pharmacodynamic relationship of therapeutic monoclonal antibodies used in oncology: Part 1, monoclonal antibodies, antibody-drug conjugates and bispecific T-cell engagers

European Journal of Cancer xxx (xxxx) xxx

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Review

Pharmacokinetic/pharmacodynamic relationship of therapeutic monoclonal antibodies used in oncology: Part 1, monoclonal antibodies, antibody-drug conjugates and bispecific T-cell engagers Angelo Paci a,b,*, Aude Desnoyer b,c, Julia Delahousse a, Louis Blondel a, Christophe Maritaz a,b, Nathalie Chaput b,c, Olivier Mir d, Sophie Broutin a a

Gustave Roussy Cancer Campus, Department of Pharmacology, Villejuif, F-94805, France University Paris-Saclay, Faculty of Pharmacy, Chatenay-Malabry, F-92290, France c Gustave Roussy Cancer Campus, Laboratory of Immunomonitoring in Oncology, Villejuif, F-94805, France d Gustave Roussy Cancer Campus, Department of Ambulatory Care, Villejuif, F-94805, France b

Received 10 November 2019; received in revised form 2 January 2020; accepted 7 January 2020 Available online - - -

KEYWORDS Monoclonal antibodies; Antibodyedrug conjugates; Pharmacokinetics; Pharmacodynamics; Therapeutic drug monitoring; Cancer

Abstract More than 25 therapeutic monoclonal antibodies (mAbs) used in oncology have been approved since 1997. Their nature has been largely modified through the last 20 years, from the chimeric IgG1 rituximab with pharmacokinetic parameters specific of murin or chimeric mAbs to humanized or human mAbs. Doses and administration frequency have been chosen based on this nature. More recently, the developed and registered mAbs are mostly IgG1, IgG2, IgG3 or IgG4 humanized or 100% human. Therefore, their behavior is different from the first mAbs authorized leading to lower systemic clearance and shorter half-life due to higher cellular uptake balanced by FcRn recognition with recirculation. The complexity of the pharmacokinetics and the pharmacokinetics/pharmacodynamics relation are increased for antibody-drug conjugates or bispecific T-cell engagers. However, significant number of studies reported pharmacokinetics/pharmacodynamics relations, with positive exposure-response link justifying the exploration of the pharmacokinetics in routine clinical practice of these therapeutic mAbs to prevent treatment failures and to limit their toxicities. ª 2020 Elsevier Ltd. All rights reserved.

* Corresponding author: Gustave Roussy Cancer Campus, Department of Pharmacology, 114 Rue Edouard Vaillant, Villejuif, F-94805, France E-mail address: [email protected] (A. Paci), [email protected] (A. Desnoyer), [email protected] (J. Delahousse), [email protected] (L. Blondel), [email protected] (C. Maritaz), [email protected] (N. Chaput), [email protected] (O. Mir), [email protected] (S. Broutin). https://doi.org/10.1016/j.ejca.2020.01.005 0959-8049/ª 2020 Elsevier Ltd. All rights reserved.

Please cite this article as: Paci A et al., Pharmacokinetic/pharmacodynamic relationship of therapeutic monoclonal antibodies used in oncology: Part 1, monoclonal antibodies, antibody-drug conjugates and bispecific T-cell engagers, European Journal of Cancer, https://doi.org/10.1016/ j.ejca.2020.01.005

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Since the late 1990s, many therapeutic monoclonal antibodies (mAbs) used in oncology have been approved by the US Food and Drug Administration (FDA) and European Medicines Agency (EMA). The first was rituximab, approved in 1997, a chimeric immunoglobulin G1 (IgG1). Today, most of them exhibit pharmacokinetic (PK) characteristics typical of mAbs, with low clearance, low volume of distribution and long half-life (Table 1). By contrast, they vary in their nature (chimeric, humanized, or human), type (IgG1-4) and even binding sites (monospecific, bispecific). This variability explains in particular the differences between the PK profiles of mAbs. Indeed, as described in the first part of this review, PK profiles depend on physicochemical properties, chemical structure and recognition and binding characteristics. This part of the review describes the PK profile and the potential PK/pharmacodynamic (PD) relationship of (1) therapeutic mAbs, (2) antibodyedrug conjugates (ADCs) and (3) bispecific T-cell engagers (BiTE) antibodies. 1. Therapeutic monoclonal antibodies used in oncology 1. Anti-CD20 mAbs
Rituximab (MABTHERA, BLITZIMA, RITEMVIA, RITUZENA, RIXIMYO, RIXATHON, TRUXIMA) Rituximab is a chimeric monoclonal IgG1 directed against CD20, a specific marker of B lymphocytes. It was the first anticancer mAb approved by the FDA in 1997 and the EMA in 1998. It is indicated in oncology for treating chronic lymphoid leukaemia (CLL) and diffuse and follicular non-Hodgkin’s lymphoma (NHL). The dose of rituximab, administered as an intravenous (IV) infusion, is 375 mg/m2, then 500 mg/m2 in CLL (total of 6 cycles) or

375 mg/m2 in NHL (total of 8 cycles). Subcutaneous administration is also possible at a fixed dose of 1400 mg. The PK of rituximab, after IV administration, was described by a two-compartment open model with firstorder elimination. It is non-linear in humans, with an impact of antigeneantibody binding: its clearance is important after the first administration and decreases over time with reduction of the antigenic target [1]. The specific clearance, volume of distribution (Vd) and median terminal elimination (t1/2) of rituximab are presented in Table 1. A PK/PD relationship for rituximab was reported as early as 1998 and has since been confirmed in many studies. Berinstein et al. [2] first showed an association between serum rituximab levels and antitumor response in treating recurrent lymphoma in 166 patients. Thus, at each time point, the median serum level of rituximab was higher for responders than for non-responders. This difference was significant at the second injection, and 3 months after the last administration, median serum level in responders was 25.4 mg/mL versus 5.9 mg/mL in non-responders (P Z 0.001). In 2002, Igarashi et al. [3] found a statistically significant correlation between progression-free survival (PFS) and serum rituximab level in 66 patients with lymphoma (70 mg/mL, P Z 0.007), with no difference between responders and non-responders. In 2004, a Japanese study of a small number of patients (N Z 12) with aggressive B-cell lymphoma showed serum level of rituximab and area under the concentrationetime curve (AUC) higher for responders than for non-responders (59.7  11.4 versus 43.0  6.4 mg/mL and 608,585  147,373 versus 383,053  176,903 mg h/mL) (P < 0.05) [4]. More recently, Jager et al. [5] reported PK results from a phase II study evaluating rituximab in NHL as maintenance therapy (N Z 17 patients), demonstrating significant interindividual variability in serum rituximab level related to sex, initial bone-marrow infiltration (tumor burden marker) and quality and duration of clinical

