response and hazard ratios for overall survival, across exposure quantiles to evaluate the E-R relationship using clinical trial datasets. The E-R conclusions between LR/CoxPH and XGB models are overall consistent, and largely aligned with historical pharmacometric analyses findings. Overall, applying this interpretable ML workflow provides a promising alternative method to assess E-R relationships for impacting key dosing decisions in drug development.
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Affiliation(s)
- Gengbo Liu
- Department of Clinical PharmacologyGenentechSouth San FranciscoCaliforniaUSA
| | - James Lu
- Department of Clinical PharmacologyGenentechSouth San FranciscoCaliforniaUSA
| | - Hong Seo Lim
- Department of Clinical PharmacologyGenentechSouth San FranciscoCaliforniaUSA
| | - Jin Yan Jin
- Department of Clinical PharmacologyGenentechSouth San FranciscoCaliforniaUSA
| | - Dan Lu
- Department of Clinical PharmacologyGenentechSouth San FranciscoCaliforniaUSA
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9
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Beaumont K, Pike A, Davies M, Savoca A, Vasalou C, Harlfinger S, Ramsden D, Ferguson D, Hariparsad N, Jones O, McGinnity D. ADME and DMPK considerations for the discovery and development of antibody drug conjugates (ADCs). Xenobiotica 2022; 52:770-785. [PMID: 36314242 DOI: 10.1080/00498254.2022.2141667] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/06/2022]
Abstract
The therapeutic concept of antibody drug conjugates (ADCs) is to selectively target tumour cells with small molecule cytotoxic drugs to maximise cell kill benefit and minimise healthy tissue toxicity.An ADC generally consists of an antibody that targets a protein on the surface of tumour cells chemically linked to a warhead small molecule cytotoxic drug.To deliver the warhead to the tumour cell, the antibody must bind to the target protein and in general be internalised into the cell. Following internalisation, the cytotoxic agent can be released in the endosomal or lysosomal compartment (via different mechanisms). Diffusion or transport out of the endosome or lysosome allows the cytotoxic drug to express its cell-killing pharmacology. Alternatively, some ADCs (e.g. EDB-ADCs) rely on extracellular cleavage releasing membrane permeable warheads.One potentially important aspect of the ADC mechanism is the 'bystander effect' whereby the cytotoxic drug released in the targeted cell can diffuse out of that cell and into other (non-target expressing) tumour cells to exert its cytotoxic effect. This is important as solid tumours tend to be heterogeneous and not all cells in a tumour will express the targeted protein.The combination of large and small molecule aspects in an ADC poses significant challenges to the disposition scientist in describing the ADME properties of the entire molecule.This article will review the ADC landscape and the ADME properties of successful ADCs, with the aim of outlining best practice and providing a perspective of how the field can further facilitate the discovery and development of these important therapeutic modalities.
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Affiliation(s)
- Kevin Beaumont
- Drug Metabolism and Pharmacokinetics, Early Oncology Research and Development, Cambridge, UK
| | - Andy Pike
- Drug Metabolism and Pharmacokinetics, Early Oncology Research and Development, Cambridge, UK
| | - Michael Davies
- Drug Metabolism and Pharmacokinetics, Early Oncology Research and Development, Cambridge, UK
| | - Adriana Savoca
- Drug Metabolism and Pharmacokinetics, Early Oncology Research and Development, Cambridge, UK
| | - Christina Vasalou
- Drug Metabolism and Pharmacokinetics, Early Oncology Research and Development, AstraZeneca, Boston, MA, USA
| | - Steffi Harlfinger
- Drug Metabolism and Pharmacokinetics, Early Oncology Research and Development, Cambridge, UK
| | - Diane Ramsden
- Drug Metabolism and Pharmacokinetics, Early Oncology Research and Development, AstraZeneca, Boston, MA, USA
| | - Douglas Ferguson
- Drug Metabolism and Pharmacokinetics, Early Oncology Research and Development, AstraZeneca, Boston, MA, USA
| | - Niresh Hariparsad
- Drug Metabolism and Pharmacokinetics, Early Oncology Research and Development, AstraZeneca, Boston, MA, USA
| | - Owen Jones
- Drug Metabolism and Pharmacokinetics, Early Oncology Research and Development, Cambridge, UK
| | - Dermot McGinnity
- Drug Metabolism and Pharmacokinetics, Early Oncology Research and Development, Cambridge, UK
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10
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Nakagawa K, Garon EB, Gao L, Callies S, Zimmermann A, Walgren R, Visseren-Grul C, Reck M. RELAY, ramucirumab plus erlotinib versus placebo plus erlotinib in untreated EGFR-mutated metastatic non-small cell lung cancer: exposure-response relationship. Cancer Chemother Pharmacol 2022; 90:137-148. [PMID: 35841410 PMCID: PMC9360106 DOI: 10.1007/s00280-022-04447-x] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/07/2021] [Accepted: 06/04/2022] [Indexed: 11/25/2022]
Abstract
PURPOSE In RELAY, ramucirumab plus erlotinib (RAM + ERL) improved progression-free survival (PFS) in patients with untreated, metastatic, EGFR-mutated, non-small cell lung cancer (NSCLC). Here, we present the exposure-response relationship of RAM from RELAY. METHODS Patients received ERL (150 mg/day) with either RAM (10 mg/kg) or placebo (PBO + ERL) every 2 weeks (Q2W). A population pharmacokinetic model predicted RAM minimum concentration after first dose (Cmin,1), and at steady state (Cmin,ss), which were used to evaluate correlation between RAM exposure and efficacy and safety. The Kaplan-Meier method and Cox regression analyses were utilized to evaluate exposure-efficacy by Cmin,1 quartile. Exposure-safety was evaluated by assessing incidence rates for safety parameters by Cmin,ss quartile, with ordered categorical analysis used for ALT/AST only. RESULTS Analyses included 216 patients treated with RAM + ERL and 225 patients treated with PBO + ERL. Adjusting for significant baseline covariates, no exposure-efficacy relationship was identified in RELAY: PFS hazard ratio (mean, 95% confidence intervals) for the Cmin,1 quartiles were 0.67 (0.45-0.99), 0.77 (0.53-1.12), 0.57 (0.38-0.84), and 0.50 (0.33-0.76). No apparent exposure-safety relationship was observed for selected safety endpoints, including Grade ≥ 3 hypertension, diarrhea, and dermatitis acneiform, and any grade hypertension, any grade and Grade ≥ 3 proteinuria, and any grade ALT/AST increased within liver failure/liver injury. CONCLUSIONS No association was observed between RAM exposure and response, suggesting that the RELAY regimen of RAM 10 mg/kg Q2W with ERL is an optimized, efficacious, and safe first-line treatment for patients with untreated, metastatic, EGFR-mutated NSCLC. TRIAL REGISTRATION ClinicalTrials.gov, NCT02411448.
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Affiliation(s)
- Kazuhiko Nakagawa
- Department of Medical Oncology, Faculty of Medicine, Kindai University, Osakasayama City, 377-2, Ohno-higashi, Osaka, 589-8511, Japan.
- Kindai University Faculty of Medicine, Osaka, Japan.
| | - Edward B Garon
- David Geffen School of Medicine at University of California Los Angeles, Translational Research in Oncology US Network, Los Angeles, CA, USA
| | - Ling Gao
- Eli Lilly and Company, Bridgewater, USA
| | | | | | | | | | - Martin Reck
- LungenClinic, Airway Research Center North, German Center for Lung Research, Grosshansdorf, Germany
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11
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Advances with antibody-drug conjugates in breast cancer treatment. Eur J Pharm Biopharm 2021; 169:241-255. [PMID: 34748933 DOI: 10.1016/j.ejpb.2021.10.016] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/15/2021] [Revised: 08/21/2021] [Accepted: 10/13/2021] [Indexed: 12/21/2022]
Abstract
Antibody-drug conjugate-based therapy for treatment of cancer has attracted much attention because of its enhanced efficacy against numerous cancer types. Commonly, an ADC includes a mAb linked to a therapeutic payload. Antibody, linker and payload are the three main components of ADCs. The high specificity of antibodies is integrated with the strong potency of payloads in ADCs. ADCs with potential cytotoxic small molecules as payloads, generate antibody-mediated cancer therapy. Recently, ADCs with DNA-damaging agents have shown favor over microtubule-targeting agents as payloads. Although ADC resistance can be a barrier to effectiveness, several ADC therapies have been either approved or are in clinical trials for cancer treatment. The ADC-based treatments of breast cancers, particularly TNBC, MDR and metastatic breast cancers, have shown promise in recent years. This review discusses ADC drug designs, and developed for different types of breast cancer including TNBC, MDR and metastatic breast cancer.
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12
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Ko MJ, Song D, Kim J, Kim JY, Eom J, Sung B, Son YG, Kim YM, Lee SH, You WK, Jung J. N-terminal selective conjugation method widens the therapeutic window of antibody-drug conjugates by improving tolerability and stability. MAbs 2021; 13:1914885. [PMID: 33904380 PMCID: PMC8081041 DOI: 10.1080/19420862.2021.1914885] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/24/2020] [Revised: 03/23/2021] [Accepted: 04/06/2021] [Indexed: 01/26/2023] Open
Abstract
Antibody-drug conjugates (ADCs) are targeted therapeutic agents that treat cancers by selective delivery of highly potent cytotoxic drugs to tumor cells via cancer-specific antibodies. However, their clinical benefit is limited by off-target toxicity and narrow therapeutic windows. To overcome these limitations, we have applied reductive alkylation to develop a new type of ADC that has cytotoxic drugs conjugated to the N-terminal of an antibody through amine bonds introduced via reductive alkylation reactions (NTERM). To test whether the NTERM-conjugated ADCs can widen therapeutic windows, we synthesized three different ADCs by conjugating trastuzumab and monomethyl auristatin-F using three different methods, and compared their stability, efficacy, and toxicity. The NTERM-conjugated ADC was more stable in vitro and in vivo than the thiol-conjugated and the lysine-conjugated ADCs. The NTERM-conjugated ADC showed lower toxicity compared to other ADCs, whereas its efficacy was comparable to that of the thiol-conjugated ADC and better than that of the lysine-conjugated ADC. These results suggest that the NTERM conjugation method could widen the therapeutic window of ADCs by enhancing its stability and reducing toxicity.
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MESH Headings
- Alkylation
- Animals
- Antineoplastic Agents, Immunological/chemistry
- Antineoplastic Agents, Immunological/pharmacokinetics
- Antineoplastic Agents, Immunological/pharmacology
- Antineoplastic Agents, Immunological/toxicity
- Breast Neoplasms/drug therapy
- Breast Neoplasms/genetics
- Breast Neoplasms/metabolism
- Breast Neoplasms/pathology
- Cell Line, Tumor
- Drug Compounding
- Drug Stability
- Female
- Immunoconjugates/chemistry
- Immunoconjugates/pharmacokinetics
- Immunoconjugates/pharmacology
- Immunoconjugates/toxicity
- Oligopeptides/chemistry
- Oligopeptides/pharmacokinetics
- Oligopeptides/pharmacology
- Oligopeptides/toxicity
- Protein Stability
- Rats, Nude
- Rats, Sprague-Dawley
- Receptor, ErbB-2/antagonists & inhibitors
- Receptor, ErbB-2/genetics
- Receptor, ErbB-2/metabolism
- Trastuzumab/chemistry
- Trastuzumab/pharmacokinetics
- Trastuzumab/pharmacology
- Trastuzumab/toxicity
- Tumor Burden/drug effects
- Xenograft Model Antitumor Assays
- Rats
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Affiliation(s)
- Min Ji Ko
- ABL Bio Inc., Seongnam-si, Republic of Korea
| | - Daehae Song
- ABL Bio Inc., Seongnam-si, Republic of Korea
| | - Juhee Kim
- ABL Bio Inc., Seongnam-si, Republic of Korea
| | - Jae Yong Kim
- Global Support Center, Samsung Biologics, Incheon, Republic of Korea
| | - Jaehyun Eom
- ABL Bio Inc., Seongnam-si, Republic of Korea
| | | | | | - Young Min Kim
- BIO Business Division, Reyon Pharmaceutical Co., Ltd, Seoul, Republic of Korea
| | | | | | - Jinwon Jung
- ABL Bio Inc., Seongnam-si, Republic of Korea
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13
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Kawakatsu S, Bruno R, Kågedal M, Li C, Girish S, Joshi A, Wu B. Confounding factors in exposure-response analyses and mitigation strategies for monoclonal antibodies in oncology. Br J Clin Pharmacol 2020; 87:2493-2501. [PMID: 33217012 DOI: 10.1111/bcp.14662] [Citation(s) in RCA: 26] [Impact Index Per Article: 5.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/17/2020] [Revised: 11/03/2020] [Accepted: 11/08/2020] [Indexed: 12/29/2022] Open
Abstract
Dose selection and optimization is an important topic in drug development to maximize treatment benefits for all patients. While exposure-response (E-R) analysis is a useful method to inform dose-selection strategy, in oncology, special considerations for prognostic factors are needed due to their potential to confound the E-R analysis for monoclonal antibodies. The current review focuses on 3 different approaches to mitigate the confounding effects for monoclonal antibodies in oncology: (i) Cox-proportional hazards modelling and case-matching; (ii) tumour growth inhibition-overall survival modelling; and (iii) multiple dose level study design. In the presence of confounding effects, studying multiple dose levels may be required to reveal the true E-R relationship. However, it is impractical for pivotal trials in oncology drug development programmes. Therefore, the strengths and weaknesses of the other 2 approaches are considered, and the favourable utility of tumour growth inhibition-overall survival modelling to address confounding in E-R analyses is described. In the broader scope of oncology drug development, this review discusses the downfall of the current emphasis on E-R analyses using data from single dose level trials and proposes that development programmes be designed to study more dose levels in earlier trials.
