Expert Opinion on Biological Therapy

ISSN: 1471-2598 (Print) 1744-7682 (Online) Journal homepage: https://www.tandfonline.com/loi/iebt20

Pembrolizumab for the treatment of Cervical

Cancer

Grégoire Marret, Edith Borcoman & Christophe Le Tourneau

To cite this article: Grégoire Marret, Edith Borcoman & Christophe Le Tourneau (2019):
Pembrolizumab for the treatment of Cervical Cancer, Expert Opinion on Biological Therapy, DOI:
10.1080/14712598.2019.1646721

To link to this article: https://doi.org/10.1080/14712598.2019.1646721

Accepted author version posted online: 19

Jul 2019.

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 Publisher: Taylor & Francis & Informa UK Limited, trading as Taylor
& Francis Group

Journal: Expert Opinion on Biological Therapy

DOI: 10.1080/14712598.2019.1646721
Pembrolizumab for the treatment of Cervical Cancer

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Grégoire Marret,1 Edith Borcoman,2 Christophe Le Tourneau2,3,4

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1
Hôpital Européen Georges Pompidou, Paris, France; 2Department of Drug Development and

Innovation (D3i), Institut Curie, Paris & Saint-Cloud, France; 3INSERM U900 Research Unit,

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Saint-Cloud, France; 4Paris-Saclay University, Paris, France
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Corresponding author:
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Prof. Christophe Le Tourneau, MD, PhD

Head, Department of Drug Development and Innovation (D3i)

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Institut Curie

26, rue d’Ulm

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75005 Paris
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France

Phone/Fax: +33-1-4432-4675/+33-1-5310-4006
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Email: christophe.letourneau@curie.fr

Abstract

Introduction

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 The prognosis of patients with recurrent and/or metastatic cervical cancer remains poor, with

a 5-year survival rate of 17%. Most of cervical cancers are associated with the human

papillomavirus (HPV) infection that leads to viral antigens production, supporting the

development of immunotherapy in cervical cancer.

Areas covered

Here we report the pharmacologic properties, clinical efficacy, and safety profile of

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pembrolizumab, an IgG4-kappa humanized monoclonal antibody against the programmed cell

death protein 1 (PD-1) receptor, for the treatment of cervical cancer.

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Expert Opinion

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Single agent pembrolizumab has limited efficacy in the recurrent and/or metastatic setting in

an unselected patient population. However, durable responses in PD-L1-expressing cervical

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cancer patients led the U.S. Food and Drug Administration to grant accelerated approval of

pembrolizumab in this patient population. Outside this patient population, further

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development involves combinations with other treatment options including chemotherapy,

radiotherapy and other immunotherapeutic agents. The identification of biomarkers of

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efficacy beyond PD-L1 expression will be essential in order to identify patients who will most
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likely benefit from pembrolizumab.

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Keywords: cervical cancer, HPV, immune checkpoint, PD-1, pembrolizumab

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 Article Highlights

• Evidence-based data regarding cervical cancer and checkpoint blockade are scarce and

preliminary.

• Pembrolizumab has been approved in PD-L1-positive cervical cancer patients based

on sustained responses.

• Combinations of pembrolizumab with chemoradiation and in earlier disease stages are

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being evaluated.

• The identification of biomarkers of efficacy beyond PD-L1 expression is urgently

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needed.