Table 1 Overview of pharmacokinetics data on targeted molecular therapy monoclonal antibodies (mAbs), antibodyedrug conjugates (ADCs) and bispecific antibody used in cancer. Name (INN, Trademarks)

Ig type

Vd (L)

Clearance (mL/h)

t1/2

Therapeutic Cmin or AUC

Ref.

Rituximab (MabThera, Rixathon, Truxima) Obinutuzumab (Gazyvaro) Ofatumumab (Arzerra) Bevacizumab (Avastin) Cetuximab (Erbitux) Panitumumab (Vectibix) Trastuzumab (Herceptine) Pertuzumab (Perjeta) Alemtuzumab (Campath) Daratumumab (Darzalex) Ozogamicine-gemtuzumab (Mylotarg) Vedotin-brentuximab (Adcetris) Emtansine-trastuzumab (Kadcyla) Ozogamicine-inotuzumab (Besponsa) Blinatumomab (Blincyto)

IgG1

2.7

25

22 days

[2,5]

IgG1 IgG1 IgG1 IgG1 IgG2 IgG1 IgG1 IgG1 IgG1 IgG4 IgG1 IgG1 IgG4 n.a.

3.0 5.3 2.7e3.3 5.0 6.54 2.6e3.6 2.5e3.11 10.5 4.2 21.0a 6e10b 4.0b 12b 4.5

3.3e4.6 7.5 7.9e9.2 22 14 4.7e7.3 9.8 n.a. n.a. 265a 73b 38b 33.3b 122

26e37 days 21.8 days 18e20 days 4 days 7 days e 18 days 6 days 18e23 days 72 ha 4e6 daysb 3e4 daysb 12.3 daysb 2h

Cmin: 25 mg/mL AUC: 9400 mg h/L Cmin: 244 mg/mL n.a. Cmin: 15.5 mg/L Cmin: 33.8 mg/mL n.a. Cmin: 20 mg/mL n.a. AUC: 5 mg h/mL Cmin: 274 mg/mL n.a. n.a. n.a. n.a. Cmin >1830 pg/mL

[10] [70] [13] [18] [71] [22,23] [72] [31,32] [33] [44] [47] [54] [62] [64]

Abbreviations: AUC, area under the concentrationetime curve; Cmin, serum trough concentration; Ig, immunoglobulin; INN, International Nonproprietary Name; n. a., not available; Ref, references; t1/2, half-life; Vd, volume of distribution. a Data for mAbs alone. b Data for ADCs.

Please cite this article as: Paci A et al., Pharmacokinetic/pharmacodynamic relationship of therapeutic monoclonal antibodies used in oncology: Part 1, monoclonal antibodies, antibody-drug conjugates and bispecific T-cell engagers, European Journal of Cancer, https://doi.org/10.1016/ j.ejca.2020.01.005

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response. Overall, the median AUC for males represented 81% of the values for females. Several studies had already shown male sex as a poor prognostic factor in follicular lymphoma and diffuse large B-cell lymphoma. This difference was associated with better PFS in women in the RICOVER-60 study and was confirmed in the CORAL study [1]. Jager et al. also showed that at the sixth maintenance cycle, the serum concentration was <25 mg/mL for patients with relapse and >25 mg/mL for patients with remission. These results suggested the value of monitoring serum rituximab levels as an early marker of response. Also in 2012, Ternant et al. [6] used a previously validated PK/PD model not only to link serum rituximab level and PFS in patients with NHL but also to study the effect of the genetic polymorphism of the gene encoding the FcgRIIIa receptor (CD16). The model predicts a potential benefit of a maintenance dose of rituximab of 1500 mg/m2 used as monotherapy or in the ReCHOP protocol. The model also shows that the PFS remains lower for carriers of the FCGR3A-F variant than homozygous FCGR3AVVV carriers, even with significantly higher doses of rituximab. Finally, the authors suggest a benefit of increasing rituximab doses in this pathology during both induction and maintenance treatments. Finally, Tout et al. [7] recently published the results of a study describing for the first time the influence of total metabolic tumour volume on rituximab PK and the concentrationeresponse relation in patients with diffuse large B-cell lymphoma. Patients with high tumour volume had lower exposure to rituximab, which was associated with poorer clinical response and shorter survival than patients with low tumour volume. The authors suggested that the dose be adapted to the initial total metabolic tumour volume to achieve an optimal AUC value of 9400 mg h/mL, associated at the first cycle with better response and longer PFS and overall survival (OS). The standard dose of rituximab is higher in patients with CLL than in those with NHL (500 versus 375 mg/m2), justified by a faster clearance observed in the phase II study, thereby leading to lower exposure to rituximab and poorer outcomes [8]. This difference between CLL and NHL may be related to a higher antigenic burden in patients with CLL than in those with NHL [8]. In addition, in CLL, an inverse correlation between antigenic mass and rituximab clearance suggests that the tumour may consume the antibody. Cartron et al. [9], studying the effect of CD20 expression on rituximab exposure and clinical response, just reported the results of a randomized phase II study (N Z 140 patients) evaluating the efficacy of high-dose rituximab compared with the standard dose. The overall response rate (complete and partial) was 94%, with no difference between treatment groups. Exposure to rituximab in patients receiving the high-dose regimen was significantly increased, but this did not result in an increase in the complete response rate. However, the AUC0e12M was significantly higher for patients with complete response than for non-responder patients in the general population and according to treatment group. In addition, an optimal rituximab threshold, defined by an AUC0e12M of 995 mg h/mL, allowed for separating patients in terms of PFS (38.9 months versus NA, P < 0.0001). Also, PFS was affected by a high CD20 antigen burden, assessed by lymphocyte