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Affiliation(s)
- Sonoko Kawakatsu
- Clinical Pharmacology, Development Sciences, gRED, Genentech/Roche, South San Francisco, CA, USA.,Thomas J. Long School of Pharmacy, University of the Pacific, Stockton, CA, USA
| | - René Bruno
- Clinical Pharmacology, Development Sciences, gRED, Genentech/Roche, South San Francisco, CA, USA
| | - Matts Kågedal
- Clinical Pharmacology, Development Sciences, gRED, Genentech/Roche, South San Francisco, CA, USA
| | - Chunze Li
- Clinical Pharmacology, Development Sciences, gRED, Genentech/Roche, South San Francisco, CA, USA
| | - Sandhya Girish
- Clinical Pharmacology, Development Sciences, gRED, Genentech/Roche, South San Francisco, CA, USA
| | - Amita Joshi
- Clinical Pharmacology, Development Sciences, gRED, Genentech/Roche, South San Francisco, CA, USA
| | - Benjamin Wu
- Clinical Pharmacology, Development Sciences, gRED, Genentech/Roche, South San Francisco, CA, USA
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14
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Papachristos A, Kemos P, Kalofonos H, Sivolapenko G. Correlation Between Bevacizumab Exposure and Survival in Patients with Metastatic Colorectal Cancer. Oncologist 2020; 25:853-858. [PMID: 32272489 DOI: 10.1634/theoncologist.2019-0835] [Citation(s) in RCA: 20] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/04/2019] [Accepted: 03/20/2020] [Indexed: 01/04/2023] Open
Abstract
BACKGROUND Bevacizumab treatment is subject to large interpatient variability in efficacy, which may partly be explained by differences in complex bevacizumab pharmacokinetic characteristics that influence bevacizumab exposure. Exposure-response relationships have been identified for other monoclonal antibodies. We aimed to identify possible exposure-survival relationships in bevacizumab-treated patients with metastatic colorectal cancer (mCRC). MATERIALS AND METHODS Patients with mCRC who started first-line bevacizumab-based chemotherapy between July 2012 and July 2014, and from whom serial blood samples and survival were prospectively collected, were included. Follow-up was carried out until July 2018. Total bevacizumab trough concentrations were measured from cycle 2 to cycle 30 of treatment. The receiver operating characteristic (ROC) curve analysis and Cox analysis were used to identify the relationship between concentrations and overall survival (OS). In addition, OS was compared between different trough concentration groups. RESULTS One hundred fifty-seven blood samples from 46 patients were evaluable for analyses. ROC analysis showed a clear separation in survival based on trough levels (area under the curve = 0.739, p = .009). Cox regression also showed a strong positive correlation between trough levels and survival (p = .0004). Three distinct groups of exposure were identified: low (median trough concentration [Ctm ] ≤41.9 mg/L); medium (Ctm 43-87.2 mg/L) with median OS of 12.8 and 36 months, respectively (p = .0003); and high (Ctm ≥7.9 mg/L), where the majority of patients were still alive 60 months after the initiation of treatment. CONCLUSION This study shows that survival was proportional to the magnitude of exposure in patients with mCRC. Further clinical research should focus on clarifying these exposure-outcome relationships in order to optimize dosing. IMPLICATIONS FOR PRACTICE Bevacizumab-based chemotherapy is standard first-line treatment in metastatic colorectal cancer. Moreover, bevacizumab presents complicated pharmacokinetics, and in many cases, clinical outcomes can be highly variable, with some patients responding remarkably well and others not. This study's results show that patients who experienced longer overall survival also had significantly higher exposure to bevacizumab. Therefore, bevacizumab trough concentrations could be used both as a predictive biomarker and as a tool for treatment monitoring and optimization. Finally, the development of validated, rapid, and sensitive assays for bevacizumab concentration measurements in combination with these results may lead to a therapeutic drug monitoring-guided approach in bevacizumab treatment with better clinical outcomes.
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Affiliation(s)
- Apostolos Papachristos
- Laboratory of Pharmacokinetics, Department of Pharmacy, School of Health Sciences, University of Patras, Patras, Greece
| | - Polychronis Kemos
- Blizard Institute, Queen Mary University of London, London, United Kingdom
| | | | - Gregory Sivolapenko
- Laboratory of Pharmacokinetics, Department of Pharmacy, School of Health Sciences, University of Patras, Patras, Greece
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15
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16
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Sun Q, Seo S, Zvada S, Liu C, Reynolds K. Does Hepatic Impairment Affect the Exposure of Monoclonal Antibodies? Clin Pharmacol Ther 2020; 107:1256-1262. [PMID: 31899819 DOI: 10.1002/cpt.1765] [Citation(s) in RCA: 12] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/28/2019] [Accepted: 12/13/2019] [Indexed: 11/08/2022]
Abstract
Limited information is available regarding the effect of hepatic impairment (HI) on the pharmacokinetics of monoclonal antibodies (mAbs). The results of an earlier report based on therapeutic proteins, including mAbs, approved through the end of 2012 were inconclusive due to limited HI data available at that time. New HI data for mAbs or antibody-drug conjugates (ADCs; with a focus on the mAb component) available between 2013 and 2018 were evaluated. The investigation indicates there is almost no data for severe HI, limited data for moderate HI, and abundant data for mild HI. A significant exposure decrease was found for several mAbs or ADCs and a trend for decreasing area under the concentration-time curve (AUC) was observed for other mAbs. Multiple potential mechanisms may contribute to the exposure decrease. Dose may need to be adjusted for patients with HI, after taking into account the exposure-response relationships for both efficacy and safety.
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Affiliation(s)
- Qin Sun
- Division of Infectious Disease Pharmacology, Office of Clinical Pharmacology, Office of Translational Sciences, Center for Drug Evaluation and Research, US Food and Drug Administration, Silver Spring, Maryland, USA
| | - Shirley Seo
- Division of Cardiometabolic and Endocrine Pharmacology, Office of Clinical Pharmacology, Office of Translational Sciences, Center for Drug Evaluation and Research, US Food and Drug Administration, Silver Spring, Maryland, USA
| | - Simbarashe Zvada
- Division of Pharmacometrics, Office of Clinical Pharmacology, Office of Translational Sciences, Center for Drug Evaluation and Research, US Food and Drug Administration, Silver Spring, Maryland, USA
| | - Chao Liu
- Division of Pharmacometrics, Office of Clinical Pharmacology, Office of Translational Sciences, Center for Drug Evaluation and Research, US Food and Drug Administration, Silver Spring, Maryland, USA
| | - Kellie Reynolds
- Division of Infectious Disease Pharmacology, Office of Clinical Pharmacology, Office of Translational Sciences, Center for Drug Evaluation and Research, US Food and Drug Administration, Silver Spring, Maryland, USA
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17
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Pegram MD, Miles D, Tsui CK, Zong Y. HER2-Overexpressing/Amplified Breast Cancer as a Testing Ground for Antibody-Drug Conjugate Drug Development in Solid Tumors. Clin Cancer Res 2019; 26:775-786. [PMID: 31582515 DOI: 10.1158/1078-0432.ccr-18-1976] [Citation(s) in RCA: 34] [Impact Index Per Article: 5.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/26/2019] [Revised: 07/17/2019] [Accepted: 09/30/2019] [Indexed: 11/16/2022]
Abstract
Efficacy data from the KATHERINE clinical trial, comparing the HER2-directed antibody-drug conjugate (ADC) ado-trastuzumab emtansine (T-DM1) to trastuzumab in patients with early-stage HER2-amplified/overexpressing breast cancer with residual disease after neoadjuvant therapy, demonstrates superiority of T-DM1 (HR for invasive disease or death, 0.50; P < 0.001). This establishes foundational precedent for ADCs as effective therapy for treatment of subclinical micrometastasis in an adjuvant (or post-neoadjuvant) early-stage solid tumor setting. Despite this achievement, general principles from proposed systems pharmacokinetic modeling for intracellular processing of ADCs indicate potential shortcomings of T-DM1: (i) C max limited by toxicities; (ii) slow internalization rate; (iii) resistance mechanisms due to defects in intracellular trafficking [loss of lysosomal transporter solute carrier family 46 member 3, (SLC46A3)], and increased expression of drug transporters MDR1 and MRP1; and (iv) lack of payload bystander effects limiting utility in tumors with heterogeneous HER2 expression. These handicaps may explain the inferiority of T-DM1-based therapy in the neoadjuvant and first-line metastatic HER2+ breast cancer settings, and lack of superiority to chemotherapy in HER2+ advanced gastric cancer. In this review, we discuss how each of these limitations is being addressed by manipulating internalization and trafficking using HER2:HER2 bispecific or biparatopic antibody backbones, using site-specific, fixed DAR conjugation chemistry, and payload swapping to exploit alternative intracellular targets and to promote bystander effects. Newer HER2-directed ADCs have impressive clinical activity even against tumors with lower levels of HER2 receptor expression. Finally, we highlight ongoing clinical efforts to combine HER2 ADCs with other treatment modalities, including chemotherapy, molecularly targeted therapies, and immunotherapy.
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Affiliation(s)
- Mark D Pegram
- Stanford Comprehensive Cancer Institute, Stanford University School of Medicine, Stanford, California.
| | - David Miles
- Mount Vernon Cancer Centre, Mount Vernon Hospital, Northwood, London, United Kingdom
| | - C Kimberly Tsui
- Department of Genetics, Stanford University School of Medicine, Stanford, California
| | - Yu Zong
- Stanford Comprehensive Cancer Institute, Stanford University School of Medicine, Stanford, California
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18
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Alternative dosing regimens for atezolizumab: an example of model-informed drug development in the postmarketing setting. Cancer Chemother Pharmacol 2019; 84:1257-1267. [PMID: 31542806 PMCID: PMC6820606 DOI: 10.1007/s00280-019-03954-8] [Citation(s) in RCA: 66] [Impact Index Per Article: 11.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/06/2019] [Accepted: 09/03/2019] [Indexed: 01/24/2023]
Abstract
PURPOSE To determine the exposure-response (ER) relationships between atezolizumab exposure and efficacy or safety in patients with advanced non-small cell lung cancer (NSCLC) or urothelial carcinoma (UC) and to identify alternative dosing regimens. METHODS ER analyses were conducted using pooled NSCLC and UC data from phase 1 and 3 studies (PCD4989g, OAK, IMvigor211; ClinicalTrials.gov IDs, NCT01375842, NCT02008227, and NCT02302807, respectively). Objective response rate, overall survival, and adverse events were evaluated vs pharmacokinetic (PK) metrics. Population PK-simulated exposures for regimens of 840 mg every 2 weeks (q2w) and 1680 mg every 4 weeks (q4w) were compared with the approved regimen of 1200 mg every 3 weeks (q3w) and the maximum assessed dose (MAD; 20 mg/kg q3w). Phase 3 IMpassion130 (NCT02425891) data were used to validate the PK simulations for 840 mg q2w. Observed safety data were evaluated by exposure and body weight subgroups. RESULTS No significant ER relationships were observed for safety or efficacy. Predicted exposures for 840 mg q2w and 1680 mg q4w were comparable to 1200 mg q3w and the MAD and consistent with observed PK data from IMpassion130. Observed safety was similar between patients with a Cmax above and below the predicted Cmax for 1680 mg q4w and between patients in the lowest and upper 3 body weight quartiles. CONCLUSION Atezolizumab regimens of 840 mg q2w and 1680 mg q4w are expected to have comparable efficacy and safety as the approved regimen of 1200 mg q3w, supporting their interchangeable use and offering patients greater flexibility.