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 1. Introduction

Although largely preventable using screening and vaccination against the human

papillomavirus (HPV), an estimated 527,600 new cervical cancer cases were diagnosed in

2012 worldwide, and 265,700 patients died from this disease that year [1]. Cervical cancer is

the second most commonly diagnosed cancer and third leading cause of cancer death among

females in low-resource countries, whereas cervical cancer rates have decreased by as much

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as 65% over the past 40 years in several Western countries thank the available screening

programmes [1]. Cervical cancer is induced by a persistent infection with one of the high-risk

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strains of the HPV, most frequently HPV 16 and HPV 18 [2]. Based on histological features,

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invasive cervical carcinoma can be classified as squamous cell carcinoma (SCC),

adenocarcinoma, or adenosquamous carcinoma, with squamous cell carcinoma representing

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the majority of histological variants worldwide [3]. The most commonly applied

dichotomization is squamous cell carcinoma versus adenocarcinoma, both differing in terms

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of mutational profile [4,5] and PD-L1 expression [6]. PD-L1 expression is more frequent in

the squamous histology (34%) than in adenocarcinoma (17%) [5]. PD-L1 is expressed in 29%
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of adenosquamous carcinomas [7].

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While surgery can cure most of early stage cervical cancers [8–10], concurrent

chemoradiation (CRT) followed by high-dose-rate brachytherapy is standard of care for

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locally advanced cervical cancer. Despite this multimodal strategy, only two thirds of patients

will still be alive at 5 years [11]. In the recurrent and/or metastatic (R/M) setting, the
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prognosis is poor with a 5-year survival rate of 17% [10]. In that situation, cisplatin-based

chemotherapy is the most effective treatment option [12]. However, the majority of patients

do not respond, with objective response rates ranging from 22% with cisplatin plus

gemcitabine to 29% with cisplatin plus paclitaxel [13]. Recently, bevacizumab, a monoclonal

antibody targeting the vascular-endothelial growth factor, has been the first drug to

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 demonstrate an overall survival (OS) benefit in first-line R/M setting, yet the OS benefit is

limited and responses remain short-lived [14,15].

Targeting the immune system to fight cancer has recently been demonstrated to be a

successful strategy with the advent of immune check point inhibitors. Targeting the cytotoxic

T-lymphocyte associated protein 4 (CTLA-4) and the programmed cell death protein 1 (PD-1)

expressed on activated T cells has been shown to be able to counteract the immunologic

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tolerance to cancer cells in the tumor microenvironment. Agents targeting these immune

check points have been demonstrated to improve OS in several cancer types [16–21].

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Since most cervical cancers are associated with high-risk HPV encoding two defined

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tumor-specific viral antigens, namely E6 and E7, there is a strong rationale to evaluate

immunotherapy in patients with cervical cancer. The PD-1/PD-L1 axis attenuates T-cell
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responses and promotes T-cell tolerance during chronic viral infection [22]. This impaired

HPV-specific cell-mediated immunity contributes to the pathogenesis of persistent high-risk

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HPV infection and related cervical intraepithelial neoplasia (CIN) [23,24]. PD-1 and PD-L1
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expressions on cervical T-cells and dentritic cells respectively were associated with a high

risk HPV positivity and correlated with cytological or histological alterations in CIN samples
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[25]. In addition, PD-L1 expression was associated with a poor prognosis in cervical cancer

patients [6].
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2. Overview of the market

There are currently two main unmet clinical needs in the treatment of cervical cancer. The

first one is to increase the rates of patients with locally advanced cervical cancer who will be

cured with surgery and/or radiation-based therapy. The second one is the urgent need to

develop drugs in the R/M setting that will produce durable responses. Given the strong

scientific rationale to evaluate immunotherapy in cervical cancer patients and the ability of

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 immunotherapy to produce durable responses in other cancer types [26,27], several immune

checkpoint inhibitors have been and are currently being evaluated in these patients.

The pharmacologic inhibition of CTLA-4 has shown dismal efficacy in a phase I/II

clinical trials investigating ipilimumab in patients with R/M cervical cancer. The median PFS

and OS were 2.5 months and 8.5 months, respectively [28]. The safety and tolerability of

ipilimumab are being investigated in combination with chemoradiation in patients with locally

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advanced node-positive cervical cancer in the phase I GOG 9929 trial (NCT01711515).