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count, CD20 level and tumour volume, thus highlighting the role of the antigenic mass on rituximab exposure. However, only 32% of the interindividual variability in rituximab elimination rate was explained by the circulation of CD20 antigen, which suggests that the CD20 antigenic mass is not the main factor. The authors suggested that CLL and NHL display completely different PK models for rituximab. In patients with CLL, rituximab elimination is rapid, not significantly affected by the antigenic CD20 mass and cannot be corrected by high doses of rituximab, whereas in patients with NHL, tumour metabolic volume appears to be the main factor affecting rituximab exposure.
Obinutuzumab (GAZYVARO, GAZYVA) Obinutuzumab is a recombinant humanized IgG1 antiCD20 type II mAb modified by glycoengineering. It is a biobetter of rituximab. Obinutuzumab specifically targets the extracellular loop of the CD20 transmembrane antigen present on the surface of mature, malignant and nonmalignant pre-B and B lymphocytes but absent from the surface of hematopoietic stem cells, pro-B cells, normal plasmocytes and other normal tissues. In addition, its Fc fragment was modified to have higher affinity for FcgRIII receptors on the surface of effector immune cells, such as natural killer cells, macrophages and monocytes. Obinutuzumab is indicated for treating CLL and follicular lymphoma at a fixed dose of 1000 mg. Gibiansky et al. [10] described the PK of obinutuzumab and the existence of a PK/PD relationship. A two-compartment PK model with linear and time-dependent clearance described the obinutuzumab concentrationetime course. PK parameters were mainly influenced by disease histology and tumour size at diagnosis and by body weight and sex to a lesser extent. The decrease in clearance was faster in patients with a smaller initial tumour volume than in those with larger volume. The clearance and Vd parameters of obinutuzumab (Table 1) are not related to age or renal function. In patients with CLL, although exposure to obinutuzumab has not been associated with safety, it has been associated with efficacy. High exposure to obinutuzumab (>244 mg/ mL) was associated with prolonged PFS. When data were stratified on initial tumour mass, PFS was prolonged in only patients with large tumours (>1.750 mm2). Therefore, the authors suggested the investigation of whether increased exposure improves efficacy in patients with high basal tumor burden.
Ofatumumab (ARZERRA) Ofatumumab is a human IgG1 that specifically recognizes a new epitope encompassing both small and large loops of the CD20 surface antigen. Ofatumumab binds to CD20 with high affinity and induces complementdependent cytotoxicity and antibody-dependent cell-mediated cytotoxicity, thereby resulting in lysis of normal and malignant B cells expressing CD20. It is indicated for treating CLL at fixed doses of 300 mg for the first infusion and 2000 mg for subsequent infusions. A two-compartment linear model with first-order elimination combined with a target-mediated non-linear clearance component was selected as the PK model [11]. Ofatumumab PK parameters (Table 1) were affected by body surface area, basal IgG concentration and sex, but Struemper et al. [11] found that none of these parameters had a clinical impact. However,

Please cite this article as: Paci A et al., Pharmacokinetic/pharmacodynamic relationship of therapeutic monoclonal antibodies used in oncology: Part 1, monoclonal antibodies, antibody-drug conjugates and bispecific T-cell engagers, European Journal of Cancer, https://doi.org/10.1016/ j.ejca.2020.01.005

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no PK/PD studies have been specifically conducted for this mAb. 2. Antivascular endothelial growth factor mAbs: bevacizumab (AVASTIN, MVASI, ZIRABEV)

Bevacizumab is a humanized IgG1 mAb targeting vascular endothelial growth factor (VEGF). It inhibits neovascularization, an essential mechanism for the development and progression of metastases in malignant tumours. In Europe, bevacizumab is approved in several cancers, including metastatic colorectal cancer, nonsquamous non-small-cell lung cancer, kidney, breast, cervix, ovarian and fallopian tube cancers. Its IV doses are 5 or 10 mg/kg every 2 weeks (Q2W) or 7.5 or 15 mg/ kg Q3W. Its PK has been described as linear up to 10 mg/kg. The average clearance value is 7.8 mL/h for female patients and 9.2 mL/h for male patients. The characteristic value of the Vd in the central compartment is 2.73 L for female patients and 3.28 L for male patients. In a two-compartment model, the reference t1/2 is 18 days for female patients and 20 days for male patients [12] (Table 1). PK variability of bevacizumab has been associated with sex, body weight and concomitant chemotherapy. It can also be affected by genetic polymorphisms, in particular the FcRn encoded by the Fc fragment of the IgG receptor and transporter, which is involved in IgG recycling [13]. In 2012, preliminary data suggested a PK/PD association for bevacizumab in a small cohort of 17 patients with glioma or breast cancer [14]. More recently, Caulet et al. [13] showed that bevacizumab exposure affects OS and PFS in patients with metastatic colorectal cancer. On univariate analysis, risk factors for OS and PFS were the presence of extrahepatic metastases, high basal levels of VEGF and carcinoembryonic antigen and low residual concentration (Cmin). On multivariate analysis, independent risk factors for OS and PFS were the basal level of VEGF and Cmin with bevacizumab on day 14 (Cmin  15.5 mg/L). This proposed threshold in metastatic colorectal cancer should be evaluated in other cancers treated with bevacizumab. 3. Antiepidermal growth factor receptor mAbs
Cetuximab (ERBITUX) Cetuximab is a chimeric IgG1 directed against epidermal growth factor receptor (EGFR). It is indicated for treating EGFR-expressing, RAS wild-type metastatic colorectal cancer and for treating squamous cell cancer of the head and neck. The first recommended dose is 400 mg/m2 and subsequent weekly doses are 250 mg/m2. In 2007, Fracasso et al. [15] reported an exposureeresponse relationship based on the results of a phase I study evaluating the effects of cetuximab on patients with epithelial malignancies. The Cmin exposure of patients in partial response or with stable disease was ~60 mg/L and ~33 mg/L for patients with disease progression, which suggests a link between the Cmin