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19
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Baverel P, Roskos L, Tatipalli M, Lee N, Stockman P, Taboada M, Vicini P, Horgan K, Narwal R. Exposure-Response Analysis of Overall Survival for Tremelimumab in Unresectable Malignant Mesothelioma: The Confounding Effect of Disease Status. Clin Transl Sci 2019; 12:450-458. [PMID: 30883000 PMCID: PMC6742946 DOI: 10.1111/cts.12633] [Citation(s) in RCA: 13] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/26/2018] [Accepted: 02/11/2019] [Indexed: 12/29/2022] Open
Abstract
Tremelimumab, an anti-cytotoxic T-lymphocyte antigen-4 monoclonal antibody that enhances T-cell activation, was evaluated in a randomized, double-blind, placebo-controlled, phase IIb study (NCT01843374) in patients with unresectable malignant mesothelioma. The study demonstrated no clinically meaningful differences in overall survival (OS). The objective of this analysis was to evaluate the relationship of exposure with OS. A population pharmacokinetic (PK) model adequately described the PK data. Three factors (sex, C-reactive protein, and baseline tumor size) were identified as statistically significant PK predictors (P < 0.05 on clearance). A positive association between exposure and OS was observed. However, an association between key baseline factors with OS (regardless of treatment) and imbalances in prognostic factors favoring patients with higher exposure (upper vs. lower PK quartile) was seen. Taken together, these results suggest that the exposure OS relationship observed for tremelimumab in mesothelioma is likely spurious rather than a true association of exposure with efficacy.
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20
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Tang E, Rowland A, McKinnon RA, Sorich MJ, Hopkins AM. Effect of early adverse events resulting in ado-trastuzumab emtansine dose adjustments on survival outcomes of HER2+ advanced breast cancer patients. Breast Cancer Res Treat 2019; 178:473-477. [PMID: 31399933 DOI: 10.1007/s10549-019-05393-8] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/09/2019] [Accepted: 08/02/2019] [Indexed: 12/22/2022]
Abstract
PURPOSE Ado-trastuzumab emtansine (T-DM1) treatment in HER2+ advanced breast cancer patients is generally well tolerated, but when adverse events occur dose adjustments may be required. This study evaluated the impact of early adverse events requiring T-DM1 dose interruptions or reductions on overall survival (OS) and progression-free survival (PFS) in HER2+ advanced metastatic breast cancer patients in the clinical trials EMILIA and TH3RESA. PATIENTS AND METHODS The study included 893 participants initiated on T-DM1 treatment. A landmark approach set at 4 months was used to evaluate the association between early adverse events requiring T-DM1 dose interruptions or reductions and OS/PFS. Cox proportional hazard analysis modeled the association between events requiring T-DM1 dose interruptions or reductions and OS/PFS. Associations were reported as hazard ratios with 95% confidence intervals. RESULTS Adverse events requiring T-DM1 dose interruptions or reductions within the first 4 months of treatment were not significantly associated with OS (hazard ratio (HR) [95% CI]: dose interrupted = 1.15 [0.85-1.55]; dose reduced = 0.75 [0.49-1.14]; P = 0.214) nor PFS (hazard ratio (HR) [95% CI]: dose interrupted = 1.13 [0.87-1.48]; dose reduced = 0.90 [0.62-1.31]; P = 0.534). CONCLUSION The occurrence of early adverse events requiring T-DM1 dose interruptions or reductions do not appear to be associated with altered long-term OS or PFS within a pooled analysis of data from EMILIA and TH3RESA.
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Affiliation(s)
- Ethan Tang
- College of Medicine and Public Health, Flinders University, Flinders Drive, Bedford Park, Adelaide, SA, 5042, Australia.
- Flinders Medical Centre, Room 5D317, Bedford Park, SA, 5042, Australia.
| | - Andrew Rowland
- College of Medicine and Public Health, Flinders University, Flinders Drive, Bedford Park, Adelaide, SA, 5042, Australia
| | - Ross A McKinnon
- College of Medicine and Public Health, Flinders University, Flinders Drive, Bedford Park, Adelaide, SA, 5042, Australia
| | - Michael J Sorich
- College of Medicine and Public Health, Flinders University, Flinders Drive, Bedford Park, Adelaide, SA, 5042, Australia
| | - Ashley M Hopkins
- College of Medicine and Public Health, Flinders University, Flinders Drive, Bedford Park, Adelaide, SA, 5042, Australia
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21
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Development of an Enzyme-Linked Immune Sorbent Assay to Measure Nivolumab and Pembrolizumab Serum Concentrations. Ther Drug Monit 2019; 40:596-601. [PMID: 29847460 DOI: 10.1097/ftd.0000000000000534] [Citation(s) in RCA: 17] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/05/2023]
Abstract
BACKGROUND Treatment with monoclonal antibodies (mAbs) against programmed cell death protein 1 receptor is subject to high variation in treatment outcome among cancer patients. For these agents, no exposure-response (ER) relationships have been investigated in routine health care settings. However, ER relationships have been identified for several other mAbs used in oncology. Methods to conveniently measure serum concentrations of anti-programmed cell death protein 1 mAbs in routine health care may clarify possible ER relationships. Therefore, the authors aimed to develop an enzyme-linked immune sorbent assay (ELISA) for the measurement of both nivolumab and pembrolizumab serum concentrations of treated cancer patients. METHODS Optimal capture antigen and detection antibody concentrations were selected based on titrations. Nivolumab calibration standards ranging from 0.2 to 300 ng/mL were tested in duplicate. Accuracy was assessed in 2 recovery experiments. Intra- and interassay variations were assessed on 3 different days by 2 independent technicians. The developed ELISA was also set up for pembrolizumab calibration curves. Cross-reactivity of nivolumab measurements with ipilimumab was assessed. Of one nivolumab treated patient, serum concentrations in follow up samples were measured and presented. RESULTS Nivolumab calibration standards of 0.20-25 ng/mL were used. Nivolumab trough concentrations after 1 cycle in 8 patients ranged from 17.3 to 31.1 mcg/mL. The range of accuracy was 84%-105%, whereas intra- and interassay variations showed a coefficient of variation of 5.5% and 10.1%, respectively. No cross-reactivity with ipilimumab was detected. Pembrolizumab trough concentrations (n = 8) ranged from 9.1 to 19.7 mcg/mL after 1 infusion. CONCLUSIONS The in-house-developed ELISA provides the opportunity to measure both nivolumab and pembrolizumab serum concentrations. This may help identify possible ER relationships in treated cancer patients and may potentially lead to dose adjustments in the future.
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Grevel J, Jentsch G, Austin R, Prins NH, Lettieri J, Mitchell D, Huang F, Brose MS, Schlumberger M, Meinhardt G, Peña CEA, Ploeger BA. Exposure-Response Modeling and Simulation of Progression-Free Survival and Adverse Events of Sorafenib Treatment in Patients With Advanced Thyroid Cancer. Clin Transl Sci 2019; 12:459-469. [PMID: 30920122 PMCID: PMC6742948 DOI: 10.1111/cts.12634] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/10/2018] [Accepted: 02/02/2019] [Indexed: 12/13/2022] Open
Abstract
Sorafenib is an oral multikinase inhibitor approved for the treatment of differentiated thyroid carcinoma (DTC), renal cell carcinoma, and hepatocellular carcinoma. In the phase III DECISION trial in patients with DTC, sorafenib exposure and the incidence of some adverse events (AEs) were higher than in previous trials; therefore, we analyzed exposure–response relationships, including progression‐free survival (PFS) and selected AEs in patients with DTC. A novel, stratified prediction‐corrected visual predictive check (pc‐VPC) was developed to show robustness of the exposure–response relationships. Time‐to‐event simulations confirmed the benefit of the recommended dosing schedule of 800 mg/day: initial doses of 800 mg/day were associated with the highest PFS, whereas lower doses (600 or 400 mg/day) were associated with improved tolerability but reduced PFS. A simulated dose‐reduction strategy of 800 mg/day for an initial two cycles followed by dose reductions seemed likely to maintain efficacy while possibly mitigating selected AEs (e.g., diarrhea and hand‐foot skin reactions).
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Affiliation(s)
| | | | | | | | - John Lettieri
- Bayer HealthCare Pharmaceuticals, Whippany, New Jersey, USA
| | - David Mitchell
- Mitchell Pharmaceutical Consulting, Lafayette, Colorado, USA
| | - Funan Huang
- Bayer HealthCare Pharmaceuticals, Whippany, New Jersey, USA
| | - Marcia S Brose
- Department of Otorhinolaryngology: Head and Neck Surgery, Abramson Cancer Center of the University of Pennsylvania, Philadelphia, Pennsylvania, USA
| | - Martin Schlumberger
- Department of Nuclear Medicine and Endocrine Oncology, Institut Gustave Roussy and Université Paris Saclay, Villejuif, France
| | | | - Carol E A Peña
- Bayer HealthCare Pharmaceuticals, Whippany, New Jersey, USA
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23
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Yao HP, Feng L, Suthe SR, Chen LH, Weng TH, Hu CY, Jun ES, Wu ZG, Wang WL, Kim SC, Tong XM, Wang MH. Therapeutic efficacy, pharmacokinetic profiles, and toxicological activities of humanized antibody-drug conjugate Zt/g4-MMAE targeting RON receptor tyrosine kinase for cancer therapy. J Immunother Cancer 2019; 7:75. [PMID: 30871619 PMCID: PMC6419354 DOI: 10.1186/s40425-019-0525-0] [Citation(s) in RCA: 16] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/31/2018] [Accepted: 01/31/2019] [Indexed: 12/23/2022] Open
Abstract
BACKGROUND Aberrant expression of the RON receptor tyrosine kinase is a pathogenic feature and a validated drug target in various types of cancers. Currently, therapeutic antibodies targeting RON for cancer therapy are under intensive evaluation. Here we report the development and validation of a novel humanized anti-RON antibody-drug conjugate for cancer therapy. METHODS Antibody humanization was achieved by grafting sequences of complementarity-determining regions from mouse monoclonal antibody Zt/g4 into human IgG1/κ acceptor frameworks. The selected humanized Zt/g4 subclone H1L3 was conjugated with monomethyl auristatin E using a dipeptide linker to form H-Zt/g4-MMAE. Pharmacokinetic analysis of H-Zt/g4-MMAE was determined using hydrophobic interaction chromatography and a MMAE ADC ELISA kit. Biochemical and biological assays were used for measuring RON expression, internalization, cell viability and death. Therapeutic efficacies of H-Zt/g4-MMAE were validated in vivo using three pancreatic cancer xenograft models. Toxicological activities of H-Zt/g4-MMAE were determined in mouse and cynomolgus monkey. RESULTS H-Zt/g4-MMAE had a drug to antibody ratio of 3.77:1 and was highly stable in human plasma with a dissociation rate less than 5% within a 20 day period. H-Zt/g4-MMAE displayed a favorable pharmacokinetic profile in both mouse and cynomolgus monkey. In vitro, H-Zt/g4-MMAE induced RON internalization, which results in killing of pancreatic cancer cells with IC50 values at 10-20 nM. In vivo, H-Zt/g4-MMAE inhibited pancreatic cancer xenograft growth with tumoristatic concentrations at 1~3 mg/kg bodyweight. Significantly, H-Zt/g4-MMAE eradicated tumors across multiple xenograft models regardless their chemoresistant and metastatic statuses. Moreover, H-Zt/g4-MMAE inhibited and eradicated xenografts mediated by pancreatic cancer stem-like cells and by primary cells from patient-derived tumors. Toxicologically, H-Zt/g4-MMAE is well tolerated in mice up to 60 mg/kg. In cynomolgus monkey, H-Zt/g4-MMAE up to 30 mg/kg had a manageable and reversible toxicity profile. CONCLUSIONS H-Zt/g4-MMAE is superior in eradication of pancreatic cancer xenografts with favorable pharmacokinetic profiles and manageable toxicological activities. These findings warrant the transition of H-Zt/g4-MMAE into clinical trials in the future.