Beside pembrolizumab that is the focus of this review, several other anti-PD-1/PD-L1 agents

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are being investigated, including nivolumab and atezolizumab in combination with

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chemoradiotherapy (CRT) in locally advanced cervical cancer (NCT03298893,

NCT03738228), and in second-line therapy for patients with platinum-resistant R/M cervical
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cancer in the GOG 3016 trial (NCT03257267).
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3. Introduction to the compound

Pembrolizumab (box 1) is a high affinity antibody against the PD-1 receptor, which exerts
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dual ligand blockade of the PD-1 pathway (including PD-L1 and PD-L2) on antigen
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presenting or tumour cells. Pembrolizumab reactivates tumour-specific cytotoxic T

lymphocytes in the tumour microenvironment and reactivates anti-tumour immunity.

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Pembrolizumab has been approved in advanced melanoma [29,30], non-small-cell lung

cancer [31–33], Hodgkin’s lymphoma [34], urothelial carcinoma [35,36], and head and neck
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squamous cell carcinoma [37]. Pembrolizumab was also approved by the Food and Drug

Administration (FDA) for the treatment of adult and pediatric patients with R/M

microsatellite instability-high or mismatch-repair-deficient solid tumors, regardless of tumor

type [38].

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 4. Chemistry

Pembrolizumab (molecular formula: C6504H10004N1716O2036S46) is a highly selective

humanized monoclonal IgG4/kappa isotype antibody with a stabilizing Ser228Pro sequence

mutation in the Fc region (Figure 1) [39]. This mutation has been shown to avoid the IgG4

Fab-arm exchange, a process of exchanging half-molecules among themselves to form

dynamic bispecific antibodies. The instability of IgG4 introduces unpredictability of the

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clinical efficacy and toxicity of immunotherapies, and pembrolizumab overcomes this feature

with the serine-to-proline replacement in position 228. Pembrolizumab is heterogeneously

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glycosylated at Asn297 within the Fc domain of each heavy chain, yielding a molecular

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weight of 148.9 kDa, while the most abundant forms of the heavy and light chains are 50.7

kDa and 23.7 kDa, respectively.

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5. Pharmacodynamics
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T lymphocytes play a central role in the clearance of viral infections and prevention of virus-

associated malignancies, dependant on dentritic cell presentation of antigen peptides to

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antigen-specific T lymphocytes [40,41]. These T cells are activated via the interaction
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between T-cell receptors (TCR) and peptide epitopes of tumor-associated antigens and tumor-

specific antigens bound to major histocompatibility complexes of antigen-presenting cells

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(APCs), such as dentritic cells, macrophages, Langherans cells, and B cells. This immune

response is also initiated through the interaction between costimulatory ligands on APCs and
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their cognate receptors on T lymphocytes, and inflammatory cytokine signals. PD-1 limits the

activity of T lymphocytes in peripheral tissues, maintaining self-tolerance (while central

tolerance mechanisms result in deletion of the majority of self-reactive T cells), minimizing

collateral damage during physiologic responses to pathogens, and inducing maternal tolerance

to fetal tissue [42–45]. In contrast to the important role in maintaining peripheral tolerance

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 and T cell homeostasis, the PD-1/PD-L1 axis may be engaged by tumor cells to inhibit active

T-cell immune surveillance [46–48]. Moreover, expression of PD-1 by exhausted virus-

specific T cells prevents the proliferation and function of virus-specific T effector cells and

clearance of the virus, in part reflecting chronic viral infection [49,50]. The binding of PD-1

to PD-L1 or PD-L2 causes the phosphorylation of two tyrosines in the PD-1 cytoplasmic

domain (immunoreceptor tyrosine-based switch motif) upon TCR ligation at the signaling

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central supramolecular activation cluster (c-SMAC) [51]. Phosphorylated PD-1 then recruits,

directly or indirectly, the cytosolic tyrosine phosphatases SHP-2 and SHP-1, the TCR-

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phosphorylating kinase Lck, and the inhibitory tyrosine kinase Csk [52,53]. PD-1 activation

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suppresses TCR signaling [53–55], CD28 costimulatory signaling [56], and ICOS

costimulatory signaling [57], on top of decreasing phosphorylation of various signaling

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molecules, such as ERK, Vav, PLCγ and PI3 kinase [53,56]. PD-1 was also shown to

suppress T cell function by inactivating CD28 signaling through its strong preferential
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dephosphorylation over dephosphorylation of TCR, suggesting that coinhibitory pathways

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play key roles in regulating effector T cell function and responses to immunotherapy [58].