and response. In 2011, the effect of cetuximab PK on its efficacy in patients with metastatic colorectal cancer treated in combination with FOLFIRI was confirmed in a phase II study (96 patients) [16]. In the wild-type KRAS subgroup, PFS was affected by overall clearance, a parameter that can be estimated by using cetuximab Cmin on day 14: the median PFS in patients with Cmin < 40 mg/L was 3.3 months versus 7.8 months for other patients (P Z 0.004). More recently, in a retrospective study, Pointreau et al. [17] analysed the interindividual variability of cetuximab PK and its effect on survival: OS was inversely related to overall cetuximab clearance (P Z 0.007) and was higher in patients with severe radiological dermatitis (P Z 0.005). In this cohort (N Z 34), PFS and OS were significantly extended in patients with overall cetuximab clearance below the median value of 31.1 mL/h. Finally, in 2017, Becher et al. [18] developed a plasma cetuximab assay method of liquid chromatography coupled with mass spectrometry and conducted a prospective pilot study in 25 patients with head and neck cancer. Residual concentrations of cetuximab on day 14 were higher in responders than in non-responders. The authors proposed a 33.8-mg/mL threshold as the predictive Cmin of response with 87% sensitivity and 78% specificity.
Panitumumab (VECTIBIX) Panitumumab is a fully human recombinant IgG2 that binds with high affinity and specificity to human EGFR. It is indicated as monotherapy or combined with chemotherapy for treating wild-type RAS metastatic colorectal cancer at 6 mg/kg Q2W. Lo et al. [19] provided a PK/PD evaluation of panitumumab for colorectal cancer in 2015. The PK of panitumumab is characterized by a twocompartment model with linear and non-linear clearance mechanisms, and PK parameters are reported in Table 1. Steady-state concentrations is reached at the third infusion, with a longer half-life of panitumumab than cetuximab (~7 versus 4 days). Population PK analyses showed body weight as the main covariable affecting panitumumab exposure, which is consistent with the current use of weightadjusted doses. In contrast, panitumumab PK was not significantly affected by tumour type, EGFR expression, KRAS mutation, sex, age, ethnicity or liver function. In addition, Krens et al. [20] showed that panitumumab can be used safely in patients with renal impairment without dose adjustment. Associations between panitumumab concentrations and response and between panitumumab dose and toxicity have been described [21]. Therefore, interindividual PK variability could affect, at least in part, the variability of clinical responses (therapeutic and adverse effects). Dedicated studies remain to be carried out. 4. Antihuman epidermal growth factor receptor 2 mAbs
Trastuzumab (HERCEPTIN, HERZUMA,   KANJINTI , OGIVRI , ONTRUZANT, TRAZIMERA) Trastuzumab is a recombinant humanized IgG1 mAb directed against human epidermal growth factor receptor 2 (HER2). In its IV form, it is indicated for treating gastric, gastroesophageal junction and breast cancers. The initial loading dose is 8 mg/kg, followed by a maintenance

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dose of 6 mg/kg Q3W. In its subcutaneous form, trastuzumab is indicated for breast cancer at a fixed dose of 600 mg, without a loading dose, Q3W. Of note, during the preclinical development of trastuzumab, 20 mg/mL was identified as a Cmin allowing for maximal tumour growth inhibition. Clinical trials have shown that such a PK target was achieved when trastuzumab was administered IV at 6 mg/kg after a loading dose of 8 mg/kg or subcutaneously at a fixed dose of 600 mg [22,23]. The PK of trastuzumab is described by a two-compartment model with linear and non-linear elimination. Body weight affects PK, and trastuzumab clearance is increased in patients with low albumin levels and decreased in those with previous gastrectomy [24]. In 2014, Cosson et al. [24] suggested a PK/ PD relationship in gastric and esophageal cancers. The proportion of patients with progressive disease was highest in the quartile with the lowest Cmin, and the proportion in complete remission was highest in the quartile with the highest Cmin. In addition, patients with low Cmin appeared to have a shorter median OS duration than others. These data suggest that a higher dose of trastuzumab may be required in at least some patients with advanced gastric cancer. To investigate this question, a phase IIIb study was conducted to compare standard and higher dosage regimens. The results of this study were recently reported by Shah et al. [25], who showed the maintenance dosage of high-dose trastuzumab associated with increased concentrations but not increased efficacy. This study confirmed the standard dose of trastuzumab for treating metastatic gastric or gastroesophageal adenocarcinomas. However, the analysis was not based on serum trastuzumab concentrations. For breast cancer indication and the subcutaneous route, Gonzalez et al. [23] showed in a cohort of 19 women that patient body weight and body mass index (BMI) affect the PK of trastuzumab. This study found an inverse association between patient BMI and plasma concentrations. The proportion of patients with Cmin > 20 mg/mL was 89% for those with BMI  30 kg/m2 but was only 10% for those with BMI > 30 kg/m2. The authors found an association of weight and trastuzumab concentrations: Mean Cmin was higher for patients weighing <59 kg than for those weighing >79 kg (92.6 versus 62.5 mg/mL). This study suggested that fixed doses of 600 mg of trastuzumab subcutaneously in obese patients may not be ideal for reaching plasma concentrations >20 mg/mL after the first administration. In addition, it opened the door to monitoring plasma levels of trastuzumab for treating HER2-positive breast cancer [23]. These data agree with previous work reporting reduced PFS for patients with HER2-positive breast cancer and BMI > 30 kg/m2 [26].
Pertuzumab (PERJETA) Pertuzumab is a recombinant humanized mAb that specifically targets the extracellular dimerization domain of the HER2 receptor and thus blocks ligand-dependent heterodimerization of HER2 with other HER family receptors. Its action is complementary to that of trastuzumab. It has been indicated in United States since 2012 and in Europe since 2013, in combination with trastuzumab and chemotherapy, for treating HER2-positive breast cancer at a loading dose of 840 mg IV, followed by a maintenance dose of 420 mg Q3W. Its PK parameters are reported in Table 1.