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MESH Headings
- Animals
- Antibodies, Monoclonal, Humanized/administration & dosage
- Antibodies, Monoclonal, Humanized/adverse effects
- Antibodies, Monoclonal, Humanized/chemistry
- Antibodies, Monoclonal, Humanized/pharmacokinetics
- Carcinoma, Pancreatic Ductal/drug therapy
- Carcinoma, Pancreatic Ductal/metabolism
- Cell Line, Tumor
- Cell Proliferation/drug effects
- Cell Survival/drug effects
- Female
- Gene Expression Regulation, Neoplastic/drug effects
- HCT116 Cells
- HT29 Cells
- Humans
- Immunoconjugates/administration & dosage
- Immunoconjugates/adverse effects
- Immunoconjugates/chemistry
- Immunoconjugates/pharmacokinetics
- Macaca fascicularis
- Mice
- NIH 3T3 Cells
- Oligopeptides/chemistry
- Pancreatic Neoplasms/drug therapy
- Pancreatic Neoplasms/metabolism
- Receptor Protein-Tyrosine Kinases/metabolism
- Xenograft Model Antitumor Assays
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Affiliation(s)
- Hang-Ping Yao
- State Key Laboratory for Diagnosis & Treatment of Infectious Diseases, First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China
| | - Liang Feng
- Cancer Biology Research Center, Hangzhou, China
- Department of Pharmaceutical Sciences, Texas Tech University Health Sciences Center School of Pharmacy, Amarillo, TX USA
| | - Sreedhar Reddy Suthe
- Department of Pharmaceutical Sciences, Texas Tech University Health Sciences Center School of Pharmacy, Amarillo, TX USA
| | - Ling-Hui Chen
- Zhejiang Provincial Key Laboratory for Precision Diagnosis & Treatment of Hepatic & Pancreatic Oncology, Zhejiang Province, China
- Division of Hepatobiliary & Pancreatic Surgery, First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China
| | - Tian-Hao Weng
- State Key Laboratory for Diagnosis & Treatment of Infectious Diseases, First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China
| | - Chen-Yu Hu
- State Key Laboratory for Diagnosis & Treatment of Infectious Diseases, First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China
| | - Eun Sung Jun
- Department of Biomedical Sciences, Kowloon Tong, Hong Kong
| | - Zhi-Gang Wu
- Zhejiang Provincial Key Laboratory for Precision Diagnosis & Treatment of Hepatic & Pancreatic Oncology, Zhejiang Province, China
| | - Wei-Lin Wang
- Zhejiang Provincial Key Laboratory for Precision Diagnosis & Treatment of Hepatic & Pancreatic Oncology, Zhejiang Province, China
- Division of Hepatobiliary & Pancreatic Surgery, First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China
| | - Song Cheol Kim
- Biliary and Pancreatic Cancer Center at Department of Surgery, University of Ulsan College of Medicine, Seoul, South Korea
| | - Xiang-Min Tong
- Department of Laboratory Medicine, Zhejiang Provincial People’s Hospital, Hangzhou Medical College, Hangzhou, China
| | - Ming-Hai Wang
- State Key Laboratory for Diagnosis & Treatment of Infectious Diseases, First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China
- Department of Pharmaceutical Sciences, Texas Tech University Health Sciences Center School of Pharmacy, Amarillo, TX USA
- Zhejiang Provincial Key Laboratory for Precision Diagnosis & Treatment of Hepatic & Pancreatic Oncology, Zhejiang Province, China
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24
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Basak EA, Koolen SLW, Hurkmans DP, Schreurs MWJ, Bins S, Oomen-de Hoop E, Wijkhuijs AJM, Besten ID, Sleijfer S, Debets R, van der Veldt AAM, Aerts JGJV, Mathijssen RHJ. Correlation between nivolumab exposure and treatment outcomes in non-small-cell lung cancer. Eur J Cancer 2019; 109:12-20. [PMID: 30654225 DOI: 10.1016/j.ejca.2018.12.008] [Citation(s) in RCA: 53] [Impact Index Per Article: 8.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/04/2018] [Revised: 12/02/2018] [Accepted: 12/05/2018] [Indexed: 02/07/2023]
Abstract
INTRODUCTION Nivolumab treatment is subject to large interpatient variability in both efficacy and toxicity, which may partly be explained by differences in nivolumab exposure. Exposure-response relationships in regular healthcare have not been extensively investigated for nivolumab. Therefore, we aimed to identify possible exposure-response relationships in nivolumab-treated patients with non-small-cell lung cancer (NSCLC). METHODS Patients with NSCLC who started second-line nivolumab therapy (3 mg/kg Q2W) between May 5th 2016 and August 1st 2017, and from whom serial blood samples, toxicity data and outcome data were prospectively collected, were included. Follow-up was carried out until November 1st 2017. Patients were classified according to the best overall response (BOR) based on the Response Evaluation Criteria in Solid Tumours, v1.1, and toxicities according to the Common Terminology Criteria for Adverse Events. Nivolumab trough concentrations were measured after 2, 4 and 10 weeks of treatment, excluding dose delays, and calculated geometric means were tested versus BOR or toxicity using analysis of variance and an independent samples t-test, respectively. Overall survival (OS) and progression-free survival were compared between high and low trough concentration groups. RESULTS Seventy-six patients were evaluable for analyses. Responders (n = 15) had higher mean trough concentrations than patients with progression (n = 33): 47% higher after 2 weeks (p = 0.001), 53% higher after 4 weeks (p = 0.008) and 73% higher after 10 weeks (p = 0.002). Higher trough concentrations were associated with longer OS (p = 0.001). CONCLUSIONS This study shows that patients with NSCLC with a response to nivolumab had a higher nivolumab exposure than patients with progression, indicating a potential exposure-response relationship. Further clinical research should focus on clarifying these exposure-response relationships.
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Affiliation(s)
- Edwin A Basak
- Dept. of Medical Oncology, Erasmus MC Cancer Institute, Rotterdam, the Netherlands.
| | - Stijn L W Koolen
- Dept. of Medical Oncology, Erasmus MC Cancer Institute, Rotterdam, the Netherlands; Dept. of Hospital Pharmacy, Erasmus MC, University Medical Centre, Rotterdam, the Netherlands
| | - Daan P Hurkmans
- Dept. of Medical Oncology, Erasmus MC Cancer Institute, Rotterdam, the Netherlands
| | - Marco W J Schreurs
- Dept. of Immunology, Erasmus University Medical Center, Rotterdam, the Netherlands
| | - Sander Bins
- Dept. of Medical Oncology, Erasmus MC Cancer Institute, Rotterdam, the Netherlands
| | - Esther Oomen-de Hoop
- Dept. of Medical Oncology, Erasmus MC Cancer Institute, Rotterdam, the Netherlands
| | | | - Ilse den Besten
- Dept. of Pulmonology, Erasmus University Medical Center, Rotterdam, the Netherlands
| | - Stefan Sleijfer
- Dept. of Medical Oncology, Erasmus MC Cancer Institute, Rotterdam, the Netherlands
| | - Reno Debets
- Dept. of Medical Oncology, Erasmus MC Cancer Institute, Rotterdam, the Netherlands
| | | | - Joachim G J V Aerts
- Dept. of Pulmonology, Erasmus University Medical Center, Rotterdam, the Netherlands
| | - Ron H J Mathijssen
- Dept. of Medical Oncology, Erasmus MC Cancer Institute, Rotterdam, the Netherlands
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25
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Pearce NF, Giblin EM, Buckthal C, Ferrari A, Powell JR, Cao Y, Patterson JH. Precision drug dosing: A major opportunity for patients and pharmacists. JOURNAL OF THE AMERICAN COLLEGE OF CLINICAL PHARMACY 2018. [DOI: 10.1002/jac5.1017] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/13/2023]
Affiliation(s)
- Natalie F. Pearce
- Division of Pharmacotherapy and Experimental Therapeutics UNC Eshelman School of Pharmacy, University of North Carolina at Chapel Hill Chapel Hill North Carolina
| | - Erika M. Giblin
- Division of Pharmacotherapy and Experimental Therapeutics UNC Eshelman School of Pharmacy, University of North Carolina at Chapel Hill Chapel Hill North Carolina
| | - Catherine Buckthal
- Division of Pharmacotherapy and Experimental Therapeutics UNC Eshelman School of Pharmacy, University of North Carolina at Chapel Hill Chapel Hill North Carolina
| | - Alana Ferrari
- Division of Pharmacotherapy and Experimental Therapeutics UNC Eshelman School of Pharmacy, University of North Carolina at Chapel Hill Chapel Hill North Carolina
| | - J. Robert Powell
- Division of Pharmacotherapy and Experimental Therapeutics UNC Eshelman School of Pharmacy, University of North Carolina at Chapel Hill Chapel Hill North Carolina
| | - Yanguang Cao
- Division of Pharmacotherapy and Experimental Therapeutics UNC Eshelman School of Pharmacy, University of North Carolina at Chapel Hill Chapel Hill North Carolina
| | - J. Herbert Patterson
- Division of Pharmacotherapy and Experimental Therapeutics UNC Eshelman School of Pharmacy, University of North Carolina at Chapel Hill Chapel Hill North Carolina
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Smit EF, Garon EB, Reck M, Cappuzzo F, Bidoli P, Cohen RB, Gao L, O'Brien LM, Lee P, Zimmermann A, Ferry DR, Melemed AS, Pérol M. Exposure-response relationship for ramucirumab from the randomized, double-blind, phase 3 REVEL trial (docetaxel versus docetaxel plus ramucirumab) in second-line treatment of metastatic non-small cell lung cancer. Cancer Chemother Pharmacol 2018; 82:77-86. [PMID: 29721850 DOI: 10.1007/s00280-018-3560-5] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/01/2017] [Accepted: 03/03/2018] [Indexed: 02/02/2023]
Abstract
PURPOSE Ramucirumab plus docetaxel improved survival in REVEL, a randomized phase 3 trial for patients with Stage IV non-small cell lung cancer after standard platinum-based chemotherapy. This exploratory analysis evaluated the exposure-response relationship of ramucirumab from REVEL. METHODS Patients received ramucirumab (10 mg/kg) or placebo plus docetaxel (75 mg/m2) every 3 weeks. Pharmacokinetic samples were collected. A population pharmacokinetic analysis predicted ramucirumab minimum concentration after first-dose administration (Cmin,1) and average concentration at steady state (Cave,ss). Predicted Cmin,1 and Cave,ss were used to evaluate the relationship between ramucirumab exposure and efficacy and safety, respectively. Exposure-efficacy was assessed by Kaplan-Meier and Cox regression analyses; exposure-safety was assessed by ordered categorical analyses. RESULTS Analyses included 376 patients treated with ramucirumab plus docetaxel and 366 patients treated with placebo plus docetaxel (364 for safety population). After adjusting for corresponding prognostic factors, the association between overall survival (OS) and Cmin,1 was statistically significant (p = 0.0110), although progression-free survival (PFS) showed a marginal association (p = 0.0515). At high ramucirumab exposures (Cmin,1), greater improvements (smaller hazard ratios) were seen for OS and PFS when stratified by Cmin,1 exposure quartiles. A statistically significant correlation was observed between ramucirumab Cave,ss and grade ≥ 3 febrile neutropenia and hypertension. CONCLUSIONS An association was observed between ramucirumab exposure and efficacy. Higher ramucirumab exposure was associated with improved clinical outcomes and increased toxicity in this analysis. Two exposure-response prospective randomized trials are being conducted to address causation (NCT02443883 and NCT02514551), with encouraging preliminary results (Ajani et al. in Ann Oncol 28:abstr 698P, 2017).
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Affiliation(s)
- Egbert F Smit
- Department of Thoracic Oncology, Netherlands Cancer Institute, Amsterdam, The Netherlands.
- Department of Pulmonary Diseases, VU University Medical Centre, PO Box 7057, 1007 MB, Amsterdam, The Netherlands.
| | - Edward B Garon
- David Geffen School of Medicine at UCLA/Translational Research in Oncology-US Network, Los Angeles, CA, USA
| | - Martin Reck
- Lungen Clinic Grosshansdorf, Airway Research Center North (ARCN), Member of the German Center for Lung Research (DZL), Grosshansdorf, Germany
| | | | - Paolo Bidoli
- Nuovo Ospedale San Gerardo, Via Pergolesi, Milano, Italy
| | | | - Ling Gao
- Eli Lilly and Company, Bridgewater, NJ, USA
| | | | - Pablo Lee
- Eli Lilly and Company, Bridgewater, NJ, USA
| | | | | | | | - Maurice Pérol
- Département de Cancérologie Médicale Centre Léon-Bérard, Lyon, France
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27
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Turner DC, Kondic AG, Anderson KM, Robinson AG, Garon EB, Riess JW, Jain L, Mayawala K, Kang J, Ebbinghaus SW, Sinha V, de Alwis DP, Stone JA. Pembrolizumab Exposure-Response Assessments Challenged by Association of Cancer Cachexia and Catabolic Clearance. Clin Cancer Res 2018; 24:5841-5849. [PMID: 29891725 DOI: 10.1158/1078-0432.ccr-18-0415] [Citation(s) in RCA: 161] [Impact Index Per Article: 23.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/15/2018] [Revised: 04/12/2018] [Accepted: 06/05/2018] [Indexed: 11/16/2022]
Abstract
PURPOSE To investigate the relationship of pembrolizumab pharmacokinetics (PK) and overall survival (OS) in patients with advanced melanoma and non-small cell lung cancer (NSCLC). PATIENTS AND METHODS PK dependencies in OS were evaluated across three pembrolizumab studies of either 200 mg or 2 to 10 mg/kg every 3 weeks (Q3W). Kaplan-Meier plots of OS, stratified by dose, exposure, and baseline clearance (CL0), were assessed per indication and study. A Cox proportional hazards model was implemented to explore imbalances of typical prognostic factors in high/low NSCLC CL0 subgroups. RESULTS A total of 1,453 subjects were included: 340 with pembrolizumab-treated melanoma, 804 with pembrolizumab-treated NSCLC, and 309 with docetaxel-treated NSCLC. OS was dose independent from 2 to 10 mg/kg for pembrolizumab-treated melanoma [HR = 0.98; 95% confidence interval (CI), 0.94-1.02] and NSCLC (HR = 0.98; 95% CI, 0.95-1.01); however, a strong CL0-OS association was identified for both cancer types (unadjusted melanoma HR = 2.56; 95% CI, 1.72-3.80 and NSCLC HR = 2.64; 95% CI, 1.94-3.57). Decreased OS in subjects with higher pembrolizumab CL0 paralleled disease severity markers associated with end-stage cancer anorexia-cachexia syndrome. Correction for baseline prognostic factors did not fully attenuate the CL0-OS association (multivariate-adjusted CL0 HR = 1.64; 95% CI, 1.06-2.52 for melanoma and HR = 1.88; 95% CI, 1.22-2.89 for NSCLC). CONCLUSIONS These data support the lack of dose or exposure dependency in pembrolizumab OS for melanoma and NSCLC between 2 and 10 mg/kg. An association of pembrolizumab CL0 with OS potentially reflects catabolic activity as a marker of disease severity versus a direct PK-related impact of pembrolizumab on efficacy. Similar data from other trials suggest such patterns of exposure-response confounding may be a broader phenomenon generalizable to antineoplastic mAbs.See related commentary by Coss et al., p. 5787.