Pembrolizumab can be functionally divided into a variable and constant region. The
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former binds epitopes on the immune checkpoint molecule (namely PD-1) with high affinity

and specificity, resulting in the blockade of the PD-1/PD-L1&2 interactions [59]. The binding
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affinity to the recombinant human PD-1 was measured by enzyme-linked immunosorbent

assay (ELISA). The dissociation constant (Kd) was estimated to be 29 pmol/L [59]. Since
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pembrolizumab is an IgG4, the constant region weakly induces complement and cell

activations due to the low affinity for C1q and Fc receptors [60]. Binding of pembrolizumab

with PD-1 relies heavily on interactions with the flexible loops of PD-1 (which is not involved

in the interaction with PD-L1). This interaction covers a buried surface area of 1774-2126 Å2.

Finally, the interaction of pembrolizumab with the C and C’ strands of PD-1 ensures direct

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 occupancy and steric blockade of the PD-L1 binding site associated with little conformational

changes of PD-1 [61,62]. Other known or unknown ligands of PD-1 may be differently

affected by pembrolizumab.

6. Pharmacokinetics and metabolism

The pharmacokinetics (PK) of pembrolizumab was investigated in 2,195 patients with solid

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malignancies enrolled in the phase I KEYNOTE-001 trial [39], who received doses of 1 to 10

mg/kg every 2 weeks or 2 to 10 mg/kg every 3 weeks. Since pembrolizumab is administered

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intravenously, the drug is therefore completely bioavailable and is not expected to bind to

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plasma proteins. Indeed, results from population PK analysis showed that albumin had no

impact in pembrolizumab PK parameters. Pembrolizumab is catabolized into small peptides

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and single amino acids via general protein degradation routes, with a clearance of 0.23 L/day,

and an elimination half-life of 26 days [63]. Clearance increases with increasing body weight,
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explaining the rationale for dosing on a mg/kg basis. In addition, doses of 200 mg and

2 mg/kg provide similar exposure distributions with no advantage to either dosing approach
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with respect to controlling PK variability [64]. These findings suggest that weight-based and
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fixed-dose regimens are appropriate for pembrolizumab. Steady-state concentration is reached

after 18 weeks when administered at 2 mg/kg every 3 weeks (6 doses). The volume of
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distribution is small (7.4 L; coefficient of variation: 19%), consistent with a limited

extravascular distribution.
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The effects of various covariates on the PK of pembrolizumab were assessed in

specific patient populations. Age (range 15 to 94 years), gender, mild or moderate renal

impairment, mild hepatic impairment, and tumor burden had no effect on the clearance of

pembrolizumab [63]. Pembrolizumab has not been evaluated in patients with severe renal

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 impairment or moderate to severe hepatic impairment, but there is no reason to think that this

might cause safety issues, since the metabolism of pembrolizumab is neither renal nor hepatic.

7. Clinical efficacy

7.1 Phase I studies

Pembrolizumab was first evaluated in cervical cancer patients in a multicohort, multicenter,

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phase Ib clinical trial referred to as KEYNOTE-028 [65]. In this trial, an expansion cohort

included patients with R/M PD-L1-expressing cervical cancer. Patients had to have failed

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standard of care therapy, have an Eastern Cooperative Oncology Group performance status of

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0 or 1, and a PD-L1 expression in ≥1% in tumor cells using immunohistochemistry (IHC).