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In 2014, Garg et al. [27] showed body weight and body surface area as covariables significantly affecting PK parameters of pertuzumab but explaining only a small proportion of the observed interindividual PK variability. Albumin, alkaline phosphatase and C-reactive protein (CRP) have also been identified as important covariables. However, sensitivity analyses showed that their impact on pertuzumab exposure was not sufficient to recommend a dose adjustment. An effect of CRP on clearance has also been reported for other mAbs, and authors note that the link between CRP and pertuzumab PK should be fully explored. Finally, no drug interactions between pertuzumab and trastuzumab or between pertuzumab and docetaxel have been identified. The absence of an interaction between the two anti-HER2 antibodies was confirmed in 2017 by Quartino et al. [28]. These results support a lack of association between CRP levels and pertuzumab concentrations. 5. Anti-CD52 mAb: alemtuzumab (CAMPATH)

Alemtuzumab is a humanized IgG1 kappa directed against CD52. This glycoprotein is mainly expressed on the surface of normal and malignant B and T peripheral blood lymphocytes. It was approved for treating B-cell CLL in 2001 and was voluntary withdrawn for commercial reasons in 2012. It was administered during the first week of treatment with increasing doses (3 mg on day 1, 10 mg on day 2 and 30 mg on day 3, if well tolerated). Thereafter, the recommended dose was 30 mg/day, administered 3 times a week, 1 day out of 2, over a maximum of 12 weeks. The PK of alemtuzumab is described as a two-compartment model with nonlinear clearance. Indeed, similar to mAbs that target cellular antigens, alemtuzumab has a much more complex non-linear PK, so its half-life is both dose- and time-dependent. When the antigen concentration is high, the plasma half-life is short because the mAb binds to its epitope and is quickly eliminated from the blood. However, as the antigen is depleted, plasma clearance decreases and the plasma half-life increases (Table 1). Steady-state concentrations are reached after approximately 6 weeks [29]. With a cohort of 48 patients from 2 clinical studies, Mould et al. [30] studied the doseeresponse relation of alemtuzumab. Patients who achieved a Cmin > 13.2 mg/mL had a 50% chance of complete or partial response. In addition, the maximum Cmin, the AUC of the last dose and the last total dose administered were all associated with clinical response. These results are similar to those in the study by Montillo et al. [31], who showed complete response in all patients with AUC0-12 > 5 mg h/mL. Alemtuzumab could also be administered subcutaneously, thereby reducing side-effects and allowing for easier treatment management. Montagna et al. [32] described PK properties of alemtuzumab in a population of 29 patients receiving 10 mg of alemtuzumab as consolidation therapy. The authors evaluated the possible association

Please cite this article as: Paci A et al., Pharmacokinetic/pharmacodynamic relationship of therapeutic monoclonal antibodies used in oncology: Part 1, monoclonal antibodies, antibody-drug conjugates and bispecific T-cell engagers, European Journal of Cancer, https://doi.org/10.1016/ j.ejca.2020.01.005

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between serum levels and clinical response. The PK/PD analysis revealed statistically significant differences between responders and non-responders, with higher Cmax and Cmin among responders (1.69 versus 0.44 mg/mL and 0.7 versus 0.21 mg/mL, respectively). Higher values of AUC0e12h were also significantly correlated with better clinical response, 90.5% of the 21 responders, but only 37.5% of the 8 non-responders had an exposure >5 mg h/ mL. However, no association between lymphocyte count and serum concentrations of anti-CD52 antibodies was identified. The authors suggested that the dosage could be adjusted according to serum levels to improve clinical outcomes so that when AUC0-12 values after the 7th dose (day 15) are <5 mg h/mL, the dose could be increased. 6. Anti-CD38 mAb: daratumumab (DARZALEX)

Daratumumab is a human IgG1 that binds to CD38 expressed in large quantities on the surface of multiple myeloma tumour cells and in variable quantities on the surface of other cells. It is indicated, alone or in combination, for treating multiple myeloma, at 16 mg/kg, administered as an IV infusion. In terms of PK (Table 1), daratumumab elimination is not linear, with its clearance decreasing with increasing and repeated doses, thereby suggesting a target-mediated clearance. In addition, the PK data from the phase I-II studies showed 16 mg/kg as the lowest dose that saturates the target. In 2017, Xu et al. [33] reported an association between exposure and response. With the GEN501 and SIRIUS studies, the authors showed that exposure was highly associated with OS, which increased significantly with maximum Cmin, with maximum effect of 90% achieved at >274 mg/mL at the end of the weekly administration period. Exposure was strongly related to efficacy, but no relation between exposure and toxicity was identified. 2. Antibodies conjugated with cytotoxic agents Coupling a cytotoxic agent to an mAb leading to an immunoconjugate or antibodies conjugated with cytotoxic agent (ADC) offers a strategy to improve the tolerance/efficacy balance for these highly cytotoxic molecules. Indeed, the mAb provides specificity and, consequently, improves the PK and PD of these molecules. The cytotoxic binding to the antibody via a cleavable or non-cleavable linker must satisfy several conditions: (1) the antibody must be specific for an overexpressed antigen accessible within the tumour, (2) the anticancer agent must be highly cytotoxic because the number of cytotoxic molecules on the mAb will be low and (3) the binding must be sufficiently stable in the bloodstream and release the cytotoxic agent to the target. There are two possible releases of the agent: the ADC can be cleaved externally (for non-internalizing