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Affiliation(s)
| | | | | | - Andrew G Robinson
- Cancer Centre of Southeastern Ontario at Kingston General Hospital, Ontario, Canada
| | - Edward B Garon
- David Geffen School of Medicine at UCLA, Los Angeles, California
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Schindler E, Friberg LE, Lum BL, Wang B, Quartino A, Li C, Girish S, Jin JY, Karlsson MO. A Pharmacometric Analysis of Patient-Reported Outcomes in Breast Cancer Patients Through Item Response Theory. Pharm Res 2018; 35:122. [PMID: 29675616 PMCID: PMC5908825 DOI: 10.1007/s11095-018-2403-8] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/21/2018] [Accepted: 04/05/2018] [Indexed: 12/11/2022]
Abstract
PURPOSE An item response theory (IRT) pharmacometric framework is presented to characterize Functional Assessment of Cancer Therapy-Breast (FACT-B) data in locally-advanced or metastatic breast cancer patients treated with ado-trastuzumab emtansine (T-DM1) or capecitabine-plus-lapatinib. METHODS In the IRT model, four latent well-being variables, based on FACT-B general subscales, were used to describe the physical, social/family, emotional and functional well-being. Each breast cancer subscale item was reassigned to one of the other subscales. Longitudinal changes in FACT-B responses and covariate effects were investigated. RESULTS The IRT model could describe both item-level and subscale-level FACT-B data. Non-Asian patients showed better baseline social/family and functional well-being than Asian patients. Moreover, patients with Eastern Cooperative Oncology Group performance status of 0 had better baseline physical and functional well-being. Well-being was described as initially increasing or decreasing before reaching a steady-state, which varied substantially between patients and subscales. T-DM1 exposure was not related to any of the latent variables. Physical well-being worsening was identified in capecitabine-plus-lapatinib-treated patients, whereas T-DM1-treated patients typically stayed stable. CONCLUSION The developed framework provides a thorough description of FACT-B longitudinal data. It acknowledges the multi-dimensional nature of the questionnaire and allows covariate and exposure effects to be evaluated on responses.
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Affiliation(s)
- Emilie Schindler
- Department of Pharmaceutical Biosciences, Uppsala University, Box 591, SE-75124, Uppsala, Sweden
| | - Lena E Friberg
- Department of Pharmaceutical Biosciences, Uppsala University, Box 591, SE-75124, Uppsala, Sweden
| | - Bertram L Lum
- Department of Clinical Pharmacology, Genentech Inc., South San Francisco, California, USA
| | - Bei Wang
- Department of Clinical Pharmacology, Genentech Inc., South San Francisco, California, USA
| | - Angelica Quartino
- Department of Clinical Pharmacology, Genentech Inc., South San Francisco, California, USA
| | - Chunze Li
- Department of Clinical Pharmacology, Genentech Inc., South San Francisco, California, USA
| | - Sandhya Girish
- Department of Clinical Pharmacology, Genentech Inc., South San Francisco, California, USA
| | - Jin Y Jin
- Department of Clinical Pharmacology, Genentech Inc., South San Francisco, California, USA
| | - Mats O Karlsson
- Department of Pharmaceutical Biosciences, Uppsala University, Box 591, SE-75124, Uppsala, Sweden.
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Chalouni C, Doll S. Fate of Antibody-Drug Conjugates in Cancer Cells. J Exp Clin Cancer Res 2018; 37:20. [PMID: 29409507 PMCID: PMC5802061 DOI: 10.1186/s13046-017-0667-1] [Citation(s) in RCA: 125] [Impact Index Per Article: 17.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/15/2017] [Accepted: 12/15/2017] [Indexed: 02/08/2023] Open
Abstract
Antibody-Drug Conjugates (ADCs) are a class of cancer therapeutics that combines antigen specificity and potent cytotoxicity in a single molecule as they are comprised of an engineered antibody linked chemically to a cytotoxic drug. Four ADCs have received approval by the Food and Drug Administration (FDA) and the European Medicine Agency (EMA) and can be prescribed for metastatic conditions while around 60 ADCs are currently enrolled in clinical trials. The efficacy of an ADC greatly relies on its intracellular trafficking and processing of its components to trigger tumor cell death. A limited number of studies have addressed these critical processes that both challenge and help foster the design of ADCs. This review highlights those mechanisms and their relevance for future development of ADCs as cancer therapeutics.
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Martin C, Kizlik-Masson C, Pèlegrin A, Watier H, Viaud-Massuard MC, Joubert N. Antibody-drug conjugates: Design and development for therapy and imaging in and beyond cancer, LabEx MAbImprove industrial workshop, July 27-28, 2017, Tours, France. MAbs 2018; 10:210-221. [PMID: 29239690 PMCID: PMC5825198 DOI: 10.1080/19420862.2017.1412130] [Citation(s) in RCA: 20] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/11/2022] Open
Abstract
The annual "Antibody Industrial Symposium", co organized by LabEx MAbImprove, MabDesign and Polepharma, was held in Tours, France on June 27-28, 2017. The focus was on antibody-drug-conjugates (ADCs), new entities which realize the hope of Paul Ehrlich's magic bullet. ADCs result from the bioconjugation of a highly cytotoxic drug to a selective monoclonal antibody, which acts as a vector. Building on knowledge gained during the development of three approved ADCs, brentuximab vedotin (Adcetris®), ado trastuzumab emtansine (Kadcyla®) and inotuzumab ozogamicin (Besponsa®), and the many ADCs in development, this meeting addressed strategies and the latest innovations in the field from fundamental research to manufacturing.
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Affiliation(s)
- Camille Martin
- a Equipe 4 IMT GICC, Université François Rabelais , Tours , France
| | | | - André Pèlegrin
- c IRCM, Institut de Recherche en Cancérologie de Montpellier , Université de Montpellier, Institut régional du Cancer de Montpellier , Montpellier , France
| | - Hervé Watier
- b Equipe 1 FRAME GICC, Université François Rabelais , Tours , France.,d Service d'Immunologie, CHRU de Tours , Tours , France
| | | | - Nicolas Joubert
- a Equipe 4 IMT GICC, Université François Rabelais , Tours , France
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Peck RW. Precision Medicine Is Not Just Genomics: The Right Dose for Every Patient. Annu Rev Pharmacol Toxicol 2018; 58:105-122. [DOI: 10.1146/annurev-pharmtox-010617-052446] [Citation(s) in RCA: 60] [Impact Index Per Article: 8.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/09/2022]
Affiliation(s)
- Richard W. Peck
- Pharma Research and Exploratory Development, Roche Innovation Center Basel, 4070 Basel, Switzerland
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32
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Gligorov J. Early HER2-positive breast cancers: time for a new revolution? Lancet Oncol 2018; 19:12-13. [DOI: 10.1016/s1470-2045(17)30874-4] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/09/2017] [Accepted: 10/09/2017] [Indexed: 11/27/2022]
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Ogasawara K, Breder CD, Lin DH, Alexander GC. Exposure– and Dose–response Analyses in Dose Selection and Labeling of FDA-approved Biologics. Clin Ther 2018; 40:95-102.e2. [DOI: 10.1016/j.clinthera.2017.11.012] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/21/2017] [Revised: 11/29/2017] [Accepted: 11/30/2017] [Indexed: 11/30/2022]
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Fleisher B, Ait-Oudhia S. A retrospective examination of the US Food and Drug Administration's clinical pharmacology reviews of oncology biologics for potential use of therapeutic drug monitoring. Onco Targets Ther 2017; 11:113-121. [PMID: 29343970 PMCID: PMC5749565 DOI: 10.2147/ott.s153056] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/19/2022] Open
Abstract
Background Biologics have gained traction for use in oncology, but have demonstrate clinical variability for efficacy and safety. Therapeutic drug monitoring (TDM) can benefit patients’ outcomes from a biologic therapy when the latter has a defined therapeutic window. A clinically relevant therapeutic window may exist for biologics with established exposure-response (E–R) relationships for efficacy and/or safety and a documented maximum tolerated dose (MTD). Additionally, the inter-individual variability (IIV) on the clearance (CL) parameter could determine risks for patients falling outside the proposed therapeutic window. Materials and methods The US Food and Drug Administration (FDA)-approved oncology biologics between 2005–2016 were reviewed via FDA “Purple Book” (FDA-repository for licensed biologics). Data were extracted from biologics’ pharmacokinetic models available on the clinical pharmacology reviews published on the FDA-Approved Drug Products website. Evaluated features for biologics with established E–R relationships for efficacy and/or safety and MTD include an IIV for the CL and various other covariates including demographic factors, disease factors, blood chemistry, or immunogenicity. Results Five therapies were identified with documented E–R relationships for both efficacy and safety including, Yervoy®(ipilimumab), Zaltrap® (ziv-aflibercept), Portrazza® (necitumumab), Adcetris® (brentuximab-vedotin), and Blincyto® (blinatumomab). The corresponding IIV on CL were: 34%, 33%, 29%, 47%, and 97%, respectively. Among the five therapies, only three had defined MTD including, brentuximab-vedotin, necitumumab, and blinatumomab. Conclusion Of the medications examined, blinatumomab was identified as the anticancer drug with the most available information for the establishment of TDM, and hence, may benefit through the use of TDM to optimize effectiveness and minimize patients’ toxicity. The approach used here may provide a generalizable framework to retrospectively identify anticancer biologics with high IIV that may benefit from TDM to improve patients’ clinical outcome.
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Affiliation(s)
- Brett Fleisher
- Center for Pharmacometrics and Systems Pharmacology, Department of Pharmaceutics, College of Pharmacy, University of Florida, Orlando, FL, USA
| | - Sihem Ait-Oudhia
- Center for Pharmacometrics and Systems Pharmacology, Department of Pharmaceutics, College of Pharmacy, University of Florida, Orlando, FL, USA
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Hurvitz SA, Gelmon KA, Tolaney SM. Optimal Management of Early and Advanced HER2 Breast Cancer. Am Soc Clin Oncol Educ Book 2017; 37:76-92. [PMID: 28561711 DOI: 10.1200/edbk_175630] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/20/2022]
Abstract
Approximately 15%-20% of breast cancer is HER2 positive, and patients with this subtype of disease historically had worse outcomes than patients with HER2-negative disease. However, the introduction of HER2-directed therapies has dramatically altered outcomes for these patients, especially for persons with early disease. However, despite these achievements, metastatic disease is still not curable. This review summarizes the current treatment approach for patients in the preoperative and adjuvant setting, including data regarding selecting the optimal chemotherapy partner as well as determining the duration and type of anti-HER-directed therapy. This article also reviews how to approach patients with advanced HER2-positive disease and discusses promising new therapies that are in development.