Patients received pembrolizumab at the dose of 10 mg/kg as a 30-minute intravenous infusion

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every 2 weeks for up to 24 months or until confirmed progression, intolerable toxicity, death,

or withdrawal of consent. The primary end point was the overall response rate (ORR)
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according to RECIST1.1 by investigator review. All 24 patients presented with metastatic

disease. Median age was 41.5 years. The patient population was heavily pretreated, with 22
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patients (92%) having received prior radiation therapy and 15 (63%) two or more prior lines
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of therapy before study entry. Ten patients (42%) had received prior bevacizumab. Eighteen

patients (75%) were PD-L1 positive in the tumor cells only, while the remaining 6 patients
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(25%) were positive both in the tumor and the stromal cells. An ORR of 17% was reported

(all partial responses [PR]) with a median duration of response (DR) of 5.4 months [range, 1.7
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to 8.2 months] (Table 1). All patients experiencing a PR had a PD-L1 expression on tumor

cells only. Median progression-free survival (PFS) was 2 months, highlighting the fact that

most patients didn’t respond to pembrolizumab. Median OS reached 11 months, which is

substantial in this heavily pretreated patient population.

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 Radiation therapy can kill malignant cells with ionizing radiation, resulting in

neoantigen release and cross-priming of an activated immune system stimulated by

immunotherapy. When directed at tumor-specific antigen, the immune system can initiate a

relevant immune response in the irradiated tumor, but also in distant metastases [66]. Thus,

pembrolizumab is being also investigated in the locally advanced setting in combination with

chemoradiation in a phase I trial (NCT03144466).

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7.2 Phase II studies

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The FDA granted accelerated approval for pembrolizumab in patients with R/M cervical

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cancer in June 2018 based on the results of the cervical cancer cohort of the KEYNOTE-158

phase II basket trial [67], evaluating the efficacy of pembrolizumab in 11 cancer types. The
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FDA concurrently approved the PD-L1 IHC 22C3 pharmDx Kit (Dako) as a companion

diagnostic. In the cervical cancer cohort, patients received pembrolizumab at a flat dose of
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200 mg every 3 weeks for 2 years or until progression or intolerable toxicity. No selection

was based on PD-L1 expression that was only retrospectively assessed. PD-L1 positivity was
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defined as a combined positive score [CPS] (the ratio of the number of PD-L1-expressing
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tumor and infiltrating immune cells to the total number of tumor cells) ≥ 1 that was evaluated

using IHC. Eighty-one out of the 98 patients (83%) included in this cohort had CPS score ≥
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1. The ORR was 16% in this patient population, with 3 patients (3.7%) achieving a complete
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response. Out of the 13 patients who responded, 9 patients (69%) had a response that lasted

more than six months. None of the patients with a CPS < 1 experienced an objective response

(Table 1).

Pembrolizumab is currently being investigated in patients with locally advanced

cervical cancer in combination with chemoradiation in a randomized phase II trial

(NCT02635360).

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 7.3 Phase III studies

Pembrolizumab is being investigated in first-line R/M setting in the KEYNOTE-826 phase III

trial (NCT03635567). Following a 1:1 randomization, patients will receive either

pembrolizumab (200 mg every 3 weeks) or a placebo plus one of four platinum- and taxane-

based chemotherapy regimens. The chemotherapy regimen will be given at physician’s choice

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and include paclitaxel plus cisplatin with or without bevacizumab and paclitaxel plus

carboplatin with or without bevacizumab. The primary endpoints are PFS and OS, with

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secondary endpoints including ORR and DR, the frequency and severity of adverse events

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(AEs), and health-related quality of life. Patients will be stratified based on PD-L1 expression.
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8. Safety and tolerability

No grade 4 and no deaths related to pembrolizumab were reported in the KEYNOTE-028