mAb) or inside the cell after endocytosis (for internalizing mAb). The PK of ADC is very complex because it deals with the PK characteristics of the cytotoxic molecule, the mAb, as well as the physicochemical properties of the binding. Nevertheless, it is greatly affected by the PK of the mAb because it represents more than 90% of the molecular weight. Vd is equivalent to the central compartment (plasma plus lymph). The specificity and affinity for its target are due to the mAb. Clearance is mostly due to cellular uptake via receptors such as FcgR, including recycling via the FcRn. The PK profile of the total mAb (ADC þ mAb alone) describes the best estimate of the stability and integrity of the ADC [34]. The rate of cytotoxic release is also a critical point for the PK and PD of ADCs. The blood level of ADCs is difficult to determine because the clearance is due to two simultaneous processes: the removal of the ADC from circulation due to cellular uptake and the rupture of the bond between the cytotoxic agent and the mAb. Owing to the recognition of exogenous molecules by the reticuloendoplasmic system expressing FcgR, the conjugation of a cytotoxic agent to an mAb increases the clearance of the mAb [35], and the higher the conjugation rate on the same mAb, the higher the clearance of the ADC and, consequently, the therapeutic index decreases [36]. Also, the conjugation site plays a role in the stability and PK of ADCs; as compared with conjugation on light chains, conjugation on heavy chains of an mAb would increase the clearance of the ADC [37]. In the literature, the PK of ADCs is described as a two-compartment model with high clearance at low doses and decreased clearance at higher doses because of target antigen saturation [38]. Main PK data available are presented in Table 1. The PK/PD relationship is very complex and depends on a large number of parameters: concentrations of the mAb, of free cytotoxic agent and of ADC in the central and peripheral compartment; dissociation constant between the cytotoxic agent and the mAb outside or inside the tumour or cell; internalization constant and cytotoxic agent/mAb ratio (drug/ antibody ratio [DAR]) [38]. The binding of ADC to FcRn affects the efficacy and tolerance of the ADC [39] as well as the binding to FcgR whose number is proportionally related to body weight [35]. 1. Gemtuzumab ozogamicine (MYLOTARG)

The first ADC to receive market authorization (MA) was Mylotarg, a combination of ozogamicin and gemtuzumab (mean DAR 2.5:1). Ozogamicin is a derivative of calicheamicin, a highly cytotoxic antibiotic and gemtuzumab an anti-CD33 humanized IgG4. It received MA in 2000 from the FDA for relapsing acute myeloid leukemia (AML). However, it was withdrawn from the market in 2010 and reintroduced in 2017 with an optimized dosage regimen, including a lower dose than the initial MA and a new indication for patients with

Please cite this article as: Paci A et al., Pharmacokinetic/pharmacodynamic relationship of therapeutic monoclonal antibodies used in oncology: Part 1, monoclonal antibodies, antibody-drug conjugates and bispecific T-cell engagers, European Journal of Cancer, https://doi.org/10.1016/ j.ejca.2020.01.005

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untreated de novo AML [40]. Its withdrawal in 2010 was due to adverse reactions, particularly hepatic ones that lead to death (study SWOG S0106). Indeed, CD33 is a surface marker expressed on cells of the myeloid line but also on Ku¨pffer cells [41]. In the EU, gemtuzumab ozogamicin recently obtained MA in combination with daunorubicin and cytarabine for treating previously untreated de novo CD33-positive AML. The initial recommended dose was 6e9 mg/m2 with two injections administered at least 14 days apart [42]. Other studies analysed the efficacy of gemtuzumab ozogamicine by dividing the drug into 3 doses of 3 mg/m2 each on days 1, 4 and 7 for the induction cycle and then on day 1 for the two consolidation cycles. The rationale for this fractionation is based on the saturation and internalization of the CD33eozogamicin couple after injection and is now the new approved regimen [43]. PK studies were based on determining mAb concentration by ELISA and the quantification of total and/or free ozogamicin. Dowell et al. [44] calculated for the mAb, after an initial administration of 9 mg/m2, a Cmax of 2.86  1.35 mg/mL and AUC of 123  105 mg h/mL (Table 1). Plasma concentration, t1/2 and AUC increase after the second dose, probably because of a decrease in the target. These PK data were also observed in children [45]. In this population, 92.2% of CD33 antigens were reported to be bound to the ADC at 30 min after infusion [46]. 2. Brentuximab vedotin (ADCETRIS)

The second ADC obtaining MA from the FDA in 2011 and then from the EMA in 2012 was brentuximab vedotin, indicated for treating refractory or recurrent Hodgkin’s lymphoma and anaplastic large-cell lymphoma (ALCL). This ADC also received MA for primary cutaneous ALCL (pcALCL) (FDA and EMA, 2017) and more recently as first-line treatment for Hodgkin’s lymphoma stage III or IV (FDA, 2018). Brentuximab vedotin consists of the monomethylauristatin E antimitotic (MMAE or vedotin) and the chimeric brentuximab IgG1. Brentuximab specifically targets CD30 surface receptors on the surface of activated B and T cells. The binding between the cytotoxic agent and the mAb (mean DAR 4:1) is cleavable specifically by lysosomal proteases. Exposure of ADC and free MMAE is relatively dose-proportional; the Cmax of the ADC occurs at the end of the infusion, whereas that of free MMAE occurs 1e3 days after injection. The t1/2 of brentuximab vedotin is 4e6 days and the t1/2 of the cytotoxic agent alone is 3e4 days (Table 1) [47,48]. The recommended dose determined in a phase I study is 1.8 mg/kg Q3W (with a maximum of 16 cycles) [47,48]. A second phase I study investigated the efficacy and toxicity of brentuximab vedotin administered weekly over 3 weeks; the efficacy was similar for both types of administration, but the frequency of peripheral neuropathies was higher when the ADC was

7

administered weekly [49]. A recent study described the PK behaviour of brentuximab vedotin as a threecompartment model with first-order elimination, whereas the MMAE PK is described as a twocompartment model with first-order elimination [50]. According to the Li et al. PK model [50], the clearance and Vd of both the ADC (Table 1) and MMAE would be influenced by body weight and sex and would play on the central Vd of ADC; however, only body weight would affect the AUC of the ADC in an inversely proportional manner up to a weight of 100 kg, beyond which AUC would be stable. For paediatric patients, body weight has been found to be the main factor in interindividual variability of PK; therefore, the dose adapted to the child’s body weight corresponds to that recommended for adults [51]. However, Suri et al. [52] showed a positive association between MMAE clearance and creatinine and bilirubin levels; in patients with hepatic and severe renal impairment, the recommended dose is 1.2 mg/kg [48]. The phase III ALCANZA study, including six studies (380 patients), showed that ADC exposure in pcALCL patients was about 35% higher and clearance was lower in cutaneous T-cell lymphomas (CTCL) than in other hematologic malignancies. One of the explanations for the findings for pcALCL patients is that they have higher albumin level and lower tumour burden, whereas CTCL patients are older. Low clearance of ADC and high ADC exposure in CTCL (66 patients) did not translate into high cytotoxic exposure; the ADC or MMAE exposure would not be associated with improved PFS, but only exposure of ADC (not MMAE) was a significant predictor of toxicity [52]. 3. Trastuzumab emtansine (KADCYLA)