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Affiliation(s)
- Sara A Hurvitz
- From the David Geffen School of Medicine, University of California, Los Angeles, CA; BC Cancer Agency, University of British Columbia, Vancouver, BC, Canada; Dana-Farber Cancer Institute, Boston, MA
| | - Karen A Gelmon
- From the David Geffen School of Medicine, University of California, Los Angeles, CA; BC Cancer Agency, University of British Columbia, Vancouver, BC, Canada; Dana-Farber Cancer Institute, Boston, MA
| | - Sara M Tolaney
- From the David Geffen School of Medicine, University of California, Los Angeles, CA; BC Cancer Agency, University of British Columbia, Vancouver, BC, Canada; Dana-Farber Cancer Institute, Boston, MA
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36
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Li C, Wang B, Chen SC, Wada R, Lu D, Wang X, Polhamus D, French J, Vadhavkar S, Strasak A, Smitt M, Joshi A, Samant M, Quartino A, Jin J, Girish S. Exposure-response analyses of trastuzumab emtansine in patients with HER2-positive advanced breast cancer previously treated with trastuzumab and a taxane. Cancer Chemother Pharmacol 2017; 80:1079-1090. [PMID: 29022084 DOI: 10.1007/s00280-017-3440-4] [Citation(s) in RCA: 19] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/28/2017] [Accepted: 09/20/2017] [Indexed: 11/30/2022]
Abstract
PURPOSE In the phase III EMILIA study, trastuzumab emtansine (T-DM1) significantly improved progression-free survival (PFS) and overall survival (OS) versus capecitabine plus lapatinib (control) in previously treated human epidermal growth factor receptor 2-positive advanced breast cancer. Using EMILIA data, we evaluated the T-DM1 exposure-response relationship. METHODS Exposure-response relationships were examined with four exposure metrics [model-predicted and observed minimum concentration (C min) and area under the concentration-time curve from time zero to day 21 of T-DM1 at cycle 1] and multiple efficacy (OS, PFS, objective response rate) and safety (grade ≥ 3 adverse events, grade ≥ 3 thrombocytopenia, grade ≥ 3 hepatotoxicity) endpoints. RESULTS An apparent exposure-response trend was observed between model-predicted exposure metrics and efficacy; trends for observed exposure metrics were shallower and often not significant. Although median OS and PFS were numerically longer in patients with higher versus lower model-predicted cycle 1 C min, OS and PFS hazard ratios for T-DM1-treated patients in the lowest exposure quartile (Q1) versus control were < 1 after adjusting for baseline risk factors (e.g., ECOG status, tumor burden, measurable disease, and number of disease sites). No meaningful exposure-response relationship was observed for any safety endpoints. CONCLUSION Exposure-response relationships for efficacy were inconsistent across exposure metrics; model-predicted cycle 1 C min showed the strongest exposure-response trend. The Q1 subgroup based on model-predicted cycle 1 C min had numerically similar or better OS and PFS versus control following covariate adjustment. The approved T-DM1 dose (3.6 mg/kg every 3 weeks) has a positive benefit-risk ratio versus control, even for the T-DM1 Q1 subgroup.
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Affiliation(s)
- Chunze Li
- Department of Clinical Pharmacology, Genentech, Inc., 1 DNA Way, South San Francisco, CA, 94080, USA.
| | - Bei Wang
- Department of Clinical Pharmacology, Genentech, Inc., 1 DNA Way, South San Francisco, CA, 94080, USA
| | - Shang-Chiung Chen
- Department of Clinical Pharmacology, Genentech, Inc., 1 DNA Way, South San Francisco, CA, 94080, USA
| | - Russell Wada
- Certara Strategic Consulting, Certara, Menlo Park, CA, USA
| | - Dan Lu
- Department of Clinical Pharmacology, Genentech, Inc., 1 DNA Way, South San Francisco, CA, 94080, USA
| | - Xin Wang
- Department of Clinical Pharmacology, Genentech, Inc., 1 DNA Way, South San Francisco, CA, 94080, USA
| | - Daniel Polhamus
- Stastical Modeling and Simulation, Metrum Research Group, Tariffville, CT, USA
| | - Jonathan French
- Stastical Modeling and Simulation, Metrum Research Group, Tariffville, CT, USA
| | - Shweta Vadhavkar
- Department of Clinical Pharmacology, Genentech, Inc., 1 DNA Way, South San Francisco, CA, 94080, USA
| | | | - Melanie Smitt
- Clinical Sciences, Genentech, Inc., South San Francisco, CA, USA
| | - Amita Joshi
- Department of Clinical Pharmacology, Genentech, Inc., 1 DNA Way, South San Francisco, CA, 94080, USA
| | - Meghna Samant
- Biostatistics, Genentech, Inc., South San Francisco, CA, USA
| | - Angelica Quartino
- Department of Clinical Pharmacology, Genentech, Inc., 1 DNA Way, South San Francisco, CA, 94080, USA
| | - Jin Jin
- Department of Clinical Pharmacology, Genentech, Inc., 1 DNA Way, South San Francisco, CA, 94080, USA
| | - Sandhya Girish
- Department of Clinical Pharmacology, Genentech, Inc., 1 DNA Way, South San Francisco, CA, 94080, USA
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Tabernero J, Ohtsu A, Muro K, Van Cutsem E, Oh SC, Bodoky G, Shimada Y, Hironaka S, Ajani JA, Tomasek J, Safran H, Chandrawansa K, Hsu Y, Heathman M, Khan A, Ni L, Melemed AS, Gao L, Ferry D, Fuchs CS. Exposure-Response Analyses of Ramucirumab from Two Randomized, Phase III Trials of Second-line Treatment for Advanced Gastric or Gastroesophageal Junction Cancer. Mol Cancer Ther 2017; 16:2215-2222. [PMID: 28716815 DOI: 10.1158/1535-7163.mct-16-0895] [Citation(s) in RCA: 38] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/27/2016] [Revised: 04/06/2017] [Accepted: 06/22/2017] [Indexed: 11/16/2022]
Abstract
Ramucirumab is an IgG1 monoclonal antibody specific for the vascular endothelial growth factor receptor-2. Ramucirumab, 8 mg/kg every 2 weeks, administered as monotherapy (REGARD) or in combination with paclitaxel (RAINBOW), was safe and effective in patients with previously treated advanced gastric or gastroesophageal junction (GEJ) cancer. We evaluated exposure-efficacy and exposure-safety relationships of ramucirumab from two randomized, placebo-controlled phase III trials. Sparse pharmacokinetic samples were collected, and a population pharmacokinetic analysis was conducted to predict ramucirumab minimum trough concentration at steady state (Cmin,ss). Kaplan-Meier methods and Cox proportional hazards models were used to evaluate the ramucirumab exposure (Cmin,ss)-efficacy relationship to overall survival (OS) and progression-free survival (PFS). Logistic regression analyses were used to evaluate exposure-safety relationships. Analyses included 321 ramucirumab + paclitaxel and 335 placebo + paclitaxel patients from RAINBOW and 72 ramucirumab and 35 placebo patients from REGARD. Exposure-efficacy analysis showed ramucirumab Cmin,ss was a significant predictor of OS and PFS in both trials. Higher ramucirumab exposure was associated with longer OS and PFS. In RAINBOW, grade ≥3 hypertension, leukopenia, and neutropenia, but not febrile neutropenia, significantly correlated with Cmin,ss, with increased exposure leading to increased incidence. Exploratory exposure-response analyses suggest a positive relationship between efficacy and ramucirumab exposure with manageable toxicities at exposures generated from a dose of 8 mg/kg ramucirumab given every 2 weeks for patients with advanced gastric/GEJ cancer. These findings suggest an opportunity to further optimize benefit versus risk profiles of ramucirumab treatment in patients with gastric/GEJ cancer. Mol Cancer Ther; 16(10); 2215-22. ©2017 AACR.
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Affiliation(s)
- Josep Tabernero
- Vall d'Hebron University Hospital and Institute of Oncology (VHIO), Universitat Autònoma de Barcelona, Barcelona, Spain.
| | - Atsushi Ohtsu
- National Cancer Center Hospital East, Kashiwa, Chiba, Japan
| | - Kei Muro
- Aichi Cancer Center Hospital, Nagoya, Japan
| | | | | | | | | | | | | | - Jiri Tomasek
- Masaryk Memorial Cancer Institute, Brno, Czech Republic
| | | | | | - Yanzhi Hsu
- Eli Lilly and Company, Bridgewater, New Jersey
| | | | - Azhar Khan
- Eli Lilly and Company, Windlesham, Surrey, United Kingdom
| | - Lan Ni
- Eli Lilly and Company, Indianapolis, Indiana
| | | | - Ling Gao
- Eli Lilly and Company, Bridgewater, New Jersey
| | - David Ferry
- Eli Lilly and Company, Indianapolis, Indiana
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Chen SC, Quartino A, Polhamus D, Riggs M, French J, Wang X, Vadhavkar S, Smitt M, Hoersch S, Strasak A, Jin JY, Girish S, Li C. Population pharmacokinetics and exposure-response of trastuzumab emtansine in advanced breast cancer previously treated with ≥2 HER2-targeted regimens. Br J Clin Pharmacol 2017; 83:2767-2777. [PMID: 28733983 DOI: 10.1111/bcp.13381] [Citation(s) in RCA: 16] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/27/2017] [Revised: 06/15/2017] [Accepted: 07/12/2017] [Indexed: 01/20/2023] Open
Abstract
AIMS We conducted population pharmacokinetic (PopPK) and exposure-response analyses for trastuzumab emtansine (T-DM1), to assess the need for T-DM1 dose optimization in patients with low exposure by using TH3RESA [A Study of Trastuzumab Emtansine in Comparison With Treatment of Physician's Choice in Patients With human epidermal growth factor receptor 2 (HER2)-positive Breast Cancer Who Have Received at Least Two Prior Regimens of HER2-directed Therapy] study data (NCT01419197). The randomized phase III TH3RESA study investigated T-DM1 vs. treatment of physician's choice (TPC) in patients with heavily pretreated HER2-positive advanced breast cancer. METHODS We compared a historical T-DM1 PopPK model with T-DM1 pharmacokinetics in TH3RESA and performed exposure-response analyses using model-predicted cycle 1 maximum concentration (Cmax ), cycle 1 minimum concentration (Cmin ) and area under the concentration-time curve at steady state (AUCss ). Kaplan-Meier analyses [overall survival (OS), progression-free survival (PFS)] and logistic regression [overall response rate (ORR), safety] were stratified by T-DM1 exposure metrics. Survival hazard ratios (HRs) in the lowest exposure quartile (Q1) of cycle 1 Cmin were compared with matched TPC-treated patients. RESULTS T-DM1 concentrations in TH3RESA were described well by the historical PopPK model. Patients with higher cycle 1 Cmin and AUCss exhibited numerically longer median OS and PFS and higher ORR than patients with lower exposure. Exposure-response relationships were less evident for cycle 1 Cmax . No relationship between exposure and safety was identified. HRs for the comparison of T-DM1-treated patients in the Q1 subgroup with matched TPC-treated patients were 0.96 [95% confidence interval (CI) 0.63, 1.47] for OS and 0.92 (95% CI 0.64, 1.32) for PFS. CONCLUSIONS Exposure-response relationships for efficacy were inconsistent across exposure metrics. HRs for survival in patients in the lowest T-DM1 exposure quartile vs. matched TPC-treated patients suggest that, compared with TCP, the approved T-DM1 dose is unlikely to be detrimental to patients with low exposure.
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Affiliation(s)
| | | | | | | | | | - Xin Wang
- Genentech, Inc., South San Francisco, CA, USA
| | | | | | | | | | - Jin Yan Jin
- Genentech, Inc., South San Francisco, CA, USA
| | | | - Chunze Li
- Genentech, Inc., South San Francisco, CA, USA
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Cohn AL, Yoshino T, Heinemann V, Obermannova R, Bodoky G, Prausová J, Garcia-Carbonero R, Ciuleanu T, Garcia-Alfonso P, Portnoy DC, Van Cutsem E, Yamazaki K, Clingan PR, Polikoff J, Lonardi S, O'Brien LM, Gao L, Yang L, Ferry D, Nasroulah F, Tabernero J. Exposure-response relationship of ramucirumab in patients with advanced second-line colorectal cancer: exploratory analysis of the RAISE trial. Cancer Chemother Pharmacol 2017; 80:599-608. [PMID: 28744667 PMCID: PMC5573752 DOI: 10.1007/s00280-017-3380-z] [Citation(s) in RCA: 16] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/05/2017] [Accepted: 06/27/2017] [Indexed: 01/06/2023]
Abstract
PURPOSE To characterize ramucirumab exposure-response relationships for efficacy and safety in patients with metastatic colorectal cancer (mCRC) using data from the RAISE study. METHODS Sparse pharmacokinetic samples were collected; a population pharmacokinetic analysis was conducted. Univariate and multivariate Cox proportional hazards models analyzed the relationship between predicted ramucirumab minimum trough concentration at steady state (C min,ss) and survival. Kaplan-Meier analysis was used to evaluate survival from patients in the ramucirumab plus folinic acid, 5-fluorouracil, and irinotecan (FOLFIRI) treatment arm stratified by C min,ss quartiles (Q). An ordered categorical model analyzed the relationship between C min,ss and safety outcomes. RESULTS Pharmacokinetic samples from 906 patients were included in exposure-efficacy analyses; samples from 905 patients were included in exposure-safety analyses. A significant association was identified between C min,ss and overall survival (OS) and progression-free survival (PFS) (p < 0.0001 for both). This association remained significant after adjusting for baseline factors associated with OS or PFS (p < 0.0001 for both). Median OS was 11.5, 12.9, 16.4, and 16.7, and 12.4 months for ramucirumab C min,ss Q1, Q2, Q3, Q4, and placebo group, respectively. Median PFS was 5.4, 4.6, 6.8, 8.5, and 5.2 months for ramucirumab C min,ss Q1, Q2, Q3, Q4, and placebo group, respectively. The risk of Grade ≥3 neutropenia was associated with an increase in ramucirumab exposure. CONCLUSIONS Exploratory exposure-response analyses suggested a positive relationship between efficacy and ramucirumab exposure with manageable toxicities in patients from the RAISE study with mCRC over the ranges of exposures achieved by a dose of 8 mg/kg every 2 weeks in combination with FOLFIRI.