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study. Five patients (21%) experienced a grade 3 AE, including rashes, proteinuria, colitis,

and Guillain-Barre syndrome [65]. AEs occurring in more than 10% of patients included rash
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and pyrexia.
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Grade 3 or 4 AEs were reported in 11 patients (11.2%) in the KEYNOTE-158 trial

with no treatment-related deaths. AEs occurring in at least 10% of patients included fatigue,
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pain, pyrexia, peripheral oedema, musculoskeletal pain, diarrhea/colitis, abdominal pain,

nausea, vomiting, constipation, decrease appetite, hemorrhage, infections, rash,

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hypothyroidism, headache, and dyspnea [67]. AE-related discontinuations occurred in 8% of

patients, mainly as a result of anemia, fistula, hemorrhage, and infections.

Given the mechanism of action of checkpoint inhibitors, pembrolizumab is associated

with unique drug-class specific AEs that mirror autoimmune disorders [68]. Overall, immune-

mediated AEs were encountered in six patients (25%) in the KEYNOTE-028 trial and

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 included rash, colitis, Guillain Barré syndrome, hyperthyroidism and hypothyroidism.

Although a rare outcome, immune-mediated AEs required drug discontinuation,

corticosteroids and human normal immunoglobulin infusions [65].

9. Conclusions

Pembrolizumab was granted accelerated FDA approval based on a phase II trial

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demonstrating durable responses in patients with PD-L1-positive, heavily pretreated, R/M

cervical cancer. The safety profile of pembrolizumab in this patient population is favourable

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with only a minority of patients experiencing serious AEs. Pembrolizumab is currently being

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evaluated in the first-line R/M setting in combination with standard chemotherapy, and in the

locally advanced setting in combination with chemoradiation, regardless of the PD-L1 status.
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10. Expert Opinion
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Pembrolizumab has substantial single-agent efficacy with an acceptable safety profile in

selected PD-L1 expressing R/M cervical cancer patients who exhausted standard of care
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therapy. Although a minority of patients experienced an objective response, these responses

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were sustained. It remains to be determined in the ongoing phase III trial whether these

encouraging results will translate into an OS benefit. Responses were only reported in patients
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with PD-L1 positive tumors, leading to FDA approval of pembrolizumab in this patient

population. PD-L1 expression patterns may vary depending on the histological subtype[6,7].
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More PD-L1 expression by tumor cells and higher rates of PD-L1 positive tumor-associated

macrophages were found in SCC. Diffuse PD-L1 expression may be associated with a poor

prognosis as well[69]. In these patients, pembrolizumab was given up to 2 years. No data

have been published regarding progression after interruption. It is still debated how long

patients should be treated with immunotherapy and on which criteria (CR?) treatment should

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 be stopped. Given the long half-life of pembrolizumab, less frequent treatment injections

should also be discussed. Approaches used to improve the antitumor activity of

pembrolizumab are combinations immunotherapy with other treatment modalities, such as

chemotherapy and radiotherapy.

PD-L1 staining on both tumor and tumor-associated immune cells has been the most

studied biomarker for the prediction of treatment response to immunotherapy, and PD-L1

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diagnostic assays are currently being used in the stratification of patients included in clinical

trials. However, patients whose disease is PD-L1 negative can still achieve clinical benefit

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from anti-PD1 or anti-PD-L1 therapies [28,70]. The low sensitivity and specificity of PD-L1

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expression may be due to the evaluation kits themselves, and the heterogeneous nature of the

tumors [71,72]. The identification of more sensitive and specific biomarkers of efficacy will
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be key to better select patients who will most likely benefit from pembrolizumab. Beyond PD-

L1 expression, other factors can affect responses to immunotherapy, including deficiencies in

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DNA mismatch repair mechanisms, microsatellite instability, pre-existing interferon-mediated

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adaptative immune response, POLE mutations, and high tumor mutational burden (TMB)