In solid tumors and particularly in breast cancer, the immunoconjugate based on trastuzumab, the humanized anti-HER2 mAb and emtansine or DM1, derived from maytansine (T-DM1, Kadcyla) (mean DAR 3.5:1), obtained MA in 2013 (FDA) and 2014 (EMA) for treating HER2-positive, metastatic or locally advanced, unresectable breast cancer previously treated with trastuzumab and a taxane. DM1 is a potent inhibitor of microtubule assembly, 25 to 400 times more active than paclitaxel and 100 to 5000 times more active than doxorubicin in vitro [53]; it cannot be used alone in humans because of its high cytotoxicity and the lack of specificity for cancer cells. Unlike brentuximab vedotin, the binding that connects the two entities is not cleavable by enzymes, but the release of the cytotoxic agent is via catabolism of the antibody. The recommended dose is 3.6 mg/kg Q3W [54]. Beeram et al. [55] studied the efficacy and toxicity of T-DM1 after weekly administration over 3 weeks and found a similar efficacy and toxicity profile as that obtained with Q3W administration. For practical reasons (hospital organization and patient convenience), Q3W is recommended [56]. For

Please cite this article as: Paci A et al., Pharmacokinetic/pharmacodynamic relationship of therapeutic monoclonal antibodies used in oncology: Part 1, monoclonal antibodies, antibody-drug conjugates and bispecific T-cell engagers, European Journal of Cancer, https://doi.org/10.1016/ j.ejca.2020.01.005

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doses 2.4 mg/kg, the PK of T-DM1 is linear: the higher the dose, the lower the clearance, and the t1/2 increases. The Cmax of T-DM1 is observed at the end of the infusion, with a value of 74.3  20.1 mg/mL after 3.6 mg/ kg, and the PK parameters for T-DM1 are detailed in Table 1 [54]. A population PK study analysed the different covariables affecting T-DM1 clearance: TDM1 clearance was higher for patients with high body weight, high expression of HER on the cell surface and high tumour volume, low albumin level or low trastuzumab Cmin [57]. Only weight seemed to explain the variability in AUC and Cmax, resulting in a dosage adjustment based on body weight [57]. More recently, the PK/PD relationship between efficacy and plasma exposure of ADC was confirmed in a phase III study (351 patients and 1421 sera samples); both OS and PFS were longer in patients with higher Cmin in ADC at cycle 1 and higher AUC in ADC at steady state [58]. Singh and Shah [59] developed a PK/PD model to predict the efficacy of ADC: a dose of 1.2 mg/kg Q1W or divided doses of 3.0 þ 0.3 þ 0.3 mg/kg given on days 0, 7 and 14 would be effective. In addition, Bender et al. [60] showed the importance of the number of DM1 molecules bound to trastuzumab on the deconjugation rate between these two entities; the higher the DAR, the faster the release of the molecule into the intracellular space. 4. Inotuzumab ozogamicin (BESPONSA)

The last ADC to receive MA in 2017 (FDA and EMA) was inotuzumab ozogamicin, consisting of ozogamicin and humanized inotuzumab IgG4 (mean DAR 6:1). It is indicated for relapsed or refractory CD22positive B-cell precursor acute lymphoblastic leukaemia (ALL). Inotuzumab specifically targets the CD22 surface protein present on B cells. In the phase III study, the tested dose was 1.8 mg/m2 Q3W to Q4W [61]. A weekly divided dose (0.5e0.8 mg/m2 Q1W for 3 weeks) improved the toxicity profile because of a lower peak of ADC concentration, without affecting treatment efficacy. Therefore, the current summary of product characteristics recommends the use of inotuzumab ozogamicin in divided doses. The PK studies quantifying ADC, the total form (free þ bound) of mAb and total and unbound form of ozogamicin showed that the AUC of the ADC as well as its t1/2 increased with the number of cycles owing to a decrease in CD22 antigen availability (Table 1) [61,62]. Kantarjian et al. [63] showed that the plasma ADC concentration at 3 h after the end of the infusion was higher for responders than for non-responders; in a cohort of 24 patients, 8 of 9 patients (89%) with concentration > 100 ng/mL showed complete response as compared with only 5 of 15 patients (33%) with concentration < 100 ng/mL (P Z 0.008). Approximately 220 clinical trials describing 87 different ADCs are listed at ClinicalTrials.gov. ADCs represent a

very promising therapeutic class because of the ability to target highly cytotoxic agents to the tumour with controlled release and in sufficient quantities. However, the knowledge of the PK/PD relationship of the different ADCs remains sparse and deserves further investigation to optimize therapeutic strategies. 3. Bispecific antibodies Bispecific and multispecific antibodies (bsAbs) represent a new therapeutic class. They are characterized by their ability to recognize and bind to two or more different antigens (Fig. 1). The only one that received MA is blinatumomab (Blincyto/). 1. Blinatumomab (BLINCYTO)

It was approved in adults in 2014 (FDA) and 2015 (EMA) and in paediatric patients in 2016 (FDA) and 2018 (EMA) for treating Philadelphia chromosome negative CD19-positive relapsed or refractory B-precursor ALLs. The FDA recently extended the MA for treating residual B-precursor ALLs (March 2018). Blinatumomab is a BiTE. Briefly, BiTEs have an affinity for an antigen present on the surface of immune cells (here the CD3 marker of T lymphocytes) and for an antigen present on the surface of the cancer cell (here CD19). This binding causes activation of the T lymphocytes against the target tumour cell. PK and PD information on BiTEs is still limited because of the highly innovative nature of this therapeutic strategy. Unlike a conventional mAb, blinatumomab is an antibody fragment consisting of only variable fragments (Fvs) without the Fc domain (Fig. 1, bivalent bifunctional bsAb) and thus has a molecular weight of 54 kDa.