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Affiliation(s)
- Allen Lee Cohn
- Rocky Mountain Cancer Center, 1800 Williams Street, Denver, CO, 80218, USA.
| | | | | | | | | | | | | | | | | | | | | | | | | | | | - Sara Lonardi
- Istituto Oncologico Veneto IOV - IRCCS, Padua, Italy
| | | | - Ling Gao
- Eli Lilly and Company, Bridgewater, NJ, USA
| | - Ling Yang
- Eli Lilly and Company, Bridgewater, NJ, USA
| | | | | | - Josep Tabernero
- Vall d'Hebron University Hospital and Institute of Oncology (VHIO), Barcelona, Spain
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Defective Cyclin B1 Induction in Trastuzumab-emtansine (T-DM1) Acquired Resistance in HER2-positive Breast Cancer. Clin Cancer Res 2017; 23:7006-7019. [DOI: 10.1158/1078-0432.ccr-17-0696] [Citation(s) in RCA: 50] [Impact Index Per Article: 6.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/10/2017] [Revised: 06/29/2017] [Accepted: 08/11/2017] [Indexed: 11/16/2022]
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Chigutsa E, Long AJ, Wallin JE. Exposure-Response Analysis of Necitumumab Efficacy in Squamous Non-Small Cell Lung Cancer Patients. CPT-PHARMACOMETRICS & SYSTEMS PHARMACOLOGY 2017; 6:560-568. [PMID: 28569042 PMCID: PMC5572351 DOI: 10.1002/psp4.12209] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 01/19/2017] [Revised: 05/12/2017] [Accepted: 05/15/2017] [Indexed: 12/24/2022]
Abstract
We sought to describe the exposure-response relationship of necitumumab efficacy in squamous non-small cell lung cancer patients and evaluate intrinsic and extrinsic patient descriptors that may guide dosing. SQUIRE was a phase III study comparing necitumumab in combination with gemcitabine and cisplatin vs. gemcitabine and cisplatin alone in 1,014 patients. An integrated model for tumor size dynamics and overall survival was developed, where reduction in tumor size results in a decrease in survival hazard. The change in tumor size was characterized using linear growth and first-order shrinkage. Overall survival was described using a combination of a Weibull function and Gompertz function for the hazard, with dynamic tumor size being a predictor for the hazard. Although body weight resulted in higher clearance and lower exposure, simulations showed that an 800 mg flat dose provided optimal response regardless of body weight.
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Affiliation(s)
- E Chigutsa
- PKPD&Pharmacometrics, Eli Lilly, Indianapolis, Indiana, USA
| | - A J Long
- PKPD&Pharmacometrics, Eli Lilly, Indianapolis, Indiana, USA
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Solms A, Reinecke I, Fiala-Buskies S, Keunecke A, Drenth HJ, Bruix J, Meinhardt G, Cleton A, Ploeger B. Exposure-response relationship of regorafenib efficacy in patients with hepatocellular carcinoma. Eur J Pharm Sci 2017; 109S:S149-S153. [PMID: 28549676 DOI: 10.1016/j.ejps.2017.05.050] [Citation(s) in RCA: 17] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/19/2017] [Accepted: 05/22/2017] [Indexed: 01/07/2023]
Abstract
PURPOSE To explore the relationship between regorafenib exposure and efficacy in patients with hepatocellular carcinoma (HCC) who had disease progression during sorafenib treatment (RESORCE). METHODS Exposure-response (ER) analyses for regorafenib were performed using data from a phase 3, randomized, placebo-controlled trial (RESORCE). Patients received 160mg regorafenib or placebo once daily (3weeks on/1week off in a 4-week cycle) with best supportive care until disease progression, death, or unacceptable toxicity. Kaplan-Meier analyses for overall survival (OS) and time-to-progression (TTP) were performed in which regorafenib-treated patients were grouped into four categories according to their estimated average exposure over 4weeks in cycle 1. While this analysis primarily focused on efficacy, a potential correlation between exposure and treatment-emergent adverse events (TEAEs) was also evaluated. If any differences were observed between Kaplan-Meier plots, the ER analysis continued with a multivariate Cox regression analysis to evaluate the correlation between exposure quartile categories and the efficacy and safety parameters while taking into consideration the effect of the predefined clinically relevant demographic and baseline covariates. The functional form of the ER relationship within the regorafenib treatment group was subsequently evaluated. RESULTS Based on visual assessment of the Kaplan-Meier plots, no meaningful relationship between the exposure categories and TEAEs were observed, although median OS and TTP tended to be longer in the higher exposure categories. Further ER analyses, which considered the effects of predefined covariates and the different shapes of the ER relationship, focused on efficacy. The baseline risk factors Eastern Cooperative Oncology Group (ECOG) performance status ≥1, alpha-fetoprotein levels ≥400ng/ml, and aspartate transaminase or alanine transaminase levels >3×upper limit of normal were significantly associated with OS (P<0.01) and age was associated with TTP. A statistically significant difference was found for OS and TTP between patients receiving regorafenib compared with those receiving placebo in the multivariate ER analysis (P<0.01) in favor of regorafenib. However, within the group of regorafenib-treated patients, the effect of regorafenib exposure on efficacy, either by estimating four effect sizes for each quartile, or by including a continuous linear or nonlinear relationship between individual exposure and efficacy, was not significant (P>0.01) and relatively flat. This suggests that increasing regorafenib exposure would not result in a meaningful increase in OS or TTP. CONCLUSION After considering the baseline risk factors: ECOG performance status, alpha-fetoprotein levels, and hepatic function for OS and age for TTP, the ER analysis in regorafenib-treated patients showed similar efficacy over the entire predicted exposure range in RESORCE. This supports the selected regorafenib dose of 160mg once daily (3weeks on/1week off in a 4-week cycle) in patients with intermediate or advanced HCC who have experienced disease progression on sorafenib.
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Affiliation(s)
| | | | | | | | | | - Jordi Bruix
- BCLC Group, Liver Unit, Hospital Clinic, University of Barcelona, IDIBAPS, CIBEREHD, Barcelona, Spain
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Liu C, Yu J, Li H, Liu J, Xu Y, Song P, Liu Q, Zhao H, Xu J, Maher VE, Booth BP, Kim G, Rahman A, Wang Y. Association of time-varying clearance of nivolumab with disease dynamics and its implications on exposure response analysis. Clin Pharmacol Ther 2017; 101:657-666. [PMID: 28182273 DOI: 10.1002/cpt.656] [Citation(s) in RCA: 148] [Impact Index Per Article: 18.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/12/2016] [Revised: 02/01/2017] [Accepted: 02/06/2017] [Indexed: 01/08/2023]
Abstract
Nivolumab is a human monoclonal antibody that blocks the interaction between PD-1 programmed death-1 (PD-1) and its ligands, PD-L1 and PD-L2. Nivolumab demonstrated efficacy in clinical trials for various types of cancer. A time-varying clearance was identified for nivolumab. We show that the change of clearance over time is associated with the post-treatment effects: clearance decreases when disease status improves. This interaction between posttreatment effects and drug exposure may lead to a biased steep estimate of the exposure-response (E-R) relationship for efficacy. Under this scenario, simulations were performed to develop a proposed methodology to assess the causal effect of drug exposure upon clinical response. Data from nivolumab trials were subsequently used to verify the proposed methodology for E-R analysis. The results showed that E-R analysis results based on pharmacokinetic (PK) metrics derived from the first dose are more consistent with the true E-R or dose-response relationship than the steady-state PK metrics.
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Affiliation(s)
- C Liu
- Food and Drug Administration, Silver Spring, Maryland, USA
| | - J Yu
- Food and Drug Administration, Silver Spring, Maryland, USA
| | - H Li
- Food and Drug Administration, Silver Spring, Maryland, USA
| | - J Liu
- Food and Drug Administration, Silver Spring, Maryland, USA
| | - Y Xu
- Food and Drug Administration, Silver Spring, Maryland, USA
| | - P Song
- Food and Drug Administration, Silver Spring, Maryland, USA
| | - Q Liu
- Food and Drug Administration, Silver Spring, Maryland, USA
| | - H Zhao
- Food and Drug Administration, Silver Spring, Maryland, USA
| | - J Xu
- Food and Drug Administration, Silver Spring, Maryland, USA
| | - V E Maher
- Food and Drug Administration, Silver Spring, Maryland, USA
| | - B P Booth
- Food and Drug Administration, Silver Spring, Maryland, USA
| | - G Kim
- Food and Drug Administration, Silver Spring, Maryland, USA
| | - A Rahman
- Food and Drug Administration, Silver Spring, Maryland, USA
| | - Y Wang
- Food and Drug Administration, Silver Spring, Maryland, USA
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Lukong KE. Understanding breast cancer - The long and winding road. BBA CLINICAL 2017; 7:64-77. [PMID: 28194329 PMCID: PMC5300293 DOI: 10.1016/j.bbacli.2017.01.001] [Citation(s) in RCA: 131] [Impact Index Per Article: 16.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 11/03/2016] [Revised: 12/28/2016] [Accepted: 01/24/2017] [Indexed: 12/24/2022]
Abstract
Background Despite a remarkable increase in the depth of our understanding and management of breast cancer in the past 50 years, the disease is still a major public health problem worldwide and poses significant challenges. The palpability of breast tumors has facilitated diagnosis and documentation since ancient times. The earliest descriptions of breast cancer date back to around 3500 BCE. For centuries to follow, theories by Hippocrates (460 BCE) and Galen (200 CE), attributing the cause of breast cancer to an “excess of black bile” and treatment options including the use of opium and castor oil, prevailed. Surgical resection was introduced in the 18th century. The advent of modern medicine led to the development of novel treatment options that include hormonal, targeted and chemo-therapies. There are still several therapeutic challenges including the treatment of triple negative breast cancer (TNBC), and overcoming drug resistance. Scope of review The increased incidence and awareness of breast cancer has led to significant changes in diagnosis and treatment in recent decades. But, mankind has come a long way. Herein, I have traced how our understanding of breast cancer has evolved from the early description of the disease around 460 BCE as “black bile-containing crab-like tumors” to the conventional as a heterogeneous disease with high degree of diversity between and within tumors, as well as among breast cancer patients. How is breast cancer treated today and how do risk factors, breast cancer subtype and drug resistance contribute to the therapeutic challenges at the turn of the 21st century? Major conclusions Breast cancer remains a serious public health issue worldwide. However, appreciable growth in our understanding of breast cancer in the past century has led to remarkable progress in the early detection, treatment and prevention of the disease. The clinical focus is shifting more towards tailored therapy as more targets are characterized and novel highly innovative approaches are developed. General significance Tracing the history of breast cancer, highlights how increased awareness of the disease, and progress in research and development have enhance our understanding of the disease.
The humoral, lymphatic and anti-hormonal theories of breast cancer Introduction of radical mastectomy, radiotherapy, mammography, and targeted therapy The introduction of randomized trial Breast cancer foundations, awareness and the Angelina Jolie effect Promising future for tailored therapy
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Calvo E, Walko C, Dees EC, Valenzuela B. Pharmacogenomics, Pharmacokinetics, and Pharmacodynamics in the Era of Targeted Therapies. Am Soc Clin Oncol Educ Book 2017; 35:e175-84. [PMID: 27249721 DOI: 10.1200/edbk_159061] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/08/2023]
Abstract
The complex nature of the pharmacologic aspects of cancer therapeutics has become more apparent in the past several years with the arrival of a cascade of target-based agents and the difficult challenge of bringing individualized precision medicine to oncology. Interpatient variability in drug action, singularly in novel agents, is in part caused by pharmacogenomic (PG), pharmacokinetic, and pharmacodynamic (PD) factors, and drug selection and dosing should take this into consideration to optimize the benefit for our patients in terms of antitumor activity and treatment tolerance. In this regard, somatic genetic evaluation of tumors is useful in not only predicting response to initial targeted therapies but also in anticipating and guiding therapy after the development of acquired resistance; therapeutic drug monitoring of novel small molecules and monoclonal antibodies must be incorporated in our day-to-day practice to minimize the negative effect on clinical outcome of interindividual variability on pharmacokinetic processes of these drugs for all patients, but especially for fragile patient populations and those with organ dysfunction or comorbidities. For these populations, incorporating frailty assessment tools into trials of newer agents and validating frailty-based dose adjustment should be an important part of further drug development.