[38,73–77]. Overall, the median TMB in cervical cancers is 0.67 mutations/Mb, with a range
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of 0-40.81 mutations/Mb [78]. Moderate to high TMB values were also reported in 28% of

patients, which may be a potential group that might benefit from immunotherapy. Analysis of
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the tumor microenvironment might be relevant in a clinical setting. Indeed, preliminary

results in cervical cancer samples reported a favourable prognostic impact based on the
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abundance of infiltrating T and B cells, myeloid dendritic cells, cytotoxic lymphocytes and

CD8 T cells [79]. Patients with both inflamed tumor microenvironment (including PD-L1

expression and gene-expression signatures of activated T cells) and higher tumor antigenicity

(as reflected by TMB) appear to respond better to immunotherapy [80].

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 Funding

This paper is not funded.

Declaration of Interests

C Le Tourneau has participated in advisory boards from BMS, MSD, Merck Serono, Amgen,
GSK, Roche, Astra Zeneca, and Nanobiotix. The authors have no other relevant affiliations or
financial involvement with any organization or entity with a financial interest in or financial

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conflict with the subject matter or materials discussed in the manuscript apart from those

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disclosed.

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Reviewer Disclosures
Peer reviewers on this manuscript have no relevant financial relationships or otherwise to
disclose.

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 Figure legends

Figure 1: Pembrolizumab structure.

This ribbon diagram shows the two heavy chains in blue and cyan and the two light chains in

magenta and brown. The sugars are shown as spheres colored by atom type (black, carbon;

red, oxygen; blue, nitrogen). Reproduced with permission from [60]

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 Drug Summary Box

Drug name (generic) Pembrolizumab

Phase (for indication under discussion) II (accelerated approval)

Indication (specific to discussion) Patients with recurrent and/or metastatic

cervical cancer with disease progression on

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or after chemotherapy whose tumors and

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infiltrating immune cells express PD-L1

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(CPS ≥1) as determined by an FDA-

approved test.

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Mechanism of action an PD-1 monoclonal antibody

Route of administration Intravenous

Chemical structure IgG4k humanized monoclonal antibody

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Pivotal trials KEYNOTE-028: phase Ib multicohort,

multicenter trial with an expansion cohort of

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24 patients with recurrent and/or metastatic

PD-L1-expressing (TPS > 1%) cervical

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cancer. An ORR of 17% was reported with a

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median duration of response of 5.4 months

[range, 1.7 to 8.2 months].

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KEYNOTE-158: a multicenter, non-

randomized, multicohort trial that

investigated the efficacy of pembrolizumab

in 98 patients with recurrent and/or

metastatic cervical cancer. An ORR of 16%

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 was reported in the PD-L1-expressing

subgroup of patients (CPS >1). Median

duration of response had not been reached

[range, 3.7 to 12.4 months]. Nine out of the

13 responder patients were still responding

after ≥ 9 months follow-up. No responses

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were observed in PD-L1 negative patients.

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 Table 1 Efficacy results of clinical trials evaluating pembrolizumab in cervical carcinoma

Clinical trials Phase No. of Treatment PD-L1 ORR PFS OS

patients status (%) (mo) (mo)

Recurrent and/or metastatic setting

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KEYNOTE-028 Ib 24 Pembrolizumab TPS ≥ 1% 17 2 11

KEYNOTE-158 II 81 Pembrolizumab CPS ≥ 1 16 NA NA

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17 CPS < 1 0 NA NA

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KEYNOTE-826 III Recruiting Platine + - - - -

Taxane +/-
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Pembrolizumab

Locally advanced setting

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NCT02635360 II Recruiting Pembrolizumab after CRT or during CRT

NCT03144466 I Recruiting Pembrolizumab prior to RT and in combination with

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CRT
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Abbreviations: ORR, overall response rate; OS, overall survival; PFS, progression-free

survival; PD-L1, programmed death-1 ligand; TPS, tumor proportion score; CPS, combined
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positive score; CRT, chemoradiation; RT, radiotherapy; NA, not available

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Figure 1
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