A

Bispecific antibodies Bivalent

Two (or more) mAbs directed against different antigens

1. Bifunctional

+

8

2. Trifunctional

B

Trivalent

Tetravalent

Trispecific antibodies

Fig. 1. Origin and structure of multispecific antibodies. Multispecific antibodies are fusion proteins derived from the antigenbinding sites of two or more different monoclonal antibodies. A, Bispecific antibodies consist of heavy- and light-chain variable fragments (scFvs) of 2 different antibodies (1) lacking an Fc region for bifunctional antibodies and (2) bearing an Fc region for trifunctional ones. Often one of the scFvs is specific to T cells and the other to a tumour-specific molecule, thereby allowing the T cells to be directed against cancer cells. B, Trispecific antibodies consist of 3 different antigen-recognition domains of monoclonal antibodies.

Please cite this article as: Paci A et al., Pharmacokinetic/pharmacodynamic relationship of therapeutic monoclonal antibodies used in oncology: Part 1, monoclonal antibodies, antibody-drug conjugates and bispecific T-cell engagers, European Journal of Cancer, https://doi.org/10.1016/ j.ejca.2020.01.005

A. Paci et al. / European Journal of Cancer xxx (xxxx) xxx

Therefore, its half-life is shorter than that of a mAb (t1/2 about 2 h). Blinatumomab has linear PK with rapid clearance and low Vd (Table 1); however, the clearance has very high interindividual variability (coefficient of variation 97%) [64]. No covariable seems to affect its PK, and hence, a fixed dose is recommended [65]. The phase II clinical study did not demonstrate an association between concentrations at steady-state and response time [66]; however, a recent publication showed that a concentration at steady-state > 1830 pg/ mL and AUC > 1.34 mg h/mL after 47 mg/m2/day for 28 days predicted tumour size reduction of at least 50% [67]. The efficacy of blinatumomab is time-dependent, so it is administered in a continuous infusion cycle of 4 weeks, at 9 mg/day from days 1e7 and 28 mg/day from days 8e28 in adults, with cycles spaced 2 weeks apart [68]. Trifunctional bispecific mAbs (Fig. 1) also being clinically evaluated include ertumaxomab targeting HER2/neu and CD3. Unlike bifunctional products, an Fc fragment from mice or rats is added to allow their recognition by the FcgR [69]. Approximately 130 clinical trials describing 41 different bsAbs and multispecific antibodies are listed at ClinicalTrials.gov. ADCs and bsAbs offer a promising therapeutic strategy, and the results of efficacy and tolerance are encouraging for these two therapeutic classes. However, the complexity of the PK/PD relationship owing to the addition of several factors including the PK of the mAb, the PK of the cytotoxic agent and the release kinetics requires additional studies to optimize the dosage. To conclude on this part, the PK/PD relation for ADC and BiTEs describes the PK parameters (clearance, Cmax, Ctrough) as predictive biomarkers for efficacy and/or toxicity. ADC and BiTEs have been registered recently and require prospective studies to confirm the PK/PD relationships described in silico and in preclinical studies and to assess whether dose modifications result in a change in systemic exposure that would be correlated with a better efficacy or mainly safer profile. A large number of therapeutic mAbs have been developed for many medical indications. The emphasis has been on improving the molecular target affinity and clinical activity without a full understanding of the principles of PK modelling of these compounds. Dose selection is a major challenge in developing targeted treatments, particularly for mAbs with complex PK and PD, and different from those of chemical drugs. Because the Vd is related to body size, most mAbs are dosed on the basis of body weight or body surface area to normalize exposure among patients. Nevertheless, because the therapeutic window of mAbs is wide, the current trend is toward developing flat-doses, leading back to the “one size fits all” approach, regardless of interindividual variability. However, as described, a significant interpatient variability has been reported in PK

9

studies of mAbs, with many factors affecting patients’ exposure to mAbs. Therefore, the exposureeresponse relations we describe provide encouraging evidence for further exploring therapeutic drug monitoring of these mAbs. Future studies are needed to continue to optimize the doses and dosing schedule of these mAbs, which could lead to personalized medicine via therapeutic drug monitoring and thus prevent risk of treatment failure. Funding This research did not receive any specific grant from funding agencies in the public, commercial, or not-forprofit sectors. Conflict of interest statement O. M. receives consultancy fees from Amgen, AstraZeneca, Bayer, Blueprint Medicines, Bristol MyersSquibb, Eli-Lilly, Incyte, Ipsen Biopharmaceuticals, Lundbeck, MSD, Novartis, Pfizer, Roche, Servier, and Vifor Pharma; is member of advisory boards of Amgen, Astra-Zeneca, Bayer, Blueprint Medicines, Bristol MyersSquibb, Eli-Lilly, Lundbeck, MSD, Novartis, Pfizer, Roche, Servier, and Vifor Pharma; participates in a speaker’s bureaus of Eli-Lilly, Roche, and Servier; and holds stock in Amplitude surgical and Transgene. A. P. receives consultancy fees from Amgen and is a member of advisory boards of Pierre Fabre, Fresenius, and Pfizer. C. M. is employed in Oncology Medical Department at Boehringer-Ingelheim, with no competing interest in this project. Other authors have nothing to disclose.

Acknowledgements The authors thank Ms. L. Smales (BioMedEditing, Toronto, Canada) for editing the manuscript. Figure was adapted from Smart Servier Medical Art (https://smart. servier.com/) Creative Commons Attribution 3. 0 Unported License (https://creativecommons.org/ licenses/by/3.0/).

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Please cite this article as: Paci A et al., Pharmacokinetic/pharmacodynamic relationship of therapeutic monoclonal antibodies used in oncology: Part 1, monoclonal antibodies, antibody-drug conjugates and bispecific T-cell engagers, European Journal of Cancer, https://doi.org/10.1016/ j.ejca.2020.01.005