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Affiliation(s)
- Emiliano Calvo
- From the DeBartolo Family Personalized Medicine Institute, H. Lee Moffitt Cancer Center, Tampa, FL; UNC Lineberger Comprehensive Cancer Center, Chapel Hill, NC; Platform of Oncology, Hospital Quirón, Torrevieja, Alicante, Spain; START Madrid, Early Clinical Drug Development Program, Centro Integral Oncológico Clara Campal, Madrid, Spain
| | - Christine Walko
- From the DeBartolo Family Personalized Medicine Institute, H. Lee Moffitt Cancer Center, Tampa, FL; UNC Lineberger Comprehensive Cancer Center, Chapel Hill, NC; Platform of Oncology, Hospital Quirón, Torrevieja, Alicante, Spain; START Madrid, Early Clinical Drug Development Program, Centro Integral Oncológico Clara Campal, Madrid, Spain
| | - E Claire Dees
- From the DeBartolo Family Personalized Medicine Institute, H. Lee Moffitt Cancer Center, Tampa, FL; UNC Lineberger Comprehensive Cancer Center, Chapel Hill, NC; Platform of Oncology, Hospital Quirón, Torrevieja, Alicante, Spain; START Madrid, Early Clinical Drug Development Program, Centro Integral Oncológico Clara Campal, Madrid, Spain
| | - Belén Valenzuela
- From the DeBartolo Family Personalized Medicine Institute, H. Lee Moffitt Cancer Center, Tampa, FL; UNC Lineberger Comprehensive Cancer Center, Chapel Hill, NC; Platform of Oncology, Hospital Quirón, Torrevieja, Alicante, Spain; START Madrid, Early Clinical Drug Development Program, Centro Integral Oncológico Clara Campal, Madrid, Spain
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Ou Y, Doshi S, Nguyen A, Jonsson F, Aggarwal S, Rajangam K, Dimopoulos MA, Stewart AK, Badros A, Papadopoulos KP, Siegel D, Jagannath S, Vij R, Niesvizky R, Graham R, Visich J. Population Pharmacokinetics and Exposure-Response Relationship of Carfilzomib in Patients With Multiple Myeloma. J Clin Pharmacol 2016; 57:663-677. [PMID: 27925676 DOI: 10.1002/jcph.850] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/21/2016] [Accepted: 11/01/2016] [Indexed: 11/06/2022]
Abstract
A population pharmacokinetic (PK) model and exposure-response (E-R) analysis was developed using data collected from 5 phase 1b/2 and 2 phase 3 studies in subjects with multiple myeloma. Subjects receiving intravenous infusion on 2 consecutive days each week for 3 weeks (days 1, 2, 8, 9, 15, and 16) in each cycle at doses ranging from 15 to 20/56 mg/m2 (20 mg/m2 in cycle 1 and, if tolerated, escalated to 56 mg/m2 on day 8 of cycle 1). The population PK analysis indicated that among all the covariates tested, the only statistically significant covariate was body surface area on carfilzomib clearance; however, this covariate was unlikely to be clinically significant. Despite inclusion of different populations (relapsed or relapsed/refractory), treatments (carfilzomib monotherapy or combination therapy), infusion lengths (2 to 10 minutes or 30 minutes), and different doses, the E-R analysis of efficacy showed that after adjusting for baseline characteristics, higher area under the concentration-time curve was associated with improved overall response rate (ORR), from 15 to 20/56 mg/m2 . No positive relationships between maximum concentration and ORR were identified, indicating that ORR would not be expected to be impacted by infusion length. For safety end points, no statistically significant relationship between exposure and increasing risk of adverse events was identified. The results of an E-R analysis provided strong support for a carfilzomib dose at 20/56 mg/m2 as a 30-minute infusion for monotherapy and combination therapy. This article illustrates an example of application of E-R analysis to support labeling dose recommendation in the absence of extensive clinical data.
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Affiliation(s)
- Ying Ou
- Amgen, South San Francisco, CA, USA
| | | | | | | | | | | | | | | | | | | | | | | | - Ravi Vij
- Washington University School of Medicine, St. Louis, MO, USA
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Yoon HH, Bendell JC, Braiteh FS, Firdaus I, Philip PA, Cohn AL, Lewis N, Anderson DM, Arrowsmith E, Schwartz JD, Gao L, Hsu Y, Xu Y, Ferry D, Alberts SR, Wainberg ZA. Ramucirumab combined with FOLFOX as front-line therapy for advanced esophageal, gastroesophageal junction, or gastric adenocarcinoma: a randomized, double-blind, multicenter Phase II trial. Ann Oncol 2016; 27:2196-2203. [PMID: 27765757 PMCID: PMC7360144 DOI: 10.1093/annonc/mdw423] [Citation(s) in RCA: 115] [Impact Index Per Article: 12.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/18/2016] [Revised: 08/29/2016] [Accepted: 08/30/2016] [Indexed: 12/11/2022] Open
Abstract
BACKGROUND We report the first randomized, Phase II trial of ramucirumab, an anti-vascular endothelial growth factor receptor-2 monoclonal antibody, as front-line therapy in patients with advanced adenocarcinoma of the esophagus or gastric/gastroesophageal junction (GEJ). PATIENTS AND METHODS Patients from the USA with advanced esophageal, gastric, or GEJ adenocarcinoma randomly received (1:1) mFOLFOX6 plus ramucirumab (8 mg/kg) or mFOLFOX6 plus placebo every 2 weeks. The primary end point was progression-free survival (PFS) with 80% power to detect a hazard ratio (HR) of 0.71 (one-sided α = 0.15). Secondary end points included evaluation of response and overall survival (OS); an exploratory ramucirumab exposure-response analysis was undertaken. RESULTS Of 168 randomized patients, 52% of tumors were located in the stomach/GEJ and 48% in the esophagus. The trial did not meet the primary end point of PFS [6.4 versus 6.7 months, HR 0.98 (95% confidence interval 0.69-1.37)] or the secondary end point of OS (11.7 versus 11.5 months) in the intent-to-treat (ITT) population. Objective response rates (45.2% versus 46.4%) were similar between arms. Most Grade ≥3 toxicities did not differ significantly between arms, yet premature discontinuation of FOLFOX and ramucirumab (for reasons other than progressive disease) was more common among ramucirumab- versus placebo-treated patients. In an exploratory analysis that censored for premature discontinuation, the HR for PFS favored the ramucirumab arm (HR 0.76), particularly in patients with gastric/GEJ cancer. An exploratory exposure-response analysis indicated that patients with higher ramucirumab exposure had longer OS. CONCLUSION The addition of ramucirumab to front-line mFOLFOX6 did not improve PFS in the ITT population. CLINICALTRIALSGOV IDENTIFIER NCT01246960.
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Affiliation(s)
- H H Yoon
- Medical Oncology, Mayo Clinic, Rochester, MN
| | - J C Bendell
- GI Cancer Research Program, Sarah Cannon Research Institute, Tennessee Oncology, Nashville
| | - F S Braiteh
- Medical Oncology, Comprehensive Cancer Centers of Nevada, Las Vegas
| | - I Firdaus
- Medical Oncology, Sarah Cannon Research Institute/Oncology Hematology Care, Inc., Cincinnati
| | - P A Philip
- Department of Oncology, Barbara Ann Karmanos Cancer Institute/Wayne State University, Detroit
| | - A L Cohn
- Medical Oncology, Rocky Mountain Cancer Centers/US Oncology, Denver
| | - N Lewis
- Sidney Kimmel Cancer Center, Thomas Jefferson University, Philadelphia
| | - D M Anderson
- Department of Hematology, Oncology and Transplantation, Metro-Minnesota Community Clinical Oncology Program, St. Louis Park
| | - E Arrowsmith
- Medical Oncology, Sarah Cannon Research Institute/Tennessee Oncology, Chattanooga
| | | | - L Gao
- Oncology, Eli Lilly and Company, Bridgewater
| | - Y Hsu
- Oncology, Eli Lilly and Company, Bridgewater
| | - Y Xu
- Oncology, Eli Lilly and Company, Bridgewater
| | - D Ferry
- Oncology, Eli Lilly and Company, Bridgewater
| | - S R Alberts
- Medical Oncology, Mayo Clinic, Rochester, MN
| | - Z A Wainberg
- Division of Hematology Oncology, David Geffen School of Medicine at UCLA, Los Angeles, USA
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Lu D, Lu T, Stroh M, Graham RA, Agarwal P, Musib L, Li CC, Lum BL, Joshi A. A survey of new oncology drug approvals in the USA from 2010 to 2015: a focus on optimal dose and related postmarketing activities. Cancer Chemother Pharmacol 2016; 77:459-76. [PMID: 26811176 PMCID: PMC4767861 DOI: 10.1007/s00280-015-2931-4] [Citation(s) in RCA: 42] [Impact Index Per Article: 4.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/21/2015] [Accepted: 11/24/2015] [Indexed: 11/24/2022]
Abstract
The maximally tolerated dose (MTD) of cytotoxic agents has historical precedence in treating cancer, as it was believed that dose and therapeutic effect are intrinsically linked and that the MTD would provide greatest therapeutic value. With molecularly targeted agents, the premise of preventing toxicity to normal tissues while modulating tumor growth provides a potential for an increased therapeutic window. Results from these targeted agents suggest we are entering an era of chronic cancer management, which will require design of regimens with long-term tolerability. A corresponding switch from MTD-based (toxicity-driven) dosing strategies to alternative paradigms is also expected. The challenge with these targeted agents is to fully understand the complex relationship between pharmacokinetics, pharmacodynamics, and safety and efficacy in early-stage trials, so that the optimal dose and schedule for registration trials may be identified. This review provides a systematic survey of the applications submitted to the United States Food and Drug Administration (FDA) for oncology indications, from 2010 through early 2015, and summarizes the dose selection rationale for registrational trials, the relationship of the MTD to outcomes of the final label dose, the postmarketing requirements or commitments related to dose optimization activities, the role of biomarkers, and typical exposure-response modeling methods.
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Affiliation(s)
- Dan Lu
- Department of Clinical Pharmacology, Genentech, Inc., 1 DNA Way, MS 463A, South San Francisco, CA, 94080, USA
| | - Tong Lu
- Department of Clinical Pharmacology, Genentech, Inc., 1 DNA Way, MS 463A, South San Francisco, CA, 94080, USA
| | - Mark Stroh
- Department of Clinical Pharmacology, Genentech, Inc., 1 DNA Way, MS 463A, South San Francisco, CA, 94080, USA
| | - Richard A Graham
- Department of Clinical Pharmacology, Theravance Biopharma U.S., Inc., South San Francisco, CA, USA
| | - Priya Agarwal
- Department of Clinical Pharmacology, Genentech, Inc., 1 DNA Way, MS 463A, South San Francisco, CA, 94080, USA
| | - Luna Musib
- Department of Clinical Pharmacology, Genentech, Inc., 1 DNA Way, MS 463A, South San Francisco, CA, 94080, USA
| | - Chi-Chung Li
- Department of Clinical Pharmacology, Genentech, Inc., 1 DNA Way, MS 463A, South San Francisco, CA, 94080, USA
| | - Bert L Lum
- Department of Clinical Pharmacology, Genentech, Inc., 1 DNA Way, MS 463A, South San Francisco, CA, 94080, USA.
| | - Amita Joshi
- Department of Clinical Pharmacology, Genentech, Inc., 1 DNA Way, MS 463A, South San Francisco, CA, 94080, USA
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Abstract
Understanding the basis of variability in the response of patients to the dose of a drug and a willingness to vary the dose regimen as well as the choice of drug should be one of the key pillars of precision medicine.
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Owonikoko TK, Hussain A, Stadler WM, Smith DC, Kluger H, Molina AM, Gulati P, Shah A, Ahlers CM, Cardarelli PM, Cohen LJ. First-in-human multicenter phase I study of BMS-936561 (MDX-1203), an antibody-drug conjugate targeting CD70. Cancer Chemother Pharmacol 2015; 77:155-62. [DOI: 10.1007/s00280-015-2909-2] [Citation(s) in RCA: 52] [Impact Index Per Article: 5.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/09/2015] [Accepted: 11/04/2015] [Indexed: 01/30/2023]